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Objectives: Limited information is currently available on the efficacy and safety of axitinib for metastatic renal cell carcinoma (mRCC) patients with renal impairment. Therefore, the present study investigated the efficacy and toxicity of axitinib in patients with chronic kidney disease., Methods: Post-hoc analyses were performed on a Japanese multicenter cohort study of 477 mRCC patients who received axitinib followed by 1 or 2 regimens of systemic antiangiogenic therapy between January 2012 and December 2016. Differences in clinical characteristics and the efficacy and safety of axitinib were assessed based on pretreatment renal function., Results: Patients were categorized into the following 5 renal function groups according to baseline renal function: estimated glomerular filtration rate (eGFR) ≥60 ml/min (n = 133), 45 ml/min ≤eGFR <60 ml/min (n = 153), 30 ml/min ≤eGFR< 45 ml/min (n = 130), eGFR <30 ml/min (n = 45), and dialysis (n = 16). Median progression-free survival (PFS) (95% confidence interval [CI]) in the 5 groups was 11 (8-16), 14 (11-19), 14 (10-19), 12 (8-24), and 6 (3-NR) months, respectively (p = 0.781). After adjustments for treatment-related confounders, the renal function group was not a significant prognostic factor for PFS. Objective response rates in the 5 groups were 22%, 23%, 23%, 18%, 20%, and 38%, respectively (p = 0.468). Regarding adverse events of all grades, hypertension (p = 0.0006) and renal and urinary disorders (p < 0.0001) were more frequently observed in the eGFR <30 ml/min group than in the other groups., Conclusions: Since renal function at the initiation of treatment with axitinib does not adversely affect the efficacy of VEGF-TKI therapy, clinicians do not need to avoid its administration to mRCC patients with impaired renal function in consideration of the risk of progression to end-stage renal disease., Competing Interests: Declaration of Competing Interest Takahiro Osawa has received honoraria from Takeda. Masatoshi Eto received honoraria for lectures from ONO, BMS, Pfizer, Novartis, MSD, and Chugai, and for research funding from ONO, Pfizer, Chugai, BMS, Eisai, Bayer, and MSD. Hiroyuki Nishiyama has received honoraria from Ono and Chugai, research funds from Ono, Takeda, and Astellas, and reports scholarship endowments from MSD, Astellas, AstraZeneca, and Chugai. Takahiro Kimura received honoraria from Astellas, AstraZeneca, Bayer, Janssen, and Sanofi. Akira Yokomizo received honoraria from Pfizer and MSD. Nobuo Shinohara has received honoraria from Bayer, Ono, and Astellas and reports institutional research funding from Ono, Takeda, Sanofi, Taiho, and Astellas. Yoichi M. Ito is a statistical advisor for Nipro Corporation and an IDMC member for clinical trials of Janssen Pharmaceutical K.K. The other authors have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To assess the ability of the "wall-carving (WC) image technique", which uses vascular images from 3-dimensional digital subtraction angiograms (3DDSAs). Also, to verify the accuracy of the resulting 3D-printed hollow models of intracranial aneurysms., Methods: The 3DDSA data from 9 aneurysms were processed to obtain volumetric models suitable for the stereolithography apparatus. The resulting models were filled with iodinated contrast media. 3D rotational angiography of the models was carried out, and the aneurysm geometry was compared with the original patient data. The accuracy of the 3D-printed hollow models' sizes and shapes was evaluated using the nonparametric Wilcoxon signed-rank test and the Dice coefficient index., Results: The aneurysm volumes ranged from 34.1 to 4609.8 mm 3 (maximum diameters 5.1-30.1 mm), and no statistically significant differences were noted between the patient data and the 3D-printed models (P = 0.4). Shape analysis of the aneurysms and related arteries indicated a high level of accuracy (Dice coefficient index value: 88.7%-97.3%; mean ± SD: 93.6% ± 2.5%). The vessel wall thickness of the 3D-printed hollow models was 0.4 mm for the parent and 0.2 mm for small branches and aneurysms, almost the same as the patient data., Conclusions: The WC technique, which involves volume rendering of 3DDSAs, can provide a detailed description of the contrast enhancement of intracranial vessels and aneurysms at arbitrary depths. These models can provide precise anatomic information and be used for simulations of endovascular treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: With the emergence of several effective combination therapies, information on their effects at the primary site will be crucial for planning future cytoreductive nephrectomy (CN). The present study focused exclusively on changes in primary tumor sizes following treatment with nivolumab plus ipilimumab and investigated the clinical factors associated with a good response in primary tumors., Methods and Materials: We retrospectively assessed 27 patients diagnosed with advanced renal cell carcinoma (RCC) who started treatment with nivolumab plus ipilimumab. Changes in tumor sizes at the primary site were described using waterfall and spider plots, respectively. We analyzed the correlation of tumor shrinkage between primary and metastatic site. The parameters analyzed between responders and non-responders according to primary tumor sizes were International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, peripheral blood markers, and CRP., Results: The median age and follow-up period were 66 years and 9.3 months, respectively. The median IMDC risk score was 3 (range: 1-6). Nineteen patients were diagnosed with clear-cell RCC (ccRCC) and 8 patients with non-ccRCC. Among ccRCC patients, 9 (47.4%) achieved a significant response with a maximum reduction of 30% or more in the size of the primary tumor from baseline within 4 months, while 3 (37.5%) out of 8 patients with non-ccRCC achieved a significant response. Shrinkage of the primary tumor correlated with the metastatic tumors in both ccRCC and non-ccRCC cases. Of note, 6 patients underwent CN and no viable tumor cells were detected in the surgical specimens of 3 patients whose primary tumors shrank by approximately 50%-60% with a reduction to 4 cm or less. Among ccRCC patients, the neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio were slightly lower in responders than in non-responders (P = 0.0944 and P = 0.0691). The platelet-to-lymphocyte ratio was significantly lower in responders than in non-responder (P = 0.0391)., Conclusions: Significant responses in primary tumors to nivolumab plus ipilimumab were observed in 50% of ccRCC patients, while responses varied among non-ccRCC patients. Inflammation markers may be predictive factors of treatment responses in primary tumors. Although further studies are needed, the present results suggest the importance of considering CN from radiological and pathological viewpoints., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Phthalates and bisphenol A (BPA) are estrogenic endocrine disruptors. Polymorphisms in the gene encoding estrogen receptor 1 (ESR1) may contribute to the ratio of the lengths of the second and fourth digits (2D:4D), which is considered an index of prenatal exposure to sex hormones. Thus, we investigated whether ESR1 polymorphisms modify the effects of prenatal exposure to phthalates and BPA on 2D:4D in a birth cohort. Maternal serum in the first trimester was used to determine prenatal exposure to these compounds. Six hundred twenty-three children (7 years of age) provided mean 2D:4D from photocopies and were genotyped for single nucleotide polymorphisms in ESR1, particularly PvuII (T > C, dbSNP: rs2234693), XbaI (A > G, dbSNP: rs9340799), and rs2077647 (A > G). The associations among compound exposure, mean 2D:4D, and ESR1 polymorphisms were assessed by multiple linear regression adjusted for potential cofounding factors. Boys with the AG/GG genotype at rs2077647 in the group exposed to high levels of mono(2-ethylhexyl) phthalate (MEHP) or Σ Di(2-ethylhexyl) phthalate (DEHP) showed feminized 2D:4D compared with boys with the AA genotype at rs2077647 who had low exposure to MEHP or ΣDEHP (MEHP: increase in mean 2D:4D of 1.51%, 95% confidence interval [CI]: 0.40-2.63; ΣDEHP: increase in mean 2D:4D of 1.37%, 95% CI: 0.25-2.49). No significant differences were found among girls. There were no associations between mean 2D:4D and metabolites other than MEHP or BPA. These data suggest that ESR1 polymorphisms modify the effects of prenatal exposure to DEHP on mean 2D:4D among boys., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Apoptosis is the prototype for a regulated form of cell death, but recent studies have revealed other types of regulated forms of cell death, including necroptosis and ferroptosis. The molecular mechanisms underlying the execution of these processes have been intensively investigated, yet the hallmarks of their morphology are not fully understood. Here, we report that electron lucent cytoplasm was a common feature of both necroptosis and ferroptosis, which was consistent with cytoplasmic vacuolization due to a defect in the cytoplasmic membrane integrity. Notably, the perinuclear space was dilated in necroptosis, but such dilation did not occur in ferroptosis. Cells undergoing ferroptosis, but not necroptosis, exhibited an electron lucent nucleus. We previously reported that one of the nuclear danger-associated molecular patterns (DAMPs), high mobility group box (HMGB)1, is rapidly released from the nucleus to the extracellular spaces of cells undergoing necroptosis through the ruptured nuclear and cytoplasmic membrane. Via time-lapse imaging of cells stably expressing HMGB1 fused to a fluorescence protein, we found that HMGB1 was also released from the nucleus to the cytosol, and then eventually released into the extracellular spaces in cells undergoing ferroptosis. Thus, nuclear membrane damage was induced prior to cytoplasmic membrane rupture in ferroptosis. Thus, dilation of the perinuclear space and an electron lucent nucleus may be the hallmarks of necroptosis and ferroptosis, respectively., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To evaluate the association between the RENAL nephrometry score (RNS) and tumor proliferative activity assessed by immunohistochemistry in patients with localized renal cell carcinoma., Methods: The current study included 145 pathological T1 (pT1) clear cell renal cell carcinomas (ccRCC). Tumor proliferative activity was assessed with the Ki67 index and microvessel density (MVD). RNS was retrospectively assessed in the present study. We divided patients into 3 groups according to RNS (RNS 4-6: low-complexity, 7-9: moderate complexity, and 10-12: high-complexity tumors) and compared the Ki67 index as well as MVD among the 3 groups. The association between the Ki67index/MVD and each component (R, E, N, A, L, h) was also evaluated., Results: There were 56 low, 84 moderate, and 5 high-complexity tumors. The median Ki67 index of all tumors was 5.34% (interquartile range: 3.28-8.57). The median Ki67 index of low, moderate, and high-complexity tumors was 3.97%, 6.39%, and 11.27%, respectively, with a significant difference among the 3 groups (Kruskal-Wallis test, P = 0.0004). On the other hand, the median MVD of low, moderate, and high-complexity tumors was 14.11%, 14.42%, and 21.22%, respectively, and there were no significant differences among the 3 groups. In terms of each RNS component, there were significant differences in the Ki67 index among the 3 groups in N (P = 0.0101) and L (P = 0.0280) components, respectively., Conclusions: The revealed association between RNS and the Ki67 index in pT1 clear cell renal cell carcinomas further supports the previous findings that the anatomy of renal cell carcinoma is associated with the malignant potential of localized clear cell renal cell carcinoma, which may provide additional information for treatment decision., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In infant poliomyelitis or poliomyelitis-like paresis, there has been no means of treating residual paralysis and the policy has been to wait until an affected infant has grown sufficiently to enable tendon transfer or arthrodesis. However, recent reports have described relatively good results for early surgical intervention in the form of nerve transfer., Methods: In a 4-year and 6-month-old child we transferred a partial ulnar nerve for elbow flexor reconstruction even 3 years and 10 months after the onset of poliomyelitis-like palsy and also transferred partial accessory and radial nerves for shoulder function restoration 6 months after the first operation., Results: Elbow flexor restored M4 on the British Medical Research Council scale. The shoulder subluxation resolved, however, the strengths of the deltoid and infraspinatus remained almost M1. At the most recent clinical examination, the patient was 18 years old and the active range of motion of patient's left elbow was 0°-125°, and those of the whole shoulder girdle were abduction 35°, flexion 60°, extension 30° and external rotation 0°., Conclusions: The outcomes we achieved may support partial nerve transfer techniques as viable treatment options for persistent long-standing motor deficits following poliomyelitis-like palsy in children. However, we recommend performing partial nerve transfer as early as possible after recovery from flaccid paralysis and also use of nerves that derive from narrow spinal cord segments. After denervation, children's neuromuscular systems seem to have the ability to regenerate after a much longer period than has generally been believed. This speculation is based on only a single case report; thus, more experience is needed before this generalization can confidently be made., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

The ratio of the lengths of the 2nd and 4th digits (2D:4D) is considered an index of prenatal exposure to androgen. Indeed, androgen receptors have been linked to digit length, but estrogen receptors are rarely investigated in this context. Thus, we investigated the association between estrogen receptor 1 (ESR1) genetic polymorphisms and 2D:4D in school-aged children. The 2D:4D ratios were determined using Vernier calipers from photocopies of palms provided by 1800 children aged 7 years who were enrolled in an ongoing prospective cohort study in Hokkaido, Japan. The children were genotyped using cord blood collected at birth for single nucleotide polymorphisms in ESR1, specifically PvuII (T > C, dbSNP: rs2234693), XbaI (A > G, dbSNP: rs9340799), and rs2077647 (A > G). The association between ESR1 polymorphisms and 2D:4D was assessed by multiple linear regression adjusted for potential cofounding factors. Boys with the GG genotype at rs9340799 had a significantly lower 2D:4D in the right hand than boys with the AA/AG genotype (-0.96% lower, 95% confidence interval: -1.68 to -0.24). However, this association was detected only in boys born to non-smoking mothers. No significant differences were found between rs9340799 polymorphisms and 2D:4D among girls. There was also no link between 2D:4D and polymorphisms at rs2234693 and rs2077647. These data suggest that rs9340799 polymorphisms in ESR1 may contribute to digit length and 2D:4D., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

We report a case of Mikulicz disease (MD), an immunoglobulin G4 (IgG4)-related disease that affects the lacrimal and salivary glands. IgG4-related disease is a relatively new clinical entity and is not commonly encountered by neurosurgeons. MD sometimes mimics intraorbital tumors such as malignant lymphoma but responds well to corticosteroid treatment. Thus it is important to recognize the clinical and radiographic features of MD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Needle electromyography provides essential information about the functional aspects of the muscle. But little attention has been given in the literature to needle electromyography examinations in carpal tunnel syndrome. We examined the relationship between preoperative needle electromyography findings and functional recovery of the abductor pollicis brevis (APB) muscle in severe carpal tunnel syndrome patients., Methods: The subjects of this study were 49 patients, 58 hands, who fit the following 5 criteria: (1) idiopathic carpal tunnel syndrome; (2) pre-op MMT grade of the APB muscle was M0 or M1; (3) APB-CMAP (compound muscle action potential) was not evoked in a median nerve conduction study; (4) needle electromyography of the APB muscle had been done; (5) underwent carpal tunnel release only. The patients were divided into two groups according to the results of pre-op needle electromyography: voluntary motor unit potential of the APB muscle was evoked [MUP(+) group]or not [MUP(-) group]. We evaluated APB muscle strength at one year after surgery, and patient satisfaction and functional evaluations (CTSI-FS) at more than one year after., Results: The APB muscle recovery rate to M3 or higher was 100% in the MUP(+) group, and 57% in the MUP(-) group. Patient satisfaction was also high and functional recovery was sufficient in the MUP(+) group. No patients requested a second opponensplasty., Conclusion: Our findings suggest that post-op restoration of thumb function relates to whether or not the MUP ofthe APB muscle is evoked. Single-stage opponensplasty may be unnecessary if the MUP of the APB muscle is; evoked. Needle electromyography is therefore useful in consideration for opponensplasty., Level of Evidence: Level Ⅲ, case-control study., (Copyright © 2017. Published by Elsevier B.V.)

Aim: To clarify prognostic factors of metatstatic urothelial carcinoma treated by systemic chemotherapy in real-world clinical practice in the Japanese population., Materials and Methods: A total of 228 patients with metastatic urothelial carcinoma undergoing systemic chemotherapy between 2000 and 2013 were included in the present multi-institutional study. The gemcitabine plus cisplatin regimen was administered as first-line chemotherapy to 131 patients, whereas methotrexate, vinblastine, doxorubicin, and cisplatin or its modified regimen was given to 71 patients. Of the 228 patients, 119 received at least 2 different regimens and 22 underwent resection of metastases (metastasectomy). Multivariate survival analysis was performed using the Cox proportional hazards model. The characteristics included were age, sex, Eastern Cooperative Oncology Group performance status (PS), primary site, pathology of primary site, hemoglobin levels, lactate dehydrogenase levels, C-reactive protein levels, corrected calcium levels, estimated glomerular filtration rate levels, history of prior chemotherapy, metastatic sites, resection of primary site, number of metastatic organs, and metastasectomy., Results: The median overall survival (OS) time was 17 months. On multivariate analysis, female sex, good Eastern Cooperative Oncology Group PS at presentation, hemoglobin level≥10g/dl, and single organ metastasis were significant independent predictors of prolonged OS. For the survival effect of metastasectomy, the median OS time of the 22 patients with metastasectomy was 53 months, which was significantly longer when compared with patients not undergoing metastasectomy (15mo). After adjustment for the 4 aforementioned prognostic factors, metastasectomy still remained significant (hazard ratio: 0.364, P = 0.0008)., Conclusions: Female sex, more favorable PS at presentation, hemoglobin level>10g/dl, and single organ metastasis were favorable prognostic factors. In addition, metastasectomy was associated with long-term disease control., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Mac-2 binding protein (M2BP) was reported to be a useful biomarker for liver fibrosis and malignant tumors. We hypothesized that expression of M2BP might also change in the process of atherosclerosis., Methods: This study included subjects who visited our hospital for a physical checkup., Results: The M2BP levels in subjects with hypertension, dyslipidemia, or abnormal glucose metabolism were higher than those in subjects without such risk factors. Moreover, the M2BP levels were associated with severity of cardiovascular risk. Subdivision of M2BP levels into quartiles revealed that M2BP was significantly associated with reactive oxygen metabolites, central systolic blood pressure, and radial augmentation index (AI). Logistic regression analysis with the endpoint of high radial AI (above mean value) showed that high radial AI was independently associated with high M2BP., Conclusions: Although the spectrum was narrow as compared to that in cases of hepatic fibrosis, serum M2BP may reflect silent atherosclerosis in apparently healthy subjects., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Xerostomia and tooth loss are major oral health problems in the elderly. The aim of this longitudinal study was to characterize the influence of xerostomia on oral health-related quality of life (OHRQoL) among elderly Japanese people., Study Design: A total of 99 community-dwelling, independently living individuals aged 60 years and older were interviewed and underwent dental examination at baseline and at a 5-year follow-up. The Oral Health Impact Profile-14 and the Xerostomia Inventory were used to assess OHRQoL and xerostomia severity, respectively., Results: Participants whose xerostomia worsened over the 5-year period had a significantly poorer follow-up OHRQoL. Linear regression models showed that tooth loss and worsening xerostomia were significant predictors of poorer follow-up OHRQoL., Conclusions: Tooth loss and worsening xerostomia result in poorer OHRQoL among older Japanese people., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Mouse oocytes acquire the ability to replicate DNA during meiotic maturation, presumably to ensure that DNA replication does not occur precociously between MI and MII and only after fertilization. Acquisition of DNA replication competence requires protein synthesis, but the identity of the proteins required for DNA replication is poorly described. In Xenopus, the only component missing for DNA replication competence is CDC6, which is synthesized from a dormant maternal mRNA recruited during oocyte maturation, and a similar situation also occurs during mouse oocyte maturation. We report that ORC6L is another component required for acquisition of DNA replication competence that is absent in mouse oocytes. The dormant maternal Orc6l mRNA is recruited during maturation via a CPE present in its 3' UTR. RNAi-mediated ablation of maternal Orc6l mRNA prevents the maturation-associated increase in ORC6L protein and inhibits DNA replication in 1-cell embryos. These results suggest that mammalian oocytes have more complex mechanisms to establish DNA replication competence when compared to their Xenopus counterparts., (Copyright 2010 Elsevier Inc. All rights reserved.)

The transcription factor p73 is a structural homologue of p53 and plays an important role in tumorigenesis, differentiation and development. However, the regulation of p73 pathway has not been wholly understood. Here we reported that YY1-silencing resulted in significant reductions in the activities of the p73 promoters and the endogenous p73 expression level, conversely, overexpression of YY1 could induce the activities of them. Furthermore, we showed that YY1 and E2F1 have synergistic effect on p73 promoter activity. The results of YY1-silencing and E2F1-silencing alone revealed that both factors are involved in the doxorubicin-induced activation of p73 promoter. Immunofluorescence staining and co-immunoprecipitation assays demonstrated that cooperation of YY1 and E2F1 is concomitant with physical interaction in nuclei. The results presented here suggested the cooperative transcriptional regulation of p73 by YY1 and E2F1, and might provide a new regulation mechanism by the YY1 network on tumorigenesis, differentiation and development.

Introduction: To measure levels of phosphatidylcholine (PtdCh) in various mouse tissues, we developed a rapid and precise method using high-performance liquid chromatography (HPLC) with electrochemical detection (ECD) and an immobilized enzyme column. To generate an example data set, the effect of methoxamine (an alpha1-adrenergic agonist) on the PtdCh levels was examined by this method in the artery and the submandibular gland of the mouse in vivo., Methods: Under our modifications of the method of Zapata et al. [J. Neurosci. 18 (1998) 3597], the mixture of lipophilic choline metabolites (PtdCh, lyso-PtdCh, and sphingomyelin) extracted by chloroform from the tissue homogenate was dried without prior separation and hydrolyzed with free choline by a 1-N perchloric acid solution containing ethylhomocholine (an internal standard for choline assay) at 90 degrees C for 1 h. Subsequently, the hydrolyzed mixture was injected directly into the HPLC system for PtdCh assay., Results: The present method permitted PtdCh assay within 5 min in one chromatographic run. Recovery of an authentic PtdCh sample was 99% (n = 10). The within-run coefficients of variation for choline derived from PtdCh in the same tissue samples were 0.6% (n = 10) and 1.3% (n = 30). Under the present method, the lowest and highest PtdCh values in tissue samples were about 2 micromol/g (eye ball) and 29 micromol/g (spinal cord), respectively. Methoxamine significantly decreased PtdCh levels and increased free choline levels in mouse artery and submandibular gland., Discussion: Under the present sample processing procedure, the choline values originating from lyso-PtdCh and sphingomyelin were much less than those originating from PtdCh hydrolysis. Thus, it was possible to inject the hydrolyzed mixture directly into the HPLC system for PtdCh assay. Since the present method provides simple, rapid, and highly reliable PtdCh determination, it is suitable for routine assay of PtdCh in a large number of samples.

Introduction: To measure the levels of phosphocholine (PCh) and glycerophosphocholine (GPCh) in the tissues and organs of mice, we developed a simple and rapid method using high-performance liquid chromatography (HPLC) with electrochemical detection (ECD) and an immobilized enzyme column., Methods: Under our modifications of the separation procedure of Klein et al. [Neurochem. Int. 2 (1993) 293], PCh and GPCh in the hydrophilic phase of the homogenate samples were selectively hydrolyzed into free choline by alkaline phosphatase and a 0.4-N perchloric acid solution, respectively, and the resulting hydrolyzed mixtures were directly injected into the HPLC system for analysis., Results: The present method permits PCh or GPCh assay within 5 min in one chromatographic run. Recoveries from tissue samples were 97% for PCh and 101% for GPCh. The percentages of the crossover reaction to the authentic PCh and GPCh were 0.4% and 3.8%, respectively. The within-run coefficients of variation for choline derived from PCh and GPCh in the tissue samples were 1.2% and 1.4%, respectively., Discussion: The method is effective and has been applied to the measurement of PCh and GPCh levels in several tissues of mice.

Hrs binding protein (Hbp) tightly associated with Hrs is thought to play a regulatory role in vesicular trafficking during endocytosis and exocytosis. In this study, we have expressed dominant-negative mutants of Hbp to evaluate their effects on the degranulation of secretory granules in RBL-2H3 mast cells. The dominant-negative mutants of Hbp significantly inhibited IgE receptor (FcepsilonRI)-triggered secretory response as tested by beta-hexosaminidase release. These results suggest that Hbp functions as a regulator in the FcepsilonRI-triggered degranulation of secretory granules in mast cells., (Copyright 2000 Academic Press.)

Cigarette smoke is a major risk factor for lung cancer and respiratory infections. This increased susceptibility may result from cigarette smoke-induced impairment of the immune system. In this study, we evaluated the effect of nicotine on the production of inflammatory mediators by activated macrophages. Pretreatment with nicotine caused a significant inhibition of LPS-induced IL-1, IL-8, and PGE2 expression at the transcriptional level in U937 cells. Nicotine inhibited the activation of a transcription factor, NF-kappaB, which in turn, binds to and mediates transcriptional activation of these genes. These inhibitory effects of nicotine may contribute to cigarette smoke-induced immunosuppression., (Copyright 1998 Academic Press.)

For the rapid assay of norepinephrine (NE) and its major metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG) in the mouse brain, we developed a simple method using isocratic HPLC with coulometric detection. This method permits NE and MHPG assay within 5 min in one chromatographic run. Within-run coefficients of variation for NE and MHPG in the working standard solution were 0.8% and 0.6% (n = 50), respectively. The detector responses were linear from 0.025 to 100 pmol for NE and from 0.05 to 100 pmol for MHPG in the working standard solution. Using this method, the NE and MHPG concentrations were measured in discrete brain areas of the mouse prior treatment with or without alpha-methyl-p-tyrosine or N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4).

To clarify the pharmacological properties of ceruletide (CER) and cholecystokinin-octapeptide (CCK-8) with respect to vertical (VLA) and horizontal (HLA) locomotor activities of mice, effects of pretreatment with CER (0.5, 5, and 50 micrograms/kg, IP) and CCK-8 (5, 50, and 500 micrograms/kg, IP) on apomorphine (0.1 mg/kg, SC)- and clonidine (0.1 mg/kg, SC)-induced hypo-VLA and -HLA and on apomorphine (1 mg/kg, SC)-induced hyper-VLA and -HLA were examined. CER and CCK-8 had a dose-dependent inhibitory effect on VLA and HLA in intact mice. Pretreatment with CER had a biphasic effect (increase and decrease) on apomorphine- and clonidine-induced hypo-VLA, as well as an effect on apomorphine-induced hypo-HLA, a decreased effect on clonidine-induced hypo-HLA, and a decreased effect on apomorphine-induced hyper-VLA and -HLA. On the other hand, pretreatment with CCK-8 had no effect on apomorphine- and clonidine-induced hypo-VLA and -HLA and a decreased effect on apomorphine-induced hyper-HLA but not on hyper-VLA. These results suggest that for apomorphine- and clonidine-induced locomotion in mice CER has pharmacological properties different from those of CCK-8.

Mice were housed in a cage containing a T maze. A watering place was located at the entrance of the maze. The right and left arms of the maze each had two exits, one of which led to the home cage where food was placed, while the other led to the watering place via a bypass. The exit leading to the home cage in either the right or left arm was alternately closed every 90 min. One-way swinging doors were inserted at the entrance to each arm and between each bypass and the watering place. The mice were given a cholinergic neurotoxin--ethylcholine mustard aziridinium ion (AF64A)--(8 nmol) or saline as a control into the left ventricle 2 weeks before they were housed in the apparatus. Those mice housed in this apparatus mastered the alternation task at a 5-sec delay on day 3 in the sham group and on day 4 in the AF64A group. When a longer delay (5-90 sec) was introduced for the mice that mastered the alternation task at 5-sec delay, the AF64A group made significantly more errors than did the sham group at 60- and 90-sec delays. These results show that the apparatus is useful in estimating working memory in mice with little effort.

For simultaneous assay of the three monoamine neurotransmitters, norepinephrine, dopamine, and serotonin, and four respective metabolites in brain tissue, a rapid and simple method using high-performance liquid chromatography with coulometric detection is described. Because the present method permits the determination of these target substrates within 10 min or less in one chromatographic run, 150 samples can be analyzed using an autosampler and an integrator in a 24-h period. Within-run coefficients of variation for the target substrates in the standard solution and the whole brain sample were less than 3% and 2% (n = 40), respectively. The quantitative detection limits were 0.01-0.1 pmol. The present procedure was applied to measure the target substrates in several discrete brain areas in mice.

Mice were housed in a cage with a maze. A water tap was placed at the entrance of the maze. The exit of the maze connected with another cage (home cage). Food was placed in the home cage. Three different multiple mazes (types 1-3) were placed. 1) Mice were housed for 10 h a day in the apparatus and then removed to a normal cage for fasting. One trial per day was carried out after fasting for 13 h. In each trial, a mouse was put at the entrance of the maze and then the number of errors and the time till it reached the home cage was counted. Mice reached a learning criterion at Trial 2. 2) Administering scopolamine (0.125-0.5 mg/kg) 30 min before Trial four disturbed the maze work dose dependently in a type 3 maze, the most complex maze among the three, but did not in type 1 and 2 mazes. 3) Administering scopolamine (0.25-1.0 mg/kg) 30 min before Trial 11 to the mouse of the type 3 maze did not disturb the maze work. These results show that a mouse housed in a cage with a maze learns the maze without explicit training and scopolamine can differentially effect performance based upon the degree of training.

The arsenic trioxide (AsT) content, and monoamine levels in the cerebral cortex, hippocampus, hypothalamus and corpus striatum were determined in mice administered AsT (3 and 10 mg/kg) for 14 days. The vertical and horizontal motor activity was also examined. The AsT content in discrete brain areas differed but was clearly dose-dependent. Metabolites of norepinephrine and dopamine increased in the cerebral cortex, hippocampus and hypothalamus and decreased in the corpus striatum in AsT-treated mice. Metabolites of 5-hydroxytryptamine increased in all the discrete brain areas. The vertical and horizontal motor activity was increased by AsT at 3 mg/kg and decreased by AsT at 10 mg/kg. These results show that AsT modifies CNS metabolism and function at low doses. AsT penetrates the blood-brain barrier to cause these effects.

The effects of 24-hr fasting on the vertical (VMA) and horizontal (HMA) locomotor activities, on cage climbing activity and on brain monoamine-related substances, were examined using male ddY mice. Both the VMA and HMA increased with fasting, but not the cage climbing activity. Methamphetamine (2 mg/kg, SC) increased the VMA and HMA in both the feeding and fasting mice, whereas with apomorphine (0.1 mg/kg, SC) both decreased. Furthermore, pretreatment with haloperidol (0.025 mg/kg, SC) showed no influence on the methamphetamine-induced VMA increase in both the feeding and fasting mice. However, pretreatment with haloperidol inhibited the methamphetamine-induced HMA increase in both the feeding and fasting mice and showed a higher level of HMA in fasting mice than in feeding mice. When measuring brain monoamine-related substances, the DA, NE, 5-HT, and 5-HIAA levels in the corpus striatum increased, whereas the 3-MT levels decreased. The monoamine levels in the nucleus accumbens of fasting mice were the same as those in feeding mice, except for a decrease of the 3-MT level. These results suggest that the locomotor activity in fasting mice may be increased by a change in the sensitivity of dopaminergic neurons in the corpus striatum.

The influence of repeated administration of a low dose of apomorphine on presynaptic dopamine (DA) receptors was examined. (1) Male ddY mice were given a low dose of apomorphine (0.2 mg/kg) for 7 days. Following 2 drug-free days they were given apomorphine (0.2 mg/kg, IP), after which cage climbing behavior and the level of 3-methoxytyramine (3MT) in striatum was measured. Mice became tolerant to apomorphine's activity-depressing effect and 3MT-decreasing effect. (2) Mice were given haloperidol (1 mg/kg) for 7 days. Then after 2 drug-free days they were given 0.2 or 1.0 mg/kg of apomorphine, after which cage climbing behavior was measured. One mg/kg of apomorphine significantly increased cage climbing behavior, indicating that supersensitivity of postsynaptic DA receptors was induced by haloperidol, but the activity-depressing effect of 0.2 mg/kg of apomorphine was not modified. The results suggest that subsensitivity of presynaptic DA receptors participates in the tolerance to the activity-depressing effect of a low dose of apomorphine.

The effects of methamphetamine and morphine on the vertical (VMA) and the horizontal motor activities (HMA) in male ddY mice (six weeks of age) was investigated between 9:00 and 13:00, using an apparatus which can differentiate spontaneous motor activity into VMA and HMA, measuring their activities simultaneously. VMA and HMA were evaluated by counting the number of times that an infrared ray was blocked by the mouse in the activity cage. Nine infrared photo-couplers were used to measure the VMA and one to measure the HMA. All measurements were taken at 10 min intervals during the 180 min period after subcutaneous injection of methamphetamine (0.1, 1 and 10 mg/kg) or morphine (2, 10 and 50 mg/kg). A small dose of methamphetamine (0.1 mg/kg) did not exert influence on the counts of the VMA and the HMA, whereas a large dose enhanced both activities, especially at 10 mg/kg, where each activity showed qualitatively different biphasic patterns. On the other hand, three doses of morphine significantly inhibited the VMA for 20 min after administration, while morphine at 2 mg/kg depressed the HMA for 10 min after administration and at 10 mg/kg or more markedly enhanced it during the 180 min observation period. These results show that different doses of methamphetamine and morphine exert different effects on the VMA and the HMA in mice.

The vapour of the ligand was used as carrier-gas additive in the gas chromatography of metal chelates. The effect of trifluoro-acetylacetone on non-symmetrical peaks was examined for Be(TFA)(2), Al(TPA)(3) Cr(TFA)(3), Pe(TFA)(3), U(TFA)(4) and Th(TFA)(4). All the chromatograms appeared quite normally especially those of Th(TFA)(4); Fe(TFA)(3) and Th(TFA)(4) were improved markedly by using the carrier gas containing ligand vapour.