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Extracellular single-unit recordings were made from medial preoptic/anterior hypothalamic (MPOAH) neurones in urethane-anaesthetized female rats, and the responses of these neurones to electrical stimulation of the ventrolateral medulla (VLM) were investigated. Of 189 neurones tested, 20% were excited and 21% were inhibited following VLM stimulation. The latency of inhibitory responses showed a normal distribution and the mean latency was 47 ms, whereas the latency of excitatory responses showed a bimodal distribution with peaks in the ranges of 0-10 ms and 40-50 ms, respectively. Excitatory responses with latencies greater than 15 ms and inhibitory responses were significantly attenuated by intravenous injections of the alpha-adrenoceptor antagonist phenoxybenzamine but not the beta-adrenoceptor antagonist propranolol. In the light of these observations and the known anatomical and electrophysiological findings, it is suggested that A1 noradrenergic and/or C1 adrenergic inputs from the VLM to MPOAH neurones are, at least in part, mediated by alpha-adrenoceptors.

Camptothecins kill mammalian cells by stabilizing topoisomerase I-DNA strand passing intermediates that are converted to lethal double strand DNA breaks in DNA replication fork collisions. Camptothecin-stabilized topoisomerase I-DNA cleavage intermediates in mammalian cells are uniquely modified by ubiquitin-family proteins. The structure, composition, and function of these ubiquitin-family modifications are poorly understood. We have used capillary liquid chromatography-nanospray tandem mass spectrometry to analyze the endogenous ubiquitin-family modifications of topoisomerase I purified from camptothecin-stabilized topoisomerase I-DNA cleavage complexes in human breast cancer cells. Peptides shared by SUMO-2 and SUMO-3 were abundant, and a peptide unique to SUMO-2 was identified. Ubiquitin was also identified in these complexes. No SUMO-1 peptide was detected in human topoisomerase I-DNA cleavage complexes. Identical experiments with purified SUMO paralogues showed that SUMO-1 was well digested by our protocol and that fragments were easily analyzed by LC-MS/MS. Spiking experiments with purified SUMO paralogues determined that we could detect as little as 0.5 SUMO-1 residue per topoisomerase I molecule. These results indicate that SUMO-1 is below this detection level and that SUMO-2 or a mixture of SUMO-2 and SUMO-3 predominates. SUMO-1 capping seems unlikely to be limiting the growth of SUMO-2/3 chains formed on camptothecin-stabilized topoisomerase I-DNA cleavage complexes.

Background: In planning surgery, a low-dose aspirin regimen for prevention of thrombotic events is often discontinued in order to avoid the risk of excessive bleeding during surgery. However, this procedure increases the risk from adverse thrombotic events. We propose a different method, which may normalize the prolonged bleeding time caused by low-dose aspirin. We verified the effectiveness of this method in healthy volunteers. Methods: Volunteers with bleeding time prolonged by taking 81 mg of aspirin a day for a period of 1 week were randomly divided into two groups. The test group of 18 volunteers received a dose of 660 mg of aspirin, while the control group of 16 received placebo. Bleeding time and maximum platelet activity were then evaluated. Results: Before 660 mg of aspirin or placebo, bleeding time was prolonged: in the aspirin group from 3.1 ± 0.7 to 6.1 ± 1.4 min (n=18), and in the placebo group from 2.9 ± 0.9 to 6.1 ± 1.5 min (n=16). This prolongation was significant in both groups at the P

Aims Gefitinib shows prominent anti-tumor activity against advanced or recurrent non-small cell lung cancer (NSCLC). However, most gefitinib-responsive patients ultimately relapse. We reviewed postoperatively recurrent NSCLC patients who received gefitinib treatment, and analyzed both the clinical features and manifestations of treatment failure in patients who initially responded to gefitinib. Methods From 2002 to 2006, gefitinib was administered to in 34 postoperative recurrent lung adenocarcinoma patients. There were 13 men and 21 women with a mean age of 65years. Twenty patients had never smoked while 14 were former smokers. Epidermal growth factor receptor (EGFR) gene mutation was measured using surgical specimens of the primary tumor. Results The study group showed 1 complete response, 16 partial responses, 7 stable diseases and 8 progressive diseases. Mutations of EGFR gene were detected in 20 of 34 patients. Only the presence of EGFR gene mutations was significantly associated with the clinical response of gefitinib in our limited study ( p =0.036). In 9 of 12 responders, gefitinib treatment failed due to the appearance of new lesions. Conclusions Gefitinib was significantly effective for patients with mutations of the EGFR gene and most responders failed due to the appearance of new lesions without progression of the pre-existent target lesions.

The two known antineoplastic quinoxaline topoisomerase II poisons, XK469 (NSC 697887) and CQS (chloroquinoxaline sulfonamide, NSC 339004), were compared for DNA cleavage site specificity, using purified human topoisomerase IIalpha and human topoisomerase IIbeta. The DNA cleavage intensity pattern for topoisomerase IIalpha poisoning by CQS closely resembled that of VM-26, despite the lack of any apparent common pharmacophore. In contrast, the topoisomerase IIalpha DNA cleavage intensity patterns of XK469 and CQS were very different from one another despite the similar overall structures of the two drugs. This suggests that the differences in DNA site specificity of topoisomerase II poisoning by XK469 and CQS may be caused by differences in their geometry, side chains, or electronic structure. The topoisomerase IIbeta-mediated DNA cleavage sites of CQS and XK469 were also very different from one another, adding further support to this idea. Earlier work has demonstrated that a number of specific topoisomerase II poisons show very similar patterns of DNA cleavage with either topoisomerase IIalpha or topoisomerase IIbeta, suggesting that the topoisomerase II isozymes play only a minor role in choices of DNA cleavage sites. However, both of the quinoxaline topoisomerase II poisons in this study showed distinctly different and unique DNA cleavage intensity patterns with each topoisomerase II isozyme. This indicates that topoisomerase II isozymes can play a major role in DNA cleavage site selection for some classes of topoisomerase II poisons.

Minimal deviation endometrioid adenocarcinoma (MDA-E) of the endometrium is a rare pathological entity, and its radiological features are rarely documented. A 73-year-old Japanese woman was referred to the authors when an endometrial biopsy revealed moderately differentiated endometrioid adenocarcinoma. Preoperative radiological examinations, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) showed no evidence of cancer nests. In the hysterectomy specimen, mildly atypical glands were scattered throughout the entire depth of the myometrium, without stromal desmoplastic reaction, and a tiny focus of typical, ruptured, endometrioid adenocarcinoma glands was found in the atrophic endometrium. MRI had not been able to identify this unusual, scattered, myometrial invasion. It should be kept in mind that in cases showing Stage IA endometrial carcinoma without endometrial thickening on MRI, this rare form of invasion may be present.

Antineoplastic bis(dioxopiperazine)s, such as meso-2,3-bis(2,6-dioxopiperazin-4-yl)butane (ICRF-193), are widely believed to be only catalytic inhibitors of topoisomerase II. However, topoisomerase inhibitors have little or no antineoplastic activity unless they are topoisomerase poisons, a special subclass of topoisomerase-targeting drugs that stabilize topoisomerase-DNA strand passing intermediates and thus cause the topoisomerase to become a cytotoxic DNA-damaging agent. Here we report that ICRF-193 is a very significant topoisomerase II poison. Detection of topoisomerase II poisoning by ICRF-193 required the use of a chaotropic protein denaturant in the topoisomerase poisoning assays. ICRF-193 caused dose-dependent cross-linking of human topoisomerase IIbeta to DNA and stimulated topoisomerase IIbeta-mediated DNA cleavage at specific sites on (32)P-end-labeled DNA. Human topoisomerase IIalpha-mediated DNA cleavage was stimulated to a lesser extent by ICRF-193. In vivo experiments with MCF-7 cells also showed the requirement of a chaotropic protein denaturant in the assays and selectivity for the beta-isozyme of human topoisomerase II. Studies with two topoisomerase IIbeta-negative cell model systems confirmed significant topoisomerase II poisoning by ICRF-193 in the wild type cells and were consistent with beta-isozyme selectivity. Common use of only the detergent, SDS, in assays may have led to failure to detect topoisomerase II poisoning by ICRF-193 in earlier studies.

The present study showed a novel finding that the development of adjuvant-induced arthritis (AA) in Lewis rats was completely prevented by incomplete Freund’s adjuvant (IFA) injected 21 or 28 days before complete Freund’s adjuvant (CFA) challenge. Hexadecane also completely prevented AA and squalane, methyl oleate and pristane moderately prevented AA, though pristane by itself induced mild arthritis in two out of five rats. Concanavalin A-stimulated lymph node cells (LNCs) isolated from AA rats were able to adoptively transfer the severe polyarthritis to all the naive recipients or even to the IFA pretreated recipients with earlier onset and more rapid progression than those of AA. The LNCs from the donors who had been pretreated with IFA and subsequently challenged with CFA could induce mild arthritis in only two out of eight naive recipients, whereas all the recipients who were challenged with CFA immediately after intravenous injection of these LNCs developed significantly less severe arthritis. However, the LNCs from IFA-pretreated donors failed to prevent AA. According to the T helper type 1 (Th1)/Th2 paradigm, it was suggested that the adjuvant-active vehicles such as IFA, hexadecane, squalane, methyl oleate and pristane, can affect and deviate the Th1/Th2 balance of immune responses in host. CFA could promote the propagation of Th2 cells rather than Th1 cells in these vehicle-pretreated rats through as yet undetermined mechanisms, eventually resulting in the prevention of AA. Finally, we discussed a regulatory role of adjuvant vehicles for induction and suppression of AA.

Episomal SV40 (SV40: simian virus 40, Polyomavirus maccacae) has been reported in SV40-transformed human fibroblast cell lines the integrated SV40 sequences of which are unlikely to give rise to episomal copies by recombinational mechanisms. The levels of episomal viral DNA in these lines are high, being easily visualized by ethidium staining of agarose gels after electrophoresis. We find that the episomal mutant gmSV40 in GM637 cells represents a persistent lytic infection that can be cured by treatment with neutralizing antibody, leaving only the chromosomally integrated viral genomes. The finding that maintenance of the gmSV40 in GM637 cells is due to persistent infection raises a note of caution for SV40-transformed lines with episomal SV40 genomes because these lines often are used in studies of DNA replication and repair. An infective center assay that does not depend on plaque formation shows that gmSV40 is a host range mutant, with poor infectivity for CV-1 monkey kidney cells and greatly increased infectivity for human cells. Passage of gmSV40 through monkey kidney cells selects for variants with greatly increased infectivity for monkey cells and, independently, for cytopathic variants that produce plaques. Thus plaque assays can give very unreliable infective center values in studies of host range mutants.

Fine analysis of DNA damage and repair at the subgenomic level has indicated a microheterogeneity of DNA repair in mammalian cells, including human. In addition to the well established Southern hybridization-based approach to investigate gene-specific DNA damage and repair, alternative methods utilizing the sensitivity of PCR have been evaluated. The latter technique has relied on decreased PCR amplification due to damage in template DNA. We have developed a novel quantitative assay combining the selective recovery of DNA damage containing genomic fragments with the PCR amplification. DNA isolated from 7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) treated human skin fibroblasts was immunoprecipitated with polyclonal antibody BP-1. Recovered target sequences were amplified by PCR using primers encompassing a 149 bp target region around codon 12 of the H-ras proto-oncogene. Quantitative DNA damage specific response was observed with nanogram amounts of genomic DNA. This approach allowed analysis of the initial DNA damage at a level less than 1 anti-BPDE adduct per 6.4 kbp ras gene fragment. Repair proficient GM637 cells exposed to 2 microM anti-BPDE showed a faster removal of the adducts from the H-ras gene segment than from the genome overall. Gene-specific repair was not apparent in GM4429 xeroderma pigmentosum (complementation group A) cells. The established technique could be extended to the quantitative measurement of the repair of diverse DNA base lesions in any genomic region of known sequence.

The microlens array has been introduced into the charge coupled device (CCD) image sensor to compensate for the low sensitivity level of the sensor. To realize a higher density image sensor, the authors have introduced additional degrees of freedom into the surface profile of the microlens. As a result, they have obtained a high-efficiency microlens which can realize a high-sensitivity level in the sensor. The new simulation program for microlens design is also described. >

Antibodies have been raised against N-cyclohexyl-N-(4-methylmorpholinium)ethy carbodiimide (CMC) modified single-stranded DNA and characterized by competitive and non-competitive immunoassays to be highly specific for CMC base adduct in homopolymers poly(dG), poly(dT) and DNA. The antibodies recognize picogram concentrations of CMC treated DNA with no cross reactivity to at least 1000-fold excess of unmodified DNA or CMC treated poly(dA). The detection limit of antibodies at 1.4 fmol CMC adduct allows quantitation at a CMC/base ratio of 4.6 · 10−7. Based upon single modified base-containing synthetic oligomers, a 7-fold binding preference is observed for CMC modified thymine than guanine bases. CMC binding to supercoiled DNA is found to depend upon reaction temperature and ionic strength. CMC-modified supercoiled SV40 and ColE1 DNA, exhibit specific antibody binding proportional to the DNA concentration and extent of CMC modification. However, antibody binding observed is independent of the conformation or strandedness of CMC-modified DNA. DNA extensively modified with CMC retains its inherent capacity to specifically and quantitatively hybridize with complementary DNA immobilized to membranes upon direct blotting or Southern transfers from gels. Hybridized CMC-DNA, through antibody binding, provides for the sensitive and non-isotopic detection of the target DNA sequences.

In planning surgery, a low-dose aspirin regimen for prevention of thrombotic events is often discontinued in order to avoid the risk of excessive bleeding during surgery. However, this procedure increases the risk from adverse thrombotic events. We propose a different method, which may normalize the prolonged bleeding time caused by low-dose aspirin. We verified the effectiveness of this method in healthy volunteers.Volunteers with bleeding time prolonged by taking 81 mg of aspirin a day for a period of 1 week were randomly divided into two groups. The test group of 18 volunteers received a dose of 660 mg of aspirin, while the control group of 16 received placebo. Bleeding time and maximum platelet activity were then evaluated.Before 660 mg of aspirin or placebo, bleeding time was prolonged: in the aspirin group from 3.1 +/- 0.7 to 6.1 +/- 1.4 min (n=18), and in the placebo group from 2.9 +/- 0.9 to 6.1 +/- 1.5 min (n=16). This prolongation was significant in both groups at the P0.01 level. In the test group, bleeding time was shortened to 4.5 +/- 1.3 min (P0.01), which is in the normal range, while it remained prolonged in the control group (6.0 +/- 1.2 min). Platelet activity, on the other hand, was suppressed in both groups.We conclude that 660 mg of aspirin effectively shortens the bleeding time prolonged by daily low-dose (81 mg) aspirin.

Background: The loss-of-resistance test is the most popular method for identifying the epidural space, but it cannot confirm epidural puncture. Therefore, we developed a new method to confirm epidural puncture by assessing indirect changes in epidural pressure using the Queckenstedt-test procedure, which increases subarachnoid pressure by compressing the internal jugular veins. Because this new method depends on the dynamics of cerebrospinal fluid, blockade of cerebrospinal fluid flow, as with severe spinal stenosis, is predicted to reduce changes in epidural pressure. Thus, in this study, we examined the effect of spinal stenosis on the Queckenstedt-test procedure. Methods: Epidural puncture using the loss-of-resistance test was utilized to insert an electrode in patients undergoing cervical spine surgery. Epidural pressure was monitored during bilateral compression of the internal jugular veins to confirm epidural puncture. The insertion of the electrode into the epidural space was confirmed by observation of muscle twitch evoked by electric stimulation. Results: In 60 patients, epidural puncture was performed with the loss-of-resistance test; a second trial was required in 13 patients. Increased epidural pressure was observed in 57/73 trials. When increased epidural pressure was observed, epidural puncture was always successful. The sensitivity and specificity of this method was 92.0% and 100%, respectively. The positive and negative predictive values were 100% and 66.7%, respectively. Conclusion: An increase in epidural pressure during bilateral compression of the internal jugular veins could offer a reliable method for confirming epidural puncture in combination with the loss-of-resistance test, even if patients have potential spinal canal narrowing.

The proposed system is conceived as a part of a project entitled: "artificial body and real body". The focus on this project is to explore this dualism and the relationship between artificiality and reality of human body in a context of musical theater. For that purpose, a performance involving an automated mechanical instruments ("RoboticMusic") and a gesture controller ("BodySuit") were developed. In particular; in this paper, the proposed system is introduced which integrates the "BodySuit" and the "RoboticMusic". Furthermore, the possible uses and applications will be also discussed. "BodySuit" refers to a gesture controller in a data-suit type, which is wearied by a performer. By using such kind of gesture controller system, performer's gestures are converted into electronic signals that are used to control the movement of each of the components of the "RobotMusic". The RobotMusic is composed by five different kinds of percussion robots (humanoid robot type or so called "bio-inspired arms"). In this paper, we will detail and discuss their technical matters.

This paper presents a framework of the energy consumption based control system for humanoid walking. Unlike the existing two approaches (One is based on precise control and powerful actuators (full control and wide applicability), and the other is passive dynamic walk (no control, therefore limited applicability)), the method aims at less energy consumption with more applicability. Knee stretching posture contributed to the former in general and a search algorithm based on the computer simulation enabled to find a feasible control to the given task.

This paper presents a method for humanoid walking acquisition with less energy consumption based on a two-stage genetic algorithm. In the first phase of genetic algorithm, in order to acquire the continuous walking motion, the fitness function consists of a walking distance (longer is better). In the second phase, the fitness function consists of a walking distance (longer) and energy consumption (less) for acquisition of highly energy-efficient walking. Further, we restrain the relationship among some joints and keep knee joint straight on supporting leg in order to ensure the less energy consumption. We apply the method to our platform PINO which has low-torque actuators owing to the servo modules. In order to realize a genetic process, we encode the scaling parameter of the joint movements and the phase difference between the joints into the computational simulation which considers the characteristics of the servo module used in our platform, PINO. The evolved results are applied to a real PINO and its smooth and stable walking with less energy consumption is verified.

We present a case of a symptomatic subependymoma (SE) in a young. The patient was a 20-year-old female who suffered from severe headache and vomiting. Precontrast CT scans revealed a large spotty-calcified isodensity mass lesion in the right anterior lateral ventricle, showing scarce contrast enhancement at the center of the mass and with marked hydrocephalus. MRI demonstrated the lesion as slightly hypo-intensity on T1-weighted image, hyper-intensity on T2-weighted image. On FLAIR imaging, the lesion indicated remarkable hyperintensity and was clearly distinguishable from surrounding brain parenchyma and the cerebrospinal fluid. After Gd-DTPA infusion central vein was revealed, but no tumor enhancement was seen. The tumor was totally extirpated through the transcortical approach. Histological diagnosis was SE, and high MIB-1 staining index (9.3%) was seen. FLAIR imaging is useful for the preoperative diagnosis and the postoperative assessment of SEs.

We present a case of cerebellar juvenile pilocytic astrocytoma(JPA) with unusual neuroimaging features. The patient was a 14-year-old male who suffered from chronic headaches for a couple of weeks. Plain craniogram showed a decalcification and bulging of the occipital bone. Computed tomography(CT) scans demonstrated low density multiple components with small calcifications in the right cerebellar hemisphere extending to the left. These calcifications were found at the margin of these multi-lobular components. Magnetic resonance imaging(MRI) revealed iso or low intensity on T1 weighted image, and slightly high intensity on T2 weighted image. The lesion indicated more heterogeneous and higher intensity than brain parenchyma on FLAIR imaging, and remarkable higher intensity than brain parenchyma with some small low intensity areas on diffusion weighted imaging. He underwent the complete resection except for the cranial tissue surrounding the pons. Histologic diagnosis was juvenile pilocytic astrocytoma, because of biphasic pattern of bipolar cells and a number of Rosenthal fibers. Generally JPA has sharp and smooth demarcated cysts with well-enhanced mural nodule. It was difficult to diagnose the presented tumor as JPA before operation, since its unusual neuroimaging resembled both dermoid and high grade gliomas.

We present a case of convexity meningioma en plaque (MEP). A 51-year-old male occasionally suffering from right parietalgia and numbness of left upper limb. An intracranial abnormal mass was pointed out incidentally by the brain check up. Computed tomographic (CT) scans demonstrated a hyperostosis and an enhanced abnormal mass at the right front-parietal region. Magnetic resonant images (MRI) revealed a carpet like tumor extended along the dura mater. Cerebral angiography disclosed feedings from parietal branches of right middle meningeal artery and superficial temporal artery. The tumor was removed subtotally with adjacent dura mater, leaving the portion of close adhesion to the brain parenchyma. Histologic diagnosis was transitional meningioma. Immunohistological stainings showed a high staining index (6.9%) of MIB-1 (Ki-69 antigen) and high expression of metalloproteinase-9 (MMP-9), especially along the dura mater. Convexity MEP is so rare that we review previous reported cases of convexity MEP, and discuss the clinicopathologic features on that.

Chloroquinoxaline sulfonamide (chlorosulfaquinoxaline, CQS, NSC 339004) is active against murine and human solid tumors. On the basis of its structural similarity to the topoisomerase IIbeta-specific drug XK469, CQS was tested and found to be both a topoisomerase-IIalpha and a topoisomerase-IIbeta poison. Topoisomerase II poisoning by CQS is essentially undetectable in assays using the common protein denaturant SDS, but easily detectable with strong chaotropic protein denaturants. The finding that detection of topoisomerase poisoning can be so dependent on the protein denaturant used in the assay has implications for drug discovery efforts and for our understanding of topoisomerase poisons.

Macroscopic total resection with removal of involved dura and bone does not always prevent the recurrence of meningioma of histologically benign subtype. Many causative factors have been investigated, although the mechanism of recurrence remains unclear. Vascular endothelial growth factor (VEGF) is a key factor in meningiomas neovascularization, and the authors investigated whether VEGF expression can predict the recurrence of histologically benign meningiomas after macroscopic total resection.Fifty-four patients with supratentorial convexity meningiomas were investigated at least 3 years after surgery or until tumor recurrence to clarify risk factors for recurrence. Patients were restricted to Simpson Grade 1 resection only, and the authors excluded multiple meningiomas, neurofibromatosis, and atypical and anaplastic meningiomas. Correlation between recurrence and the following factors were statistically analyzed: age, gender, tumor volume, tumor shape, bone change, brain edema, vascular supply, histologic subtype, MIB-1 labeling index (LI), and VEGF expression.Of the 54 patients with meningioma, 34 were positive (24: +1; 10: +2) for VEGF, and 20 were negative. Six (11.1%) meningiomas recurred during the follow-up period. Multivariate analysis revealed that high levels of expression of VEGF constituted the most useful predictor of recurrence (P = 0.005), followed by high MIB-1 LI (P = 0.039). The other factors were not significant. The tumor recurrence, when it occurred, was within the brain and not durally based.The current results suggest that high levels of VEGF expression are significantly related to the recurrence of meningioma. VEGF secretion from microscopic residue remaining after surgery may induce neovascularization, which promotes the recurrence of meningioma.

Nijmegen breakage syndrome (NBS), also known as ataxia-telangiectasia (AT) variant, is an autosomal recessive disorder characterized by microcephaly, growth retardation, severe combined immunodeficiency and a high incidence of lymphoid carcinoma, the majority of which are B-cell lymphomas. To determine whether the NBS1 gene is a tumor suppressor gene in B-cell lymphoma, we screened B-cell malignant lymphoma (ML) for any evidence of NBS1 mutation.Sequence analysis of the NBS1 gene was performed from PCR products amplified from the DNA of 12 extracranial ML or RT-PCR products amplified from cDNA of 8 primary central nervous system lymphoma.Direct sequence analysis revealed that no NBS1 mutations were present in any of these patients.The present results suggested that the contribution of NBS1 mutations to B-cell ML was minimal, despite the fact that the NBS1 gene was causative factor in these cases.

The present study showed a novel finding that the development of adjuvant-induced arthritis (AA) in Lewis rats was completely prevented by incomplete Freund’s adjuvant (IFA) injected 21 or 28 days before complete Freund’s adjuvant (CFA) challenge. Hexadecane also completely prevented AA and squalane, methyl oleate and pristane moderately prevented AA, though pristane by itself induced mild arthritis in two out of five rats. Concanavalin A-stimulated lymph node cells (LNCs) isolated from AA rats were able to adoptively transfer the severe polyarthritis to all the naive recipients or even to the IFA pretreated recipients with earlier onset and more rapid progression than those of AA. The LNCs from the donors who had been pretreated with IFA and subsequently challenged with CFA could induce mild arthritis in only two out of eight naive recipients, whereas all the recipients who were challenged with CFA immediately after intravenous injection of these LNCs developed significantly less severe arthritis. However, the LNCs from IFA-pretreated donors failed to prevent AA. According to the T helper type 1 (Th1)/Th2 paradigm, it was suggested that the adjuvant-active vehicles such as IFA, hexadecane, squalane, methyl oleate and pristane, can affect and deviate the Th1/Th2 balance of immune responses in host. CFA could promote the propagation of Th2 cells rather than Th1 cells in these vehicle-pretreated rats through as yet undetermined mechanisms, eventually resulting in the prevention of AA. Finally, we discussed a regulatory role of adjuvant vehicles for induction and suppression of AA.

Chordoid meningioma is a very rare variant, especially in adults. We report an adult case of chordoid meningioma. A 52-year-old man was admitted to our hospital due to right hemiparesis. MRI revealed a left temporal convexity mass that showed two structures; the cerebral layer was shown as an isointensity area on T1WI and T2WI, and the dural layer seemed relatively hypointense on T1WI and hyperintense on T2WI. The tumor was well enhanced with gadolinium, especially on the dural side. A left external carotid arteriogram showed tumor stains with feeding vessels from the left middle meningeal artery. The tumor was totally removed via fronto-temporal craniotomy. Histological examination of the surgical specimen revealed two different structural components, meningothelial meningioma on the cerebral side, and chordoid meningioma on the dural side, consisting of clustering spindled cells and partly vacuolated ones in the mucoid stroma. In immunohistochemical examination, tumor cells showed positive staining for vimentin and epithelial membrane antigen (EMA), and negative for cytokeratin. From the above findings, this case was diagnosed as chordoid meningioma in an adult, a very rare variant of meningioma.

Although the aVL lead in exercise electrocardiography is reported to be helpful in identifying a significant narrowing of the left anterior descending coronary artery (LAD), its role in exercise testing has not been fully evaluated. Accordingly, 821 patients who underwent both standard exercise testing and coronary angiography were evaluated. In patients with aVL lead ST elevation, the incidence of a significant narrowing of the LAD (124/165 vs 348/656; p0.001) was higher than in those without. Multiple logistic regression analysis revealed that the 2 most important variables that correlated with aVL lead ST elevation were a greater number of leads with ST depression in the inferior leads and a smaller amplitude of R wave in the aVL lead. In contrast, variables correlating with aVL lead ST depression in the majority of cases were a greater number of leads with ST depression in all leads and the presence of inferior lead ST elevation. The results of this study indicate that although aVL lead ST elevation could be a marker for LAD narrowing, more important factors such as inferior lead ST-segment depression and the R-wave amplitude of the aVL lead should be taken into consideration. In contrast, ST depression in the aVL lead mostly represents exercise-induced myocardial ischemia of greater extent and severity.

The prognostic importance of age among well-known prognostic factors such as extent of coronary artery lesions, cardiac function, and myocardial ischemia was evaluated in 147 elderly patients with coronary artery disease aged 65 years or older who underwent dipyridamole perfusion scintigraphy and coronary angiography. After excluding 32 patients who initially underwent percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG), 115 patients who were initially treated medically were analysed by the Cox model for cardiac events during a mean follow-up period of 29 +/- 22 months. Among the 114 patients who were available for follow-up, nine patients (7.9%) had cardiac events, including five cardiac deaths and four non-fatal cardiac events (requiring PTCA or CABG). When the 114 patients were divided into three age-groups; 53 patients aged 65-69 years, 42 aged 70-74 years and 19 aged 75 years or older, the incidence of cardiac death was highest in those aged 75 years or older. Univariate analysis showed that age of 70 years or older (hazards ratio 15.15, p = 0.004), scintigraphic diffuse slow washout (hazards ratio 8.77, p = 0.002), and triple-vessel or left main trunk disease (hazards ratio 6.36, p = 0.05) were important prognostic factors. Multivariate analysis showed that scintigraphic diffuse slow washout (hazards ratio 6.33, p = 0.05), and triple-vessel or left main trunk disease (hazards ratio 11.94, p = 0.05) were statistically significant as independent prognostic factors. However, when age of 70 years or older was included in the analysis, it showed higher hazards ratio (21.21, p = 0.03) than that of scintigraphic diffuse slow washout (7.36) or triple-vessel or left main trunk disease (5.30). Age of 70 years or older may be a significant prognostic factor in elderly patients with coronary artery disease which has an equivalent importance to the extent of coronary lesions.

Compression of the crus cerebri against the free edge of the tentorium contralateral to a supratentorial mass, the so-called Kernohan's notch, can be a cause of false localizing sign. Kernohan's notch has been thoroughly studied clinically and pathologically, but not radiographically. The authors describe a case of left chronic subdural hematoma, which resulted in left hemiparesis caused by Kernohan's notch. Injury to the contralateral cerebral peduncle was clearly shown by magnetic resonance imaging (MRI) performed in the postoperative period. A 43-year-old man was transferred to our hospital in deep coma with dilated pupils, unreactive to light. Computed tomography (CT) scans obtained on admission revealed a left chronic subdural hematoma and a midline shift to the right. After drainage and irrigation of the left chronic subdural hematoma through a single burr hole, his clinical condition improved gradually. But 1 month after the operation, mild left hemiparesis still persisted. MRI T2-weighted images demonstrated an abnormally increased signal area in the right cerebral peduncle. T1-weighted coronal images showed the anatomical relationship between the hypointense lesion in the right cerebral peduncle and tentorial edge. Three-dimensional-MRI (3D-MRI) clearly demonstrated the surface image of Kernohan's notch. We emphasize the utility of 3D-MRI for detecting evidence of brain stem injury, such as Kerno han's notch.

The authors report a case of so-called "infected subdural hematoma" as a complication of chronic subdural hematoma. The patient was a 55-year-old man who had sustained a small laceration of the forehead in a traffic accident on March 29, 1995. No fractures were detected on skull roentgenograms, and general and neurological examinations failed to reveal any abnormal findings. In early August 1995, the patient began to experience headaches, and on August 5 he developed a fever of 38 degrees C. On August 8 he suffered a left motor seizure and was admitted to our hospital. Laboratory studies revealed a peripheral leukocyte count of 10,800/mm3 and a C-reactive protein level of 18.1 mg/dl. Computed tomography scans showed a thick right fronto-parietal subdural low density mass and a thin left frontal subdural low density mass. An emergency operation was performed via a single right fronto-parietal burr hole. A chronic subdural hematoma containing slightly yellowish, bloody, purulent fluid was found beneath an outer membrane. The hematoma was irrigated with physiological saline containing antibiotics, and a drain was inserted into the subdural space. A subdural membrane was also present on the left but it contained no pus. Aggressive antibiotic therapy was performed, and the patient was discharged without any neurological deficit. Histologically the membrane was determined to be the outer membrane of a typical chronic subdural hematoma. Enterococcus faecalis, which has rarely been reported to cause infection of the central nervous system, was detected in a bacterial culture of the pus. Systemic investigation showed no evidence of otorhinologic or other focal infection. The above clinical findings suggested that hematogenous seeding of a chronic subdural hematoma had occurred in this patient. Subdural empyema arising from hematogenous seeding to a pre-existing subdural hematoma by an infection is very rare, but this type of complication must be kept in mind not only in the elderly, infants, and compromised hosts, but in patients without complications as well.

Platelet activation in addition to blood coagulation abnormality is regarded as a primary factor of thrombosis by atherosclerotic obstruction. Therefore, the platelet activation on atherosclerosis is considered to correlate with shear stress generated between blood cells and endothelial cells in blood flow. P-selectin on the surface of the platelet membrane is measured by flowcytometry as a marker of platelet activation. Herein, we examined the phenomena of platelet activation and adherent platelets with leukocytes (ad-P.L) on stored platelet concentration (PC) and chronic rheumatoid arthritis (RA), moreover, of the adherent platelets or polymorphonuclear cells (PMN) with endothelial cells (EC) in shear stress by using an apparatus we devised. The rate of platelet activation and ad-P.L increased in PC with storage, and the sensitivity of platelets to thrombin decreased. The rate of platelet activation and ad-P.L increased in RA in vivo. Many adherent platelets with EC were found at a low shear rate on normal EC but at a high shear rate on denatured EC without any specific adherent property. Adherent PMN with EC had several hundred times more denatured EC than normal EC and the relationship with shear rate disappeared on denatured EC. The platelet activation and relationship between platelets or leukocytes and EC as to the cause of thrombosis are important subjects for future studies.

The authors report a case of adult-onset aqueductal stenosis caused by membranous occlusion of the aqueduct. The patient was a 35-year-old man, who suffered from progressive headache. On admission, computed tomography (CT) scan showed marked dilatations of the lateral and third ventricles. Midsagittal T1-weighted magnetic resonance imaging (MRI) scan showed a membranous occlusion at the lower end of the aqueduct, with dilatation of the proximal aqueduct and elevation of the tectum. Midsagittal cine-MRI demonstrated the cerebrospinal fluid flow in the aqueduct. The patient was diagnosed as having hydrocephalus resulting from membranous stenosis of the aqueduct by MRI. A ventriculo-peritoneal shunt operation was performed and his symptoms improved markedly. The membranous occlusion of the aqueduct is a rare cause of hydrocephalus. The etiology and therapy of aqueductal stenosis are discussed.

A case of cranial hypertrophic pachymeningitis of unknown etiology in a patient with 15-year history of headaches, cranial nerve palsies, and gait disturbance is reported. A 77-year-old woman was brought to our institute in a coma. CT revealed intracerebral hemorrhage in the right temporal lobe and thickening of the falx and tentorium. Fifteen years previously the patient had undergone CT scanning because of headaches, cranial nerve palsies, and progressive gait disturbance and a thickened tentorium, mild hydrocephalus and edematous change in the right temporal lobe had been reported. Since the etiology of her symptoms was unclear at the time, she did not receive adequate treatment. Her symptoms gradually progressed thereafter, and her visual acuity and hearing deteriorated. MR imaging in 1994 showed the thickened tentorium as a hypointense area with hyperintense edges on Gd-DTPA enhanced images. Angiography revealed narrowing of posterior portion of the superior sagittal sinus. The patient's condition rapidly deteriorated due to the intracranial hypertension and she subsequently died. Autopsy revealed a thickened tentorium with xanthochromic surface. This hypertrophic change was also seen in the dura mater of the posterior and middle cranial fossa. Microscopic examination of the thickened tentorium revealed extensive fibrous tissue with a chronic inflammatory infiltrate, predominantly of lymphocytes. No specific lesions were revealed by staining with hematoxylin-eosin, PAS, Gram's or Ziehl-Neelsen stains. The patient had no inflammatory or infectious diseases of other organs, and a diagnosis of idiopathic cranial hypertrophic pachymeningitis of unknown etiology was made. Considering the above findings, the thickened tentorium depicted as a hypointense area on the T1- and T2-weighted images and the Gd-enhanced edges of the tentorium are thought to be represent fibrous tissue and inflammatory regions, respectively.

A genetic approach was undertaken to investigate the physiological roles of human metallothionein-2. A constructed expression plasmid, pEXPMTII, in which human metallothionein-IIA cDNA was inserted downstream of a tryptophan-lactose promoter, was used to transform Escherichia coli JM105 strain. Cadmium-binding metallothionein was successfully expressed in E. coli in the medium containing cadmium, while copper and zinc-metallothioneins were scarcely observed in copper- or zinc-containing medium. The amino acid composition and sequence of the biosynthesized cadmium-metallothionein were analyzed. The selectivity of metals bound to metallothionein and the stability of metal-binding forms of metallothionein in E. coli were discussed. In addition, cadmium, zinc, or copper resistance of the cells expressing metallothionein was examined. Cells transformed with the plasmid pEXPMTII and cultured in a medium containing cadmium exhibited tolerance only to cadmium. It was demonstrated that human metallothionein-2 functioned for cadmium detoxification in E. coli.

Patients with myocardial infarction (MI) and triple vessel coronary disease generally have poor prognoses. However, it is not known whether there are particular angiographic variables associated with the poor prognosis in MI patients with triple vessel disease. The angiographic variables for poor prognosis were investigated in 43 MI patients with triple vessel disease (32 men and 11 women, mean age 63 +/- 9 years) who were followed medically for a mean of 32 +/- 28 months. There were 13 cardiac deaths (30%) and 10 late-coronary artery bypass grafting (23%). Twenty patients were alive and well. The patients who died of cardiac causes had lower ejection fractions (42 +/- 18% vs 49 +/- 15%, p0.05), a higher prevalence of two vessel occlusion (77% vs 40%, p0.05), and a higher prevalence of coronary occlusion opposite the MI site (69% vs 25%, p0.01) when compared to survivors, although there were no significant differences in age, MI sites, or the prevalence of occlusion in the infarct-related artery. Multivariate analysis with the Cox proportional hazards model revealed that coronary occlusion opposite the MI site (hazards ratio 16.36) and an age ofor = 65 years (4.46) indicated a significantly high ratio. The hazard ratio of the ejection fraction and two vessel coronary occlusion were not significant. The poor prognosis of MI patients with triple vessel coronary disease may be related to impaired left ventricular function and to coronary occlusion opposite the MI site and greater age. This may have important clinical implications in the initial decision for interventional therapy.

Noninvasive evaluation of coronary artery disease is difficult in elderly patients because of their limited exercise-capacity. The diagnostic and prognostic value of dipyridamole perfusion scintigraphy was assessed in 147 patients aged 65 years and older. All patients underwent coronary angiography. Initially, 32 patients had percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG). The other 115 patients were first treated medically and followed for a mean of 29 +/- 22 months. Nine patients (7.9%) had cardiac events including cardiac death and coronary intervention (PTCA or CABG) during the follow-up. Dipyridamole perfusion scintigraphy was performed safely in all patients, whereas treadmill exercise testing could not be adequately performed in 24 patients, 18 of whom had multivessel disease. Multiple regression analysis showed that: fixed defect and reversible defect were powerful detectors of coronary lesions (p = 0.0001, p = 0.0027, respectively), all patients with fixed disease and 94% of patients with only reversible defect had significant coronary lesion; Diffuse slow washout and ST depression were statistically significant for detecting multivessel coronary lesions in patients with fixed disease (p = 0.0001, p = 0.017, respectively), the sensitivity and specificity of diffuse slow washout and/or ST depression for detecting multivessel coronary lesions ware 85% and 74%, respectively, and ST depression was statistically significant for detecting multivessel coronary lesions (p = 0.0002) in patients with only reversible defect, the sensitivity and specificity of ST depression were 88% and 64%, respectively. Cox survival analysis identified diffuse slow washout as the best predictor of future cardiac events among the scintigraphic variables.(ABSTRACT TRUNCATED AT 250 WORDS)

A 68-year-old male presented with choroid plexus carcinoma in the left lateral ventricle manifesting as dysarthria and gait disturbance. Magnetic resonance imaging showed a homogeneously enhanced mass in the trigone of the left lateral ventricle. Selective left posterior cerebral arteriography showed the tumor was fed by the left medial posterior choroidal artery. Detailed examinations found no evidence of an extraneural primary focus. He underwent partial removal of the tumor followed by local Lineac irradiation (50 Gy). After irradiation, the serum level of carcinoembryonic antigen decreased and the size of the residual tumor was reduced.

The authors report a case of dural arteriovenous malformation (dAVM) in the anterior fossa that was associated with an occlusion of the unilateral middle cerebral artery with Moyamoya phenomenon. The patient was a 79-year-old man referred to our department with an episode of consciousness disturbance and headache. Computed tomography scan showed intracerebral hematoma in the left frontal lobe, combined with left frontal subdural hematoma and subarachnoid hemorrhage. Angiography revealed dAVM in the left anterior fossa, fed by the bilateral ethmoidal and the bilateral middle meningeal arteries, and draining into the superior and inferior sinuses through the pial veins with vascular sacs. While angiography revealed an occlusion of the right middle cerebral artery (M1 portion) good collaterals via leptomeningeal anastomosis had developed. T1-weighted magnetic resonance (MR) images showed an intracerebral hematoma as a low intensity area, and flow-void areas were indicative of vascular sacs. Time-of-flight MR angiography also clearly showed dAVM in the left anterior fossa. Co-existence of an occlusion of an intracranial major artery and dAVM in this location has not been reported previously and it was speculated that this association had occurred by chance.

We investigated the effects of a novel diuretic, M17055, on blood pressure and cardiovascular hypertrophy in spontaneously hypertensive rats (SHR). M17055 was orally administered once a day for 24 consecutive days to 14-week-old male SHR. M17055 at doses of 1.25, 2.5 and 5 mg/kg/day exerted a dose-related diuretic and antihypertensive effect during the treatment. The weight of the left ventricle normalized by body weight on the following day of the last dosage was significantly (P0.01) reduced by M17055 at doses of 2.5 and 5 mg/kg/day in a dose-dependent manner. The effect of M17055 on cardiac hypertrophy was more potent (P0.01) than that of captopril, when the comparison was performed at the doses of M17055 and captopril inducing the same extent of blood-pressure decrement. Vascular hypertrophy was evaluated by the media/lumen ratio (M/L) in the thoracic aorta and the first branch of the superior mesenteric artery. In the aorta, M/L was slightly, but not significantly, decreased by M17055 at doses of 2.5 and 5 mg/kg/day, whereas it was decreased significantly (P0.01) by captopril. In the mesenteric artery, the ratio was significantly (P0.05) reduced by M17055 at a dose of 5 mg/kg/day. These results suggest that M17055 possesses beneficial properties for the clinical treatment of hypertension.

By using an in vitro microperfusion technique, we examined whether a novel loop diuretic, 7-Chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(IH)-quinolinone-4-oxime-o-sul fonic acid, potassium salt (M17055), a derivative of quinolinone oxime sulfonic acids, affects Na+ and K+ transport in the distal nephron segments, including the cortical collecting duct and connecting tubule (CNT) isolated from rabbit kidneys. M17055 added to the lumen at 1 mM caused a positive deflection of transepithelial voltage (VT) by 2.2 +/- 0.4 mV. The response was less than that evoked by 10 microM amiloride (8.9 +/- 0.1 mV). In the collecting duct cell of the cortical collecting duct from normal rabbits, M17055 depolarized the basolateral membrane by 9.2 +/- 1.3 mV, whereas amiloride hyperpolarized it by 7.6 +/- 2.4 mV. In the cortical collecting duct from deoxycorticosterone acetate-treated rabbits, despite the fact that both agents depolarized the basolateral membrane of the collecting duct cell, amiloride consistently hyperpolarized the apical membrane, whereas M17055 did not cause any significant changes in apical membrane voltage. In the presence of 2mM Ba++ in the lumen, the apical membrane voltage deflection by M17055 was abolished. In addition, the magnitude of the apical membrane voltage deflection caused by an abrupt increase in luminal K+ concentration from 5 to 50 mM was significantly reduced. In the CNT, both amiloride and M17055 caused a positive deflection of VT. However, M17055 depolarized the basolateral membrane by 6.6 +/- 1.6 mV, whereas amiloride hyperpolarized it by 4.4 +/- 1.1 mV.(ABSTRACT TRUNCATED AT 250 WORDS)

To elucidate the mechanisms of relative anticalciuric effect of a diuretic, 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone-4-oxime-o-sul fonic acid, potassium salt (M17055), having sites of action on the Henle's loop plus the distal nephron segments, we measured intracellular calcium concentration ([Ca++]i) of the rabbit connecting tubule perfused in vitro by using the microscopic fluorometry with fura 2. First, we confirmed that parathyroid hormone increases [Ca++]i by a mechanism mediated by cyclic AMP. We also confirmed that the Na+/Ca++ exchanger in the basolateral membrane is essential for the extrusion of Ca++ across this membrane. In the presence of 10 nM parathyroid hormone in the bath, the elimination of Na+ from the lumen decreased [Ca++]i, supporting the view that a decrease in Na+ supply from the apical membrane enhances the Na+/Ca++ exchanger in the basolateral membrane. Under a similar condition, the addition of 10 microM amiloride in the lumen also decreased [Ca++]i, further supporting the view that the inhibition of Na+ entry across the apical membrane causes similar effect as does Na+ elimination. Under a similar condition, the addition of 1 mM M17055 in the lumen exerted a similar effect on [Ca++]i as did amiloride. Because M17055 did not further decrease [Ca++]i when Na+ was eliminated from the lumen, the effect of M17055 is mediated by an inhibition of Na+ entry across the apical membrane. From these observations we conclude that either inhibition or diminution of Na+ entry across the apical membrane of the connecting tubule increases the Ca++ extrusion across the basolateral membrane via the Na+/Ca++ exchanger.(ABSTRACT TRUNCATED AT 250 WORDS)

7-Chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid potassium salt (M17055, CAS 114417-20-8) showed potent diuretic and saluretic effects dose-dependently, in rats (p.o.), mice (p.o.) and dogs (i.v.), at doses of 0.1-100 mg/kg, 0.3-100 mg/kg and 0.01-30 mg/kg, respectively. The efficacy of M17055 for diuresis, natriuresis and chloruresis was much higher than that of hydrochlorothiazide and almost the same as that of furosemide. These results indicate that this compound may be classified as a "high ceiling diuretic". The potencies of M17055 for natriuresis in rats (p.o.), mice (p.o.) and dogs (i.v.) calculated with ED50 values were 38, 34 and 24 times, respectively, more potent than those of furosemide. Urinary excretions of sodium, chloride and potassium increased in parallel with urinary volume with the administration of M17055 or furosemide, whereas an apparent dissociation with urinary calcium and sodium excretion was observed with M17055 alone. In rats, the increase of urinary calcium excretion with M17055 was significantly lower than that with furosemide under comparable conditions of natriuresis. Moreover, in mice, M17055 decreased urinary calcium excretion at doses with low effectiveness. In clearance studies using anesthetized dogs, M17055 suppressed negative free water clearance (CH2O) under saline loaded conditions, and it decreased positive CH2O under water diuretic conditions. These changes in the effects on CH2O induced by M17055 resemble those of loop diuretics. However, M17055 could not shift negative CH2O to positive, while furosemide was able to do so. Moreover, positive CH2O decreased to nearly zero with M17055, while urine remained dilute with furosemide even at 30 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the role of DNA alkylation damage in oncogene activation, plasmid DNA containing H- ras proto-oncogene (p220-EC) and oncogene (p220-EJ) were treated with increasing concentrations of carcinogenic methylnitrosourea (MNU) and ethylnitrosourea (ENU). The modified plasmid DNA were analyzed by transfection-transformation of the NIH/3T3-recipient cells. Treatment with varying doses of MNU (0.1–5 mM) and ENU (1–15 mM) did not result in the inactivation of the plasmid containing target genes. A transformation efficiency of greater than 40% was observed upon treatment of H- ras oncogene with the highest doses of the alkylating agents. The morphologically transformed foci obtained with alkylated p220-EC ranged from 2.8 to 0.3/μg MNU alkylated and 1.6 to 0.6/μg ENU alkylated plasmid DNA. A significant proportion of the morphological transformants exhibited growth in soft agar. The Hpa II/ Msp I restriction length polymorphism (RFLP) at codon 12 of H- ras exon-1 was detected with 4 independently isolated clones obtained from MNU-alkylated p220-EC transfections. Allele-specific in situ gel hybridization with a battery of codon 12 and codon 61 oligonucleotide probes confirmed these RFLPs to be due to sequence changes at codon 12. No clone with sequence changes in the H- ras codon 61 could be detected. The data indicate that a high degree of in vitro alkylation damage of the target gene is necessary to elicit mutational activation of H- ras in transfection-transformation assay. Low frequency notwithstanding, the data demonstrate that DNA alkylation damage at critical target sites can initiate neoplastic cellular transformation.