Additive effect of BPA and Gd-DTPA for application in accelerator-based neutron source.

Because of its fast metabolism gadolinium as a commercial drug was not considered to be suitable for neutron capture therapy. We studied additive effect of gadolinium and boron co-administration using colony forming assay. As a result, the survival of tumor cells with additional 5 ppm of Gd-DTPA decreased to 1/10 compared to the cells with boron only. Using gadolinium to increase the effect of BNCT instead of additional X-ray irradiation might be beneficial, as such combination complies with the short-time irradiation regimen at the accelerator-based neutron source.

Hyaluronic acid as a potential boron carrier for BNCT: Preliminary evaluation.

Hyaluronic acid (HA), a nonimmunogenic, biocompatible polymer found in different biological tissues, has the potential to attach to CD44 receptors on the surface of certain cancer cells, where the receptor is overexpressed compared with normal cells. Boron-hyaluronic acid (BHA) was tested for its feasibility as a potential agent for BNCT. BHA with low-viscosity 30 kDa HA could be administered by intravenous injection. The compound showed a certain degree of cytotoxicity and accumulation in C6 rat glioma cells in vitro. Instability of the chelate bonds between boron and HA and/or insufficient specificity of CD44 receptors on C6 cells to BHA could account for the insufficient in vitro accumulation. To ensure the future eligibility of BHA for BNCT experiments, using alternative tumor cell lines and chemically securing the chelate bonds or synthesizing BHA with boron covalently attached to HA might be required.

Pretreatment with buthionine sulfoximine enhanced uptake and retention of BSH in brain tumor.

To determine the influence of buthionine sulfoximine (BSO) on boron biodistribution after sulfhydryl borane (BSH) administration for boron neutron capture therapy, the effectiveness of the combination of BSO with sulfhydril- (BSH) and non-sulfhydril (B12H12 and BNH3) boron compounds, and the interval between BSO and BSH administration, the retention of boron in tissues have been evaluated using a 9L rat tumor model. Simultaneous administration of BSH and BSO showed significantly higher boron accumulation compared to that without BSO, however there was no difference in tissue boron level between B12H12 and BNH3 administration with BSO or without BSO. The longer interval (6h) between BSH and BSO administration related to the highest boron concentration in the brain and subcutaneous tumors compared to shorter intervals (0.5, 3h). Boron concentration in subcutaneous and brain tumors was maintained for 6 and 12h after the administration of BSH following BSO pretreatment.

Correlation between cardiac output and reversibility of rocuronium-induced moderate neuromuscular block with sugammadex.

BACKGROUND: The aim of this study was to evaluate the correlation between cardiac output (CO) and reversibility of rocuronium-induced moderate neuromuscular block with sugammadex in elderly patients. METHODS: Fifty elderly (≥ 65 years) patients were enrolled in this study. During 1.0-1.5% end-tidal sevoflurane and remifentanil anaesthesia, contraction of the adductor pollicis muscle in response to ulnar nerve stimulation was acceleromyographically quantified. All patients initially received 1 mg/kg rocuronium followed by 0.2 mg/kg whenever the second twitch T2 of the train-of-four (TOF) response reappeared. CO was measured throughout the study using a FloTrac™/Vigileo™ monitor. After completion of surgery and at the reappearance of T2, the time required for a bolus dose of 2 mg/kg sugammadex to facilitate recovery to a TOF ratio of 0.9 was recorded, and its correlation with CO was analysed. RESULTS: Adequate recovery of neuromuscular block was achieved after sugammadex in all patients. Mean CO at the time of reversal with sugammadex was 5.3 l/min (1.3), and recovery time to a TOF ratio of 0.9 was 173.4 s (54.8). A statistically significant inverse correlation was seen between the time to recovery to a TOF ratio of 0.9 and CO [reversal time (s) = -27.7·CO + 298.7, R(2) = 0.461, P < 0.0001]. CONCLUSIONS: The time to reach a TOF ratio of 0.9 following sugammadex is dependent on CO in elderly patients.

A clinical trial protocol for second line treatment of malignant brain tumors with BNCT at University of Tsukuba.

We have evaluated the efficacy and safety of boron neutron capture therapy (BNCT) for recurrent glioma and malignant brain tumor using a new protocol. One of the two patients enrolled in this trial is a man with recurrent glioblastoma and the other is a woman with anaplastic meningioma. Both are still alive and no severe adverse events have been observed. Our findings suggest that NCT will be safe as a palliative therapy for malignant brain tumors.

Boron neutron capture therapy combined with fractionated photon irradiation for glioblastoma: a recursive partitioning analysis of BNCT patients.

Eight patients to received Boron Neuron Capture Therapy (BNCT) were selected from 33 newly diagnosed glioblastoma patients (NCT(+) group). Serial 42 glioblastoma patients (NCT(-) group) were treated without BNCT. The median OS of the NCT(+) group and NCT (-) group were 24.4 months and 14.9 months. In the high risk patients (RPA class V), the median OS of the NCT(+) group tended to be better than that of NCT(-) group. 50% of BNCT patients were RPA class V.

The status of Tsukuba BNCT trial: BPA-based boron neutron capture therapy combined with X-ray irradiation.

The phase II trial has been prepared to assess the effectiveness of BPA (250 mg/kg)-based NCT combined with X-ray irradiation and temozolomide (75 mg/m(2)) for the treatment of newly diagnosed GBM. BPA uptake is determined by (18)F-BPA-PET and/or (11)C-MET-PET, and a tumor with the lesion to normal ratio of 2 or more is indicated for BNCT. The maximum normal brain point dose prescribed was limited to 13.0 Gy or less. Primary end point is overall survival.

Parkinsonian impairment correlates with spatially extensive subthalamic oscillatory synchronization.

The local strength of pathological synchronization in the region of the subthalamic nucleus (STN) is emerging as a possible factor in the motor impairment of Parkinson's Disease (PD). In particular, correlations have been repeatedly demonstrated between treatment-induced suppressions of local oscillatory activity in the beta frequency band and improvements in motor performance. However, a mechanistic role for beta activity is brought into question by the difficulty in showing a correlation between such activity at rest and the motor deficit in patients withdrawn from medication. Here we recorded local field potential (LFP) activity from 36 subthalamic regions in 18 patients undergoing functional neurosurgery for the treatment of PD. We recorded directly from the contacts of the deep brain stimulation (DBS) electrodes as they were introduced in successive 2 mm steps, and assessed phase coherence as a measure of spatially extended, rather than local, oscillatory synchronization. We found that phase coherence in the beta frequency band correlated with the severity of Parkinsonian bradykinesia and rigidity, both in the limbs and axial body. Such correlations were frequency and site specific in so far as they were reduced when the lowermost contact of the DBS electrode was above the dorsal STN. Correlations with limb tremor occurred at sub-beta band frequencies and were more lateralized than those between beta activity and limb bradykinesia and rigidity. Phase coherence could account for up to ∼25% of the variance in motor scores between sides and patients. These new data suggest that the strength of spatially extended oscillatory synchronization, as well as the strength of local synchronization, may be worthwhile incorporating into modelling studies designed to inform surgical targeting, post-operative stimulation parameter selection and closed-loop stimulation regimes in PD. In addition, they strengthen the link between pathological synchronization and the different motor features of Parkinsonism.

Intracellular uptake of a new boronated porphyrin EC032.

We measured the toxicity and intracellular uptake of a newly developed boronated porphyrin EC032, and verified the fluorescence-based boron concentration measuring methods. Toxicity study showed that concentration required to produce a 50% reduction in viability (IC(50)) of EC032 was more than 0.25 mM. Fluorescence study showed the intracellular uptake of EC032 increased up until 24 h after its exposure to C6, 9L, U87, and U251 cells. There was also a linear correlation between ICP-AES and fluorescence intensity as an arbitrary unit about measurement of boron concentration. Fluorescence-based boron concentration measuring methods are very simple and useful methods, especially for screening of slight test dose of porphyrin compounds.

Display of the epileptogenic zone on the frontal cortical surface using dynamic voltage topography of ictal electrocorticographic discharges.

To evaluate the usefulness of computerized brain-surface dynamic voltage topography (DVT) of ictal electrocorticographic (ECoG) discharges to localize and identify epileptogenic areas, 3 patients with intractable frontal lobe epilepsy who underwent epilepsy surgery after chronic subdural electrode recording were assessed. Cortical surfaces and subdural electrodes were photographed during initial surgery to create an electrode map that could be superimposed onto a picture of the brain surface. DVT was performed by calculating sequential amplitudes of ictal ECoG discharges, which were then superimposed onto the cortical and electrode maps. In all cases, DVT clearly identified the ictal onset zone and the early propagation area on the operative field. DVT allowed recognition of spatial relationships between the epileptogenic area and structural abnormalities, functional cortex, and cortical veins; and was useful to decide on the resection area.

Detailed images of asteroid 25143 Itokawa from Hayabusa.

Rendezvous of the Japanese spacecraft Hayabusa with the near-Earth asteroid 25143 Itokawa took place during the interval September through November 2005. The onboard camera imaged the solid surface of this tiny asteroid (535 meters by 294 meters by 209 meters) with a spatial resolution of 70 centimeters per pixel, revealing diverse surface morphologies. Unlike previously explored asteroids, the surface of Itokawa reveals both rough and smooth terrains. Craters generally show unclear morphologies. Numerous boulders on Itokawa's surface suggest a rubble-pile structure.

The change of hemodynamics and heart rate variability on bathing by the gap of water temperature.

Bathing in Japanese style may carry negative effects as water pressure on the chest and thermal stimulus on hemodynamics take place. We have explored the influence of bathing in high temperature water on the change of heart rate variability (HRV). Fourteen young healthy male adults, ageing in range from 28 to 42 years old (the average was 35.8 years old) were selected and took a hot water bath (38 and 41 degrees C) for 15 min long. Bathing in 38 degrees C water brought no significant change in heart rate (HR) and blood pressure (BP), and the HR in 41 degrees C increased in early stage. In HRV, high frequency (HF) power did not have significant change with little increase in early stages of bathing in 38 degrees C and decreased continuously in 41 degrees C. Low frequency (LF) power and very low frequency (VLF) power decreased gradually in later stages of bathing, but the degree of decrease was larger in 41 degrees C. In this study, data concerning dizziness after bathing at 41 degrees C was obtained (we named it as a "dizzy case"). HF and LF trends in this case followed the same pattern in comparison with others' average, but the decrease was larger. Additionally, there was no increase in the LF/HF at later stage of bathing. It is thought that this reflects a decreased in autonomic nerve activity. In normal subjects the VLF increased in later stages of 38 and 41 degrees C bathing, but in the dizziness-experiencing subject, the increase was very significant. It is conceivable that this reflected excessive parasympathetic reflex. Except the dizzy case HF decreased continuously in later stage of bathing in both 38 and 41 degrees C, but VLF slightly increased. Recently there was an express opinion that the VLF correlates with the prognosis; therefore the change of VLF in this study is very interesting. Based upon the results of this study we propose that the optimum period of time for bathing in water 41 degrees C in temperature is 5 min or less, and that for water 38 degrees C in temperature is 10 min or less.

Combination of boron and gadolinium compounds for neutron capture therapy. An in vitro study.

In neutron capture therapy, the therapeutic effect of the boron compound is based on alpha particles produced by the B(n, alpha) reaction while with the gadolinium compound the main radiation effect is from gamma rays derived from the Gd(n, gamma) reaction. The uptake and distribution within the tumor may be different among these compounds. Thus, the combination of the boron and gadolinium compounds may be beneficial for enhancing the radiation dose to the tumor. Chinese hamster fibroblast V79 cells were used. For the neutron targeting compounds, 10B (BSH) at 0, 5, 10, and 15 ppm, and 157Gd (Gd-BOPTA) at 0, 800, 1600, 2400, 3200, and 4800 ppm, were combined. The neutron irradiation was performed with thermal neutrons for 30 min. (neutron flux: 0.84 x 10(8) n/cm2/s in free air). The combination of the boron and gadolinium compounds showed an additive effect when the gadolinium concentration was lower than 1600 ppm. This additive effect decreased as a function of gadolinium concentration at 2400 ppm and resulted in no additive effect at more than 3200 ppm of gadolinium. In conclusion, the combination of the boron and gadolinium compounds can enhance the therapeutic effect with an optimum concentration ratio. When the gadolinium concentration is too high, it may weaken the boron neutron capture reaction due to the high cross-section of gadolinium compound against neutrons.

Spatio-temporal analysis by voltage topography of ictal electroencephalogram on MR surface anatomy scan for the localization of epileptogenic areas.

A 15-year-old girl developed intractable epilepsy following a right transcallosal resection of the intraventricular teratoma. Magnetic resonance (MR) imaging showed a T (2)-prolonged subcortical lesion in the right frontal lobe as well as a residual intraventricular tumor. The integration of the voltage topography of ictal onset activities of the scalp-recorded electroencephalogram (EEG) and a surface anatomy scan of MR images clearly revealed the epileptogenic area on the cortex above the subcortical lesion, with the propagation pattern towards the frontopolar area. Excision of the epileptogenic cortex and underlying gliosis resulted in a successful cessation of the epilepsy. This non-invasive EEG technique provided useful information that accurately localized the epileptogenic area on a large structural abnormality without invasive intracranial electrocorticographic monitoring.

Metformin ameliorates treatment of obese type 2 diabetic patients with mental retardation; its effects on eating behavior and serum leptin levels.

The metabolic effects of a biguanide, metformin, on glycemic control and eating behavior were investigated in 16 type 2 diabetic subjects with mental retardation who were habitual overeaters and had difficulty in controlling their appetites. The subjects (n = 16) received metformin (750 mg/day) for 6 months and body weight, body mass index (BMI) were measured monthly. They had repetitive metabolic and hormonal studies. Their eating behavior was analyzed by questionnaires given by their guardians before and after treatment. Metformin treatment significantly reduced their body weights (p < 0.01), body mass index (BMI) (p < 0.01), the levels of HbA1c (p < 0.001), fasting blood glucose (FBG) (p < 0.05), serum insulin (p < 0.05), C-peptide (p < 0.01), triglyceride (p < 0.01), and total cholesterol (p < 0.05). Insulin resistance index (FBG (mg/dl) x serum insulin levels ( micro U/ml) x 1/405) was significantly reduced after 1-month treatment. The serum leptin levels were significantly decreased after 4 month's treatment and thereafter (p < 0.05). Analysis of the questionnaires before and after treatment showed that the daily intake of regular and additional foods significantly decreased after treatment (p < 0.01 and p < 0.001, respectively) with improvements of eating behavior. We conclude that metformin may have beneficial effects not only to control glycemia but also to correct eating behavior in obese type 2 diabetic patients with the difficulty in controlling their appetites. The improvement was related to the reduction of insulin resistance and serum leptin levels.

Cell cycle dependence of boron uptake from two boron compounds used for clinical neutron capture therapy.

In neutron capture therapy, it is important that the boron is selectively uptaken by tumor cells. In the present study, we used flow cytometry to sort the cells in the G0/G1 phase and those in the G2/M phase, and the boron concentration in each fraction was measured with inductively coupled plasma atomic emission spectroscopy. The results revealed that sodium borocaptate and boronophenylalanine (BPA), were associated with higher rates of boron uptake in the G2/M than in the G0/G1 phase. However, the difference was more prominent in the case of BPA. The G2/M:G0/G1 ratio decreased as a function of exposure time in BPA containing culture medium, thereby indicating the cell cycle dependency of BPA uptake. Such heterogeneity of boron uptake by tumor cells should be considered for microdosimetry.

[The effects of media violence on aggression: focus on the role of anger evoked by provocation].

This study investigated the effects of anger evoked by earlier provocation on cognition, emotion, and aggressive behavior after being exposed to media violence. Sixty male undergraduates participated in the experiment. Before viewing one of three videos (either highly violent, violent with high entertainment, or nonviolent), half of the subjects were provoked by a confederate posing as another subject. Subjects' heart rates and eyeblink rates were recorded while viewing the video. After viewing the video, subjects described their thoughts that occurred while watching the video and rated their affective reactions toward the video. Finally, subjects' aggressive behavior toward the confederate was measured. Results of covariance structure analysis suggested that (a) anger evoked by provocation and high level of violence in videos additively elicited negative cognition and affect, which further facilitated aggressive behavior, and (b) high level of entertainment in videos elicited positive cognition and affect, which alleviated negative cognition and affect.

Competitive uptake of porphyrin and LDL via the LDL receptor in glioma cell lines: flow cytometric analysis.

We examined the simultaneous uptake of porphyrin and (LDL) by four established cell lines of glioma and normal fibroblasts using flow cytometry (FCM). The results indicated porphyrin and LDL showed competitive conjugation with the LDL receptor. These results support the theory of the porphyrin uptake via the LDL receptor.

Glomerulocystic kidney associated with subacute necrotizing-encephalomyelopathy.

A 22-year-old man with subacute necrotizing-encephalomyelopathy (SNE; Leigh's disease) was diagnosed as having progressive renal dysfunction. The clinical diagnosis of Leigh's disease was obtained by the typical central nervous lesions, abnormalities in other organs, and increased lactate concentrations in blood and cerebrospinal fluid. We performed an open biopsy of the right kidney. Light microscopic studies of the renal specimen showed diffuse glomerulocystic kidney (GCK) with tubulointerstitial damage. Electron microscopic examination showed marked swelling and increase in the number of mitochondria of the renal tubular epithelial cells. Therefore, it is suggested that mitochondrial disease seems to play an important role in developing GCK.