Search for the Lepton Flavor Violating Decays B

We present a search for the lepton flavor violating decays B^{+}→K^{+}τ^{±}ℓ^{∓}, with ℓ=(e,µ), using the full data sample of 772×10^{6} BB[over ¯] pairs recorded by the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. We use events in which one B meson is fully reconstructed in a hadronic decay mode. We find no evidence for B^{±}→K^{±}τℓ decays and set upper limits on their branching fractions at the 90% confidence level in the (1-3)×10^{-5} range. The obtained limits are the world's best results.

Longitudinal changes in 18 F-THK5351 positron emission tomography in corticobasal syndrome.

BACKGROUND AND PURPOSE: Corticobasal syndrome (CBS) is pathologically characterized by tau deposits in neuronal and glial cells and by reactive astrogliosis. In several neurodegenerative disorders, 18 F-THK5351 has been observed to bind to reactive astrocytes expressing monoamine oxidase B. In this study, the aim was to investigate the progression of disease-related pathology in the brains of patients with CBS using positron emission tomography with 18 F-THK5351. METHODS: Baseline and 1-year follow-up imaging were acquired using magnetic resonance imaging and positron emission tomography with 18 F-THK5351 in 10 subjects: five patients with CBS and five age-matched normal controls (NCs). RESULTS: The 1-year follow-up scan images revealed that 18 F-THK5351 retention had significantly increased in the superior parietal gyrus of the patients with CBS compared with the NCs. The median increases in 18 F-THK5351 accumulation in the patients with CBS were 6.53% in the superior parietal gyrus, 4.34% in the precentral gyrus and 4.33% in the postcentral gyrus. In contrast, there was no significant increase in the regional 18 F-THK5351 retention in the NCs. CONCLUSIONS: Longitudinal increases in 18 F-THK5351 binding can be detected over a short interval in the cortical sites of patients with CBS. A monoamine oxidase B binding radiotracer could be useful in monitoring the progression of astrogliosis in CBS.

Performance evaluation of the small-animal PET scanner ClairvivoPET using NEMA NU 4-2008 Standards.

The aim of this study was to evaluate the performance of ClairvivoPET using NEMA NU4 standards. The ClairvivoPET incorporates a LYSO dual depth-of-interaction detector system with 151 mm axial field of view (FOV). Spatial resolution, sensitivity, counting rate capabilities, and image quality were evaluated using NEMA NU4-2008 standards. Normal mouse imaging was also performed for 10 min after intravenous injection of (18)F(-)-NaF. Data were compared with 19 other preclinical PET scanners. Spatial resolution measured using full width at half maximum on FBP-ramp reconstructed images was 2.16 mm at radial offset 5 mm of the axial centre FOV. The maximum absolute sensitivity for a point source at the FOV centre was 8.72%. Peak noise equivalent counting rate (NECR) was 415 kcps at 14.6 MBq ml(-1). The uniformity with the image-quality phantom was 4.62%. Spillover ratios in the images of air and water filled chambers were 0.19 and 0.06, respectively. Our results were comparable with the 19 other preclinical PET scanners based on NEMA NU4 standards, with excellent sensitivity because of the large FOV. The ClairvivoPET with iterative reconstruction algorithm also provided sufficient visualization of the mouse spine. The high sensitivity and resolution of the ClairvivoPET scanner provided high quality images for preclinical studies.

Coexistence of insulin-derived amyloidosis and an overlying acanthosis nigricans-like lesion at the site of insulin injection.

A 59-year-old patient with diabetes mellitus had been treated with human recombinant insulin for 4 years. He developed a solid mass on his left abdomen at the insulin injection site, which had an overlying pigmented verrucous plaque and keratinized papules, similar to acanthosis nigricans (AN). On histological examination, the mass was found to contain a deposit of amyloid in the dermis, with hyperkeratosis, papillomatosis and acanthosis in the epidermis. Using immunohistochemistry, the amyloid deposits were found to be positive for insulin. A few cases of localized insulin-derived amyloid deposits at injection sites have been reported previously, but none had significant epidermal changes. The coexistence of dermal insulin-derived amyloidosis and an overlying AN-like change, as found in our patient, has not been reported previously, to our knowledge. The presence of a tumour-like lesion at the injection site should be carefully examined, as injection of insulin into amyloid deposits can result in insulin resistance.

Application of positron emission tomography in physical medicine.

Positron emission tomography (PET) is widely used in the fields of clinical and basic medicine. The PET device utilizes coincidence logic to detect annihilation photons emitted from positrons and estimates physiological functions of human organs in vivo. Radiopharmaceutical 18F- fluorodeoxyglucose (FDG), an analogue of glucose, is trapped metabolically in cells after being administered into the body, and can be substantially used for evaluating physiological and biochemical functions in vivo. Here, we attempted to describe the basics of PET as well as to apply the technique together with 18F-FDG as a tracer for evaluating organ glucose metabolism induced by exercise. Three-dimensional (3D) FDG-PET was applied to normal volunteers who performed exercise to evaluate whole-body glucose metabolism. Regions of interest analysis were drawn on visually defined regions (i.e., lower limbs, thigh, liver, intestine, brain, heart, etc.) to determine radioactivity distribution. FDG-PET clearly showed the recruitment of energy resources from abdominal organs to lower limb skeletal muscles to balance energy expenditures. The results suggested that 3D FDG-PET can be applied as an imaging tool to physical medicine.

Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.

In the previous paper, we described a series of 2-phenylethenesulfonamide derivatives, a novel class of ET(A)-selective endothelin (ET) receptor antagonists, including the 2-methoxyethoxy derivative 2a and the 2-fluoroethoxy derivative (2b). In this paper, we wish to report further details of structure-activity relationships (SARs) of the two regions of the molecule in compound 2b, which were the alkoxy region at the 6-position of the core pyrimidine ring and the 2-phenylethenesulfonamide region. In these modifications, replacement of the 2-fluoroethoxy group with a methoxy group (6e) and replacement of the 2-phenylethenesulfonamide group with a 2-(pyridin-3-yl)ethenesulfonamide group (6l) or 2-phenylethanesulfonamide group (6q) were well tolerated both in the ET(A) binding affinity and ET(A) selectivity. Among them, compound 6e showed further improvement in oral activity compared to 2b. After oral administration, compound 6e inhibited the big ET-1 induced pressor response in conscious rats at 0.3mg /kg with a duration of >6.5h. Compound 6e also exhibited a potent antagonistic activity in the pithed rats.

Electrodermal and cardiovascular manifestations of emotions in children.

The purpose of this paper is to analyze the current state of developmental researches in the area of psychophysiology of emotions in preschool and elementary school children. Electrodermal and cardiovascular activity measures are considered as the sources of indices of the autonomic nervous system activation during emotion-eliciting stimulation in children. We discuss the question of sensitivity of phasic and tonic autonomic measures for the identification of occurrence of emotion, mapping it along with valence and arousal dimensions in affective space, and to further differentiate emotions by their physiological manifestations. Considered are the conceptual and methodological issues related to psychophysiological measurements and developmental factors affecting the emotional reactivity in children. Special attention is devoted to the developmental aspects of psychophysiological studies on emotion such as the maturation of organs, integration of the autonomic and central nervous systems, age and gender-related changes in autonomic reactivity, and development of inhibitory control. Summarized are main findings relevant to psychophysiology of emotions in preschool and early school-age children and suggested are most perspective directions of their integration in the framework of modern theories of emotion.

Ethenesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.

In the present article we wish to report the discovery of a novel class of ET(A)-selective endothelin (ET) receptor antagonists through the modification of the ET(A)/ET(B) non-selective antagonist, Ro47-0203 (Bosentan, 1). Replacement of the benzenesulfonamide group of 1 with a 2-phenylethenesulfonamide group gave compound 5a and resulted in improvement in ET(A)-selectivity. Optimization of the alkoxy side chain attached to the core pyrimidine ring yielded the 2-fluoroethoxy derivative (5n) with further improvement of ET(A)-selectivity. [IC50=2.1 nM for ET(A) receptor, ET(B)/ET(A) ratio=1200]. After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR2 value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.

Evaluation of resting brain conditions measured by two different methods (i.v. and oral administration) with 18F-FDG-PET.

Our aim was to evaluate regional differences between brain activity in two resting control conditions measured by 3D PET after administration of FDG through either the intravenous (i.v.) or the oral route. Ten healthy male volunteers engaged in the study as the i.v. group (mean age, 26 +/- 9.3 years, +/- S.D.) who received FDG intravenously and another 10 volunteers as the oral group (mean age, 27.9 +/- 11.3 years, +/- S.D.) who received FDG per os. A set of 3D-PET scans (emission and transmission scans) were performed in both groups. To explore possible functional differences between the brains of the two groups, the SPM-96 software was used for statistical analysis. The results revealed that glucose metabolism was significantly higher in the superior frontal gyrus, superior parietal lobule, lingual gyrus and left cerebellar hemisphere in the i.v. group than in the oral group. Metabolically active areas were found in the superior, middle and inferior temporal gyrus, parahippocampal gyrus, amygdaloid nucleus, pons and cerebellum in the oral group when compared with the i.v. group. These differences were presumably induced by differences between FDG kinetics and/or time-weighted behavioral effects in the two studies. This study suggests the need for extreme caution when selecting a pooled control population for designated activation studies.

Synthesis and structure-activity relationships in a series of ethenesulfonamide derivatives, a novel class of endothelin receptor antagonists.

In the previous paper, we described a series of the 2-arylethenesulfonamide derivatives, a novel class of ETA-selective endothelin (ET) receptor antagonists, including the compounds 1a, b. Compound 1a showed excellent oral antagonistic activities and pharmacokinetic profiles, and the monopotassium salt of 1 (YM-598 monopotassium) is in clinical trials. In this paper, we wish to report the investigation of the further details of structure-activity relationships (SARs) of the 2-phenylethenesulfonamide region in 1a. It was found that methyl substitutions at the 2-, 4- and 6-positions of the phenyl group in 1a led to the discovery of the ET(A)/ET(B) mixed antagonist (6s) with an IC50 of 2.2 nM for the ET(A) receptor. We also found that introduction of an ethyl group to the 1-position of the ethenyl group in 1a gave the ET(A) selective antagonist (6u) with an oral endothelin antagonistic activity in rats.

A case for multisite studies in critical care.

Studies in critical care settings are essential to improve critical care practice. Critical care research conducted at a single site may be limited with respect to sample size leading to large type II error, diminished statistical power, decreased generalizability, and inconclusive results. Multiple-site studies are more likely to change nursing practice in critical care. They allow for larger sample size, broader sampling, faster accrual rates, and meaningful subgroup analyses. Successful multisite research requires more thorough planning, and deliberate steps are required to ensure its feasibility and acceptability. Multisite research protocols can be challenging regarding communication, reliability, and data integrity. However, defining and addressing these challenges and selecting subjects and settings appropriately can lead to results that are more generalizable and relevant to practice.

[Investigation of the resolution and count recovery coefficients of a whole-body PET scanner (Shimadzu SET-2400W) in 2D and 3D mode image].

UNLABELLED: We measured the resolution and count recovery coefficients (RC) of the SET-2400W whole-body PET scanner (Shimadzu Co., Japan) in the 2D and 3D clinical modes. METHOD: The 3D images were reconstructed by using the full 3D image reconstruction method (3-D reprojection algorithm: 3DRP) and the Fourier rebinning method (FORE). The 2D images were reconstructed with conventional filtered back-projection method (FBP). The measurements of resolution and recovery coefficient were according to JRIA (Japan Radioisotope Association) protocols. RESULTS: The transaxial resolutions of all methods were better than 7 mm FWHM at a radius of 10 cm with 1.25 cm-1 cutoff frequency. The average slice width of 2D FBP, 3DRP and FORE are 5.8 mm, 8.0 mm and 6.8 mm respectively at the center of transaxial field of view. The RC values were measured in a range from 10 mm to 27 mm at 6 cm from the center with the cylindrical and spherical hot area phantoms. In all methods, RC values at 27 mm diameter were nearly 1.0 in both type of hot area. RC values at 10 mm diameter in 2D FBP, 3DRP and FORE of cylindrical hot area were 0.69, 0.72, 0.73 and those of spherical hot area were 0.52, 0.51, 0.53 respectively. CONCLUSION: At the SET-2400W, resolution and recovery coefficient of 3D mode image under the clinical mode showed the value which did not differ from the 2D mode image.

Predominant contribution of the G protein-mediated mechanism to NaF-induced vascular contractions in diabetic rats: association with an increased level of G(qalpha) expression.

The purpose of this study was to determine the mechanism responsible for alterations in NaF-induced contractions of blood vessels from streptozotocin-induced diabetic rats. In the presence of AlCl(3), NaF (>/=7.5 mM) produced significantly greater contractions in diabetic aorta and mesenteric artery compared with age-matched controls. Pretreatment with 1 microM nifedipine eliminated the enhanced contractile responses of diabetic vessels to NaF, resulting in no difference in the magnitude of NaF-induced contractions between control and diabetic vessels. In the presence of 100 microM deferoxamine, an Al(3+) chelator, NaF-induced contractions of diabetic vessels were markedly attenuated, whereas only the responses to lower concentrations of NaF were reduced in control vessels. No significant difference was found in the peak amplitude of transient contractions induced by 10 microM cyclopiazonic acid between control and diabetic vessels. The addition of 10 microM okadaic acid produced attenuated contractions in diabetic vessels. These findings indicate no involvement of the inhibitory effects of NaF on endoplasmic reticular Ca(2+)-pump ATPase and protein phosphatases in the genesis of the enhanced responsiveness of diabetic vessels to NaF. Western blot analysis showed a 2.5-fold increase in the expression of G(qalpha) in diabetic aortic membranes. In contrast, the G(ialpha) level was modestly decreased and the G(salpha) and G(betagamma) levels were unchanged in diabetes. The present results suggest that enhanced vascular contractions to NaF in diabetes is attributed predominantly to a G protein-mediated Ca(2+) channel activation that results from markedly increased G(qalpha) expression in vascular tissues under this pathological state.

Differential gene transcriptional regulation of Gi isoforms and Gs protein expression in diabetic rat hearts.

Many cardiac diseases can be associated with alterations in the function and quantity of G proteins. We examined the gene expressions and protein levels of Gi-1alpha, Gi-2alpha, Gi-3alpha and G(s alpha) in ventricular myocardial preparations from rats 4-6 weeks after induction of diabetes with streptozotocin in comparison with those from age-matched control rats. Diabetic rat myocardium exhibited reductions in the protein levels of Gi-2alpha and Gi-3alpha by 22+/-2% and 57+/-2%, respectively. In diabetes, 22% and 53% reductions in myocardial mRNA levels of Gi-2alpha and Gi-3alpha were observed. Although a faint protein signal of Gi-1alpha was detectable, no apparent expression of mRNA for Gi-1alpha was found in either control or diabetic myocardium. The reduced protein and mRNA levels of Gi-2alpha and Gi-3alpha were prevented by insulin therapy. No change was found in the protein and mRNA levels of G(s alpha) in diabetic myocardium. In conclusion, diabetes leads to a differential regulation of protein expressions of G(i alpha) isoforms and G(s alpha) in ventricular myocardium. The reduced expression of Gi-2alpha and Gi-3alpha proteins can be explained, at least in part, by the decreases in the transcriptional levels.

Easy detection of tumor in oncologic whole-body PET by projection reconstruction images with maximum intensity projection algorithm.

Whole-body PET scanning for an oncology study produces a large number of transaxial images by data acquisition over multiple bed positions. The sagittal and coronal reformatted images are often used for better understanding of radioisotope distribution. We reduced the number of PET images by calculating projection images and evaluated the merit of additional data processing for the visualization and detection of tumors. After reconstructing whole-body 18F-FDG PET images (6-8 bed positions) of eight cancer patients, antero-posterior and lateral projection images were calculated by the maximum intensity projection (MIP) algorithm, the standard deviation projection (SD) algorithm and the summed voxel projection (SUM) algorithm. The projection images were compared with 2D whole-body images for visualizing foci. The focal uptakes of various positions in original whole-body PET data (294-392 transaxial images) were visualized on only two MIP reformatted images when superimposition of hot spots did not occur. Even if one hot spot was superimposed over the other hot spot, we could recognize the existence of at least one focus and determine the true positions of the hot spots from corresponding transaxial images. The SD image was found inferior for showing a contrast of small foci to the corresponding MIP images in the neck, mediastinum and abdomen. The SUM image failed to visualize many metastatic lesions. MIP is a promising technique for the easy preliminary assessment of tumor distribution in oncologic whole-body PET study.

18F-FDG PET imaging of muscle activity in runners.

UNLABELLED: PET with three-dimensional data acquisition using 18F-fluorodeoxyglucose (FDG) was applied to evaluate skeletal muscle activity in runners. METHODS: Seven healthy adult male volunteers were studied. They ran for a total of 35 min, 15 min before and 20 min after intravenous injection of FDG. Another 7 adult male control subjects were also examined at rest. Images obtained through a set of whole-body PET scans were analyzed. Regions of interest (ROIs) were manually drawn on images of muscles of both thighs, legs and feet, and the standardized uptake ratio (SUR) and total radioactivity distribution (TRD) for each region were calculated. RESULTS: The work load was below the anaerobic threshold. SUR of foot, leg and thigh were low at rest but during running increased 5.19, 4.30 and 1.74 times, respectively. The SUR of posterior-to- anterior compartment of the leg was 1.1+/-0.1 at rest and 1.6+/-0.5 (P < 0.01) during running. The laterality index of both SUR and TRD changed significantly only in the foot of the dominant side during running. TRD of the leg, less than half that of the thigh at rest, became equivalent to that of the thigh during running. TRD of the foot did not change significantly. CONCLUSION: Sole muscles showed highest metabolic activation per unit volume during running, which was higher in the dominant side. Comparison of whole muscle activity during running indicated the highest metabolic activation was in the posterior compartment of the leg, whereas thigh muscles showed relatively little changes during running. Our data indicate that whole-body FDG PET, especially three-dimensional data acquisition, is a useful tool for the investigation of muscular activity during exercise.

Development of a new method for simultaneously evaluating mucociliary clearance and pulmonary epithelial permeability in rabbit experiments by means of 18FDG, three-dimensional positron emission tomography and rectilinear scan.

We tried to simultaneously obtain the elimination constant of mucociliary clearance and the pulmonary epithelial permeability constant after inhalation of 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) solution by carrying out whole lung positron emission tomography and a rectilinear scan in rabbit experiments. The elimination constant of pulmonary epithelial permeability was obtained from the decrease in the amount of the radioactivity with time in the region of interest (ROI) confined to the lungs, trachea and tracheal cannula in the rectilinear scan. The total elimination constant of the radioactivity in the lungs was obtained from the ROI confined to the lungs in the tomography. The mucociliary clearance rate constant in the lungs was then obtained after subtracting the elimination constant of the pulmonary epithelial permeability from the total elimination constant of the 18FDG in the lungs. The mucociliary clearance constant in the trachea was calculated from the residual radioactivity in the trachea and the mucociliary clearance constant in the lungs. The mean pulmonary epithelial permeability constant was 0.0020% min(-1) obtained from the rectilinear scan. The mean mucociliary clearance constants of the lungs and the trachea were 0.0006 and 0.025% min(-1), respectively. These results indicated that the pulmonary epithelial permeability and mucociliary clearance could be evaluated simultaneously with 18FDG by using three-dimensional positron emission tomography and a rectilinear scan.

Novel 5-hydroxytryptamine 4 (5-HT4) receptor agonists. Synthesis and gastroprokinetic activity of 4-amino-N-[2-(1-aminocycloalkan-1-yl)ethyl]-5-chloro-2-methoxybenzamide s.

A novel series of 4-amino-N-[2-(1-aminocycloalkan-1-yl)ethyl]-5-chloro-2-methoxyb enzamides. derivatives (1), which had amines conformationally restricted due to the effect of repulsion by neighboring substituents, were prepared and evaluated for 5-hydroxytryptamine 4 (5-HT4) agonistic activities by using the contraction of longitudinal muscle myenteric plexus (LMMP) of guinea pig ileum. One of the most potent compounds in this series was 4-amino-5-chloro-N-[2-(1-dimethylamino-1-cyclohexyl)ethyl]-2-methoxybenz amide (1c, YM-47813) with an EC50 value of 1.0 microM on LMMP. This compound effectively enhanced gastric motility and gastric emptying in conscious dogs by oral administration (1-3 mg/kg).

Estimation of absorbed dose for 2-[F-18]fluoro-2-deoxy-D-glucose using whole-body positron emission tomography and magnetic resonance imaging.

The purpose of this study was to measure the cumulated activity and absorbed dose in organs after intravenous administration of 2-[F-18]fluoro-2-deoxy-D-glucose (18F-FDG) using whole-body positron emission tomography (PET) and magnetic resonance imaging (MRI). Whole-body dynamic emission scans for 18F-FDG were performed in six normal volunteers after transmission scans. The total activity of a source organ was obtained from the activity concentration of the organ measured by whole-body PET and the volume of that organ measured by whole-body T1-weighted MRI. The cumulated activity of each source organ was calculated from the time-activity curve. Absorbed doses to the individuals were estimated by the MIRD (medical internal radiation dosimetry) method using S-values adjusted to the individuals. Another calculation of cumulated activities and absorbed doses was performed using the organ volumes from the MIRD phantom and the "Japanese reference man" to investigate the discrepancy of actual individual results against the phantom results. The cumulated activities of 18 source organs were calculated, and absorbed doses of 27 target organs estimated. Among the target organs, bladder wall, brain and kidney received the highest doses for the above three sets of organ volumes. Using measured individual organ volumes, the average absorbed doses for those organs were found to be 3.1x10(-1), 3.7x10(-2) and 2.8x10(-2) mGy/MBq, respectively. The mean effective doses in this study for individuals of average body weight (64.5 kg) and the MIRD phantom of 70 kg were the same, i.e. 2.9x10(-2) mSv/MBq, while for the Japanese reference man of 60 kg the effective dose was 2.1x10(-2) mSv/MBq. The results for measured organ volumes derived from MRI were comparable to those obtained for organ volumes from the MIRD phantom. Although this study considered 18F-FDG, combined use of whole-body PET and MRI might be quite effective for improving the accuracy of estimations of the cumulated activity and absorbed dose of positron-labelled radiopharmaceuticals.

Estimation of internal absorbed dose of L-[methyl-11C]methionine using whole-body positron emission tomography.

L-[Methyl-11C]-methionine (11C-methionine) is proposed as a useful radiotracer for tumour diagnosis. Human biodistribution data of cumulated activities and absorbed doses estimated by the MIRD (medical internal radiation dosimetry) method for 11C-methionine are not available in the literature. In this study we measured the organ activity for 11C-methionine by using whole-body positron emission tomography (PET) and estimated the absorbed doses to 25 organs by the MIRD method. Whole-body dynamic PET scans were performed on five normal volunteers to measure the time course of the organ activity concentration (activity/volume) after intravenous administration of 11C-methionine. Cumulated activities of the ten source organs were calculated from the time-activity curves, obtained from the dynamic PET data. Absorbed dose estimates were performed by the MIRD method for the Caucasian reference man and for the Japanese reference man. The organs which received the highest absorbed doses for the Caucasian reference man were found to be the bladder wall (2.7x10(-2) mGy/MBq), the pancreas (1.9x10(-2) mGy/ MBq), the liver (1.8x10(-2) mGy/MBq) and the kidney (1.1x10(-2) mGy/MBq). The effective doses for the Caucasian reference man and the Japanese reference man were calculated as 5.2x10(-3) and 5.0x10(-3) mSv/MBq, respectively.