Limit on neutrinoless ßß decay of 136Xe from the first phase of KamLAND-Zen and comparison with the positive claim in 76Ge.

We present results from the first phase of the KamLAND-Zen double-beta decay experiment, corresponding to an exposure of 89.5 kg yr of (136)Xe. We obtain a lower limit for the neutrinoless double-beta decay half-life of T(1/2)(0ν)>1.9×10(25) yr at 90% C.L. The combined results from KamLAND-Zen and EXO-200 give T(1/2)(0ν)>3.4×10(25) yr at 90% C.L., which corresponds to a Majorana neutrino mass limit of <(120-250) meV based on a representative range of available matrix element calculations. Using those calculations, this result excludes the Majorana neutrino mass range expected from the neutrinoless double-beta decay detection claim in (76)Ge, reported by a part of the Heidelberg-Moscow Collaboration, at more than 97.5% C.L.

Effects of liquefied sake lees on growth performance and faecal and blood characteristics in Japanese Black calves.

Liquefied sake lees, a by-product of Japanese sake, is rich in Saccharomyces cerevisiae, proteins, and prebiotics derived from rice and yeast. Previous studies have reported that Saccharomyces cerevisiae fermentation products improved the health, growth, and faecal characteristics of preweaning calves. This study investigated the effects of adding liquefied sake lees to milk replacer on the growth performance, faecal characteristics, and blood metabolites of preweaning Japanese Black calves from 6 to 90 days of age. Twenty-four Japanese Black calves at 6 days of age were randomly assigned to one of three treatments: No liquefied sake lees (C, n = 8), 100 g/d (on a fresh matter basis) liquefied sake lees mixed with milk replacer (LS, n = 8), and 200 g/d (on a fresh matter basis) liquefied sake lees mixed with milk replacer (HS, n = 8). The intake of milk replacer and calf starter, as well as, the average daily gain did not differ between the treatments. The number of days counted with faecal score 1 in LS was higher than in HS (P < 0.05), while the number of days with diarrhoea medication in LS and C was lower than HS (P < 0.05). The faecal n-butyric acid concentration tended to be higher in LS compared to C (P = 0.060). The alpha diversity index (Chao1) was higher in HS than in C and LS at 90 days of age (P < 0.05). The principal coordinate analysis (PCoA) using weighted UniFrac distance showed that the bacterial community structures in faeces among the treatments at 90 days of age were significantly different (P < 0.05). The plasma ß-hydroxybutyric acid concentration, an indicator of rumen development, was higher for LS than in C throughout the experiment (P < 0.05). These results suggested that adding liquefied sake lees up to 100 g/d (on a fresh matter basis) might promote rumen development in preweaning Japanese Black calves.

Durability of protective effect of dulaglutide on pancreatic ß-cells in diabetic mice: GLP-1 receptor expression is not reduced despite long-term dulaglutide exposure.

AIMS: It is well-known that chronic exposure to large amounts of ligand leads to downregulation of its receptor. It is not known, however, whether a GLP-1R agonist downregulates its receptor. For this reason, our study examined whether GLP-1R expression is reduced after long-term exposure to dulaglutide (Dula) in non-diabetic and diabetic mice. METHODS: Seven-week-old male db/db and db/m mice were given either Dula (0.6mg/kg×2/week) or a control vehicle (CTL) for 17 weeks. Various metabolic parameters, such as glucose-stimulated insulin secretion (GSIS), insulin and TG content in islets, were evaluated after the intervention. ß-cell-related gene expression was also analyzed by real-time RT-PCR. RESULTS: In db/m mice, GLP-1R expression in ß-cells did not decrease, not even after long-term administration of Dula, compared with control mice, while GLP-1R expression in 24-week-old db/db mice treated with Dula was augmented, rather than downregulated, compared with 24-week-old CTL db/db mice. This was probably due to improved glycaemic control. In db/db mice treated with Dula, food intake and blood glucose levels were significantly decreased up to 24 weeks of age compared with CTL db/db mice, and their expression levels of various ß-cell-related genes, insulin content and GSIS were also enhanced. In contrast, oxidative and endoplasmic reticulum stress, inflammation, fibrosis and apoptosis were suppressed with Dula treatment. CONCLUSION: Dula exerts beneficial effects on glycaemic control and has long-lasting protective effects on pancreatic ß-cells. GLP-1R expression levels were not reduced at all in non-diabetic as well as diabetic mice despite long-term dulaglutide exposure.

A wild-type sequence p53 peptide presented by HLA-A24 induces cytotoxic T lymphocytes that recognize squamous cell carcinomas of the head and neck.

Evidence has accumulated indicating that HLA-A2-restricted CTLs specific for human wild-type sequence p53 epitopes lyse tumor cells expressing mutant p53. To explore the possibility that wild-type sequence p53 peptides could also be used in vaccines for patients expressing HLA-A24 antigen, another frequent HLA class I allele, we investigated the induction of HLA-A24-restricted p53-specific CTLs from the peripheral blood lymphocytes of normal donors. Of six p53-derived peptides possessing an HLA-A24 binding motif, the p53 peptide 125-134 (p53(125-134)) was found to have a high binding capacity and induced peptide-specific CTLs from peripheral blood mononuclear cells, using peptide-pulsed autologous dendritic cells and subsequent cultivation with cytokines interleukin 2 and interleukin 7. Bulk CTL populations lysed peptide-pulsed HLA-A24+ targets as well as HLA-A24+ squamous cell carcinoma of the head and neck (SCCHN) cell lines. However, IFN-gamma pretreatment of HLA-A24+ SCCHN cell lines was necessary for lysis, suggesting that a ligand density higher than that normally expressed by tumor cells is required for these CTLs to mediate lysis. Moreover, a cloned CTL, designated TH#99, isolated from the bulk population by limiting dilution, lysed HLA-A24+ SCCHN targets more efficiently than the bulk CTL population. Lysis was inhibited by anti-HLA class I monoclonal antibody but not by anti-HLA-DR monoclonal antibody. These results indicate that HLA-A24-restricted CTLs recognizing the wild-type sequence p53(125-134) can be generated using autologous dendritic cells from precursors present in peripheral blood lymphocytes obtained from normal HLA-A24+ donors. This finding suggests that vaccine strategies targeting wild-type sequence p53 epitopes can be extended to a wider range of cancer patients.

A new pseudo-peptide of Arg-Gly-Asp (RGD) with inhibitory effect on tumor metastasis and enzymatic degradation of extracellular matrix.

A series of pseudo-peptide analogs of the Arg-Gly-Asp (RGD) sequence of fibronectin have been synthesized, and their anti-metastatic effects in mice and inhibitory effects on tumor cell invasion in vitro have been examined. The partially modified retro pseudo-peptide of RGD, Rrev-COCH2CO-D (FC-63), was more effective in inhibiting tumor metastasis than the original RGDS peptide. Replacement of the malonyl moiety of FC-63 with a carboxyethylene linkage (Rrev-COCH2CH2-D, FC-303 ) achieved more potent inhibition of lung metastasis of melanoma cells than FC-63. Among the analogs, FC-336, a p-xylylendiamine derivative having two FC-303 moieties, showed the most potent inhibitory effect on experimental lung metastasis produced by i.v. co-injection with B16-BL6 melanoma or colon 26 M3.1 cells in a dose-dependent manner. Multiple administrations of FC-336 after tumor inoculation also showed efficient therapeutic potency against spontaneous lung metastasis of B16-BL6 melanoma in mice. Furthermore, FC-336 effectively inhibited the invasion, migration and adhesion of tumor cells in vitro, but its inhibitory effects were not more than those of RGDS peptide. Zymography analysis revealed that FC-336 inhibited the degradation of gelatin substrate by matrix metalloproteinases (MMPs) produced by tumor cells, while the RGDS peptide did not affect the enzymatic degradation. These findings indicate that the pseudo-peptides of the RGD sequence, possessing the inhibitory property of the degradation by MMPs differently from original RGD-containing peptides, may be advantageous and useful in preventing tumor metastasis.

Trial production of titanium orthodontic brackets fabricated by metal injection molding (MIM) with sintering.

Safety and esthetics are two indispensable factors to consider when fabricating orthodontic brackets. However, these factors are not easily achieved when conventional techniques (including forging and casting) are used in the mass production of titanium brackets, albeit the brackets exhibit excellent biocompatibility. In the present study, orthodontic brackets were manufactured by metal powder injection molding with sintering. Brackets with three different base designs were made and subjected to compression shear tests for evaluation of their bonding strength to enamel substrate. The shapes given to the dimple of the base were spherical, oval, and grooved. The maximum shear forces for each type were 11.1 kgf, 7.6 kgf, and 18.5 kgf, respectively. The bonding strengths of the titanium bracket were equivalent to those obtained with conventional stainless steel brackets. Moreover, uniform distribution of Vickers hardness values (average, 240 +/- 40 Hv) measured at three locations indicated that the titanium bracket was uniformly sintered. Accordingly, titanium brackets thus fabricated exhibit a potential for clinical application.

Arteriovenous fistula around the ventriculoperitoneal shunt system in a patient with a dural arteriovenous malformation of the posterior fossa. Case report.

A dural arteriovenous malformation (AVM) of the posterior fossa can produce persistent tinnitus, convulsions, and dementia. Successful therapeutic embolization may result in a complete cure, but in some cases, patients do not respond to the treatment. The authors report a patient with a dural AVM of the posterior fossa that did not respond to repeated intravascular treatments, but resulted in an arteriovenous shunt in the scalp around the ventriculoperitoneal shunt system. Although several hypotheses have been proposed on the pathogenesis of dural AVMs, the underlying mechanisms remain unknown. The rare complication we encountered may shed some light on the pathogenesis of dural AVMs.

Retention mechanism of hypoxia selective nuclear imaging/radiotherapeutic agent cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells.

The retention mechanism of the novel imaging/radiotherapeutic agent, Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells was clarified in comparison with that in normal tissue in vitro. With Cu-ATSM and reversed phase HPLC analysis, the reductive metabolism of Cu-ATSM in subcellular fractions obtained from Ehrlich ascites tumor cells was examined. As a reference, mouse brain was used. To determine the contribution of enzymes in the retention mechanisms, and specific inhibitor studies were performed. In subcellular fractions of tumor cells, Cu-ATSM was reduced mainly in the microsome/cytosol fraction rather than in the mitochondria. This finding was completely different from that found in normal brain cells. The reduction process in the microsome/cytosol was heat-sensitive and enhanced by adding exogenous NAD(P)H, an indication of enzymatic reduction of Cu-ATSM in tumor cells. Among the known bioreductive enzymes, NADH-cytochrome b5 reductase and NADPH-cytochrome P450 reductase in microsome played a major role in the reductive retention of Cu-ATSM in tumors. This enzymatic reduction was enhanced by the induction of hypoxia. Radiocopper labeled Cu-ATSM provides useful information for the detection of hypoxia as well as the microsomal bioreductive enzyme expression in tumor.

Vitamin D insufficiency in Japanese female college students: a preliminary report.

Vitamin D insufficiency, a risk factor for osteoporosis, has been well investigated in elderly women worldwide, but little information has been available for younger women. This study aimed to determine serum 25-hydroxyvitamin D [25(OH)D] levels in Japanese female college students, and to test whether there is an association between 25(OH)D and bone strength. Subjects were 77 Japanese female junior college students aged 19-24 years. Serum 25(OH)D was measured with high performance liquid chromatography. Bone strength of the calcaneus was evaluated using the osteo sono-assessment index (OSI), a combined index reflecting the bone mass, bone architecture, and elasticity, as measured by quantitative ultrasound densitometry (AOS-100, Aloka). The mean 25(OH)D concentration was 34.2 nmol/L (SD +/- 12.1). The proportion of subjects with 25(OH)D less than 30 nmol/L, a cut-off value for vitamin D insufficiency, was 31/77 (40.3%). Simple linear regression analysis showed that there was a significant linear relationship between 25(OH)D and OSI (R2 = 0.098, p = 0.0069). The association held even after adjusting for weight (partial R2 = 0.098, p = 0.0023). Body weight was also a significant predictor of OSI (partial R2 = 0.105, p = 0.0034). These results suggest that vitamin D insufficiency may be prevalent in healthy young women. Moreover, low levels of 25(OH)D in young women may adversely affect bone strength. An additional, newly designed epidemiological study with a sufficient sample size is needed to confirm the present findings.

Esophageal cancer complicated by acute myelofibrosis--report of an autopsy case.

An autopsy case of esophageal cancer complicated by myelofibrosis was studied. A 62-year-old Japanese patient with esophageal cancer, received surgical treatment and then splenectomy. The resected spleen was normal in appearance. Five months later he received radiation therapy for the cancer. After the therapy, his blood profile revealed thrombocytopenia and leukoerythroblastosis, and the bone marrow punctures were dry tap. He died of disseminated fungal infections at eleven months after the first operation. An autopsy of the patient revealed a striking increase in the megakaryocytes and a moderate increase in the reticulin fibers in the bone marrow. Myeloid metaplasia was noted in the lymph nodes, kidneys, and other organs and tissues, although the lymph nodes were not grossly swollen. These findings suggest esophageal cancer complicated by acute myelofibrosis. This it the first case report on esophageal cancer complicated by acute myelofibrosis.

Effect of sodium bicarbonate and deoxycholic acid on the gastric mucosa of the rabbit.

Deoxycholic acid (DC), a secondary bile acid and one of those most toxic to the gastric mucosa, is precipitated and becomes inactive in the acidic lumen of the rabbit stomach. We sought to determine whether or not oral administration of sodium bicarbonate (NaHCO3) and DC injure the rabbit gastric mucosa. Rabbits were divided into six groups. Group 1 was given 10 ml of 10% NaHCO3 followed by 50 ml of 20 mM DC orally every day. These animals had diarrhea and three of five died on the fourth or fifth day. Therefore, the two remaining animals were killed on the fourth day. Animals in group 2 were given 10 ml of water followed by 50 ml of 20 mM DC, those in group 3 were given 10 ml of 10% NaHCO3 followed by 10 mM DC, those in group 4 were given 10 ml of water followed by 50 ml of 10 mM DC, and those in group 5 were given 10 ml of 10% NaHCO3 followed by 50 ml of the DC solution. Group 6 was not treated. Although all animals in the group 2 and one of three in group 3 had diarrhea, they were alive and were killed after eight or nine days. Gross and histological examinations showed that the degrees of gastric mucosal damage in groups 1 and 2 were more severe than in groups 3 and 4. Mucosal damage in group 3 was more severe than in group 4. The gastric mucosa in group 5 was similar to that in untreated animals (group 6). These data suggest that when the gastric lumen is alkalinized by NaHCO3, DC causes more severe damage to the mucosa than it does when the lumen is acidic.

[Effects of smoking and drinking habits and vitamin A intake on serum concentrations of beta-carotene and retinol].

Serum samples from 341 males aged 10 to 59 years were obtained and stored at -40 degrees C until examined for retinol and beta-carotene concentrations by HPLC, and their relationships to smoking habit, alcohol drinking habit and vitamin A intake were studied. In univariate analysis the serum beta-carotene level was significantly lower in the smokers than in the non-smokers (smokers: 4.6 micrograms/dl, non-smokers: 7.1 micrograms/dl, p less than 0.01) and lower in the drinkers than in the non-drinkers (drinkers: 4.6 micrograms/dl, non-drinkers: 7.3 micrograms/dl, p less than 0.01). The serum retinol level was not different by smoking habit but was higher in the drinkers than in the non-drinkers (drinkers: 80.4 micrograms/dl, non-drinkers: 67.0 micrograms/dl, p less than 0.01). Serum beta-carotene was higher in the group with a greater intake of vitamin A of vegetable origin (6.1 micrograms/dl) than in the group with a smaller intake of it (4.7 micrograms/dl) (p less than 0.01), but serum retinol was not different by the amount of vitamin A intake of animal food origin. To estimate the respective effects and interactions of the above factors on serum beta-carotene and retinol levels by adjusting for the confounding effects of age, serum total cholesterol, HDL-cholesterol and triglyceride, analysis of covariance was performed. For serum beta-carotene, smoking habit (p less than 0.01), drinking habit (p less than 0.01) and the amount of vitamin A intake of vegetable food origin (p less than 0.05) had significant main effects.(ABSTRACT TRUNCATED AT 250 WORDS)

[Circadian variations of sudden death].

Characteristics of the circadian variation for sudden death (SD), were studied by analyzing summary death certificates for the period of 1984 to 1986 in Niigata prefecture. SD was defined as death within 2 hours of onset of underlying cause (n = 4,362), and the time of onset of the cause was determined by subtracting the "time elapsed until death" from the "time of death." The periodicity for time of onset of the cause was analyzed in groups stratified by year, season, sex and age with Rogers' method utilized to check the statistical significance of the periodicity. SD, as a whole, showed a statistically significant circadian variation with a low incidence during 0 to 4 A.M. and a high incidence during 6 to 8 A.M. and 6 to 8 P.M. By season, no significant circadian variation was seen in the summer unlike for other seasons. When analyzed by age group, no significant circadian variation in SD was seen for the young to middle aged group (15-54 years old). On the other hand, there was a significant circadian variation for the senior (55 to 74 years old) and the elderly group (75 years old or older) with a low incidence during 0 to 4 A.M. and high incidence during 6 to 12 A.M. and 6 to 8 P.M.. For the old age group, the number of the cases increased so remarkably as to form an evening peak. The percentage of SD for young to middle cases was higher in the summer than in the other seasons which may be the reason for absence of significant circadian variation in the summer.

[Immunocytochemical characterization of the DNA-polymerase alpha-positive colonic mucosal epithelial cells in patients with ulcerative colitis].

Colonic mucosal epithelial cells (EpC) in patients with ulcerative colitis (UC) have been shown to express HLA-DR antigen. In the present study, we observed the characteristics of HLA-DR-positive EpC using immunoperoxidase technique. In the control group, colonic EpC expressed HLA-ABC, but not HLA-DR. Only the EpC at the base of glands revealed positive for DNA-polymerase alpha (DNA-P). On the other hand, in actively inflamed mucosa of UC, about 80% of glands strongly expressed HLA-DR. Furthermore, most of EpC in the HLA-DR-positive glands showed positive nuclear stainings for DNA-P. This indicates that these EpC are not in the resting stage. It is strongly suggested that there are close relationships between the regeneration or proliferation of the EpC and class II MHC (HLA-DR) expression on the EpC in UC.

[Study on echo pattern of endometrial cancer (author's transl)].

Ultrasound imaging of endometrial cancer and its diagnostic efficacy has not been discussed in literature up to the present. 59 echograms of this entity which was pathologically confirmed postoperatively during the last 7 years were analyzed in relation to the clinical stage, growth pattern and histological features. Internal echoes of the uterine body can be classified into the following 4 patterns: type 1: anechoic, type 2: linear, type 3: cystic, type 4: massive. The incidence of type 3 and 4 account for 25.4% and 40.7% of all cases respectively. It shows that abnormality in echo pattern can be recognised without difficulty in more than a half of the cases. The difference between echo pattern (type 1+2, 3+4) and clinical stage (stage I, II-IV) was statistically significant in chi 2 test. In particular, type (3+4) amount to 81% of clinical stage (II-IV). There was also significant difference between echo pattern and growth pattern, especially the circumscribed form amount to 79.2% in type 4 and 81.3% of circumscribed form was made up of type (3+4). But the echo pattern showed no apparent correlation with the histological type and grade. Moreover, some clinically useful information about the coexistent lesions, including 2 ovarian metastasis, could be obtained by the ultrasound.

Magnetic resonance studies on the copper site of dopamine beta-monooxygenase in the presence of cyanide and azide anions.

In order to elucidate the coordination state of water molecules in the Cu(II) site of dopamine [( 3,4-dihydroxyphenyl)ethylamine] beta-monooxygenase, measurements of the paramagnetic 1H nuclear magnetic relaxation rate of solvent water in the enzyme solution containing cyanide or azide as an exogenous ligand were carried out to obtain the values of intrinsic paramagnetic relaxation rate decrements Rp1 and Rp2 for the ligand-enzyme 1:1 and 2:1 complexes, respectively. Rp1 (percent) values were 53 (pH 5.5) and 52 (pH 7.0) for cyanide and 38 (pH 5.5) and 32 (pH 7.0) for azide, while Rp2 (percent) values were 98 (pH 5.5) and 96 (pH 7.0) for azide. Although no Rp2 values for cyanide were obtained because of its reducing power at the Cu(II) site, the Rp1 and Rp2 values obtained above prove that the Cu(II) center has two coordinated water molecules that are exchangeable for exogenous ligands at either pH. Supporting evidence was provided by electron paramagnetic resonance (EPR) titration, in which the enzyme solution containing cyanide-enzyme (1:1) complex in an equal proportion to uncomplexed enzyme gave an observed paramagnetic relaxation rate decrement, Rp, of 23%. Another characteristic of the Rp1 and Rp2 values was their invariability with respect to pH, indicating that the three-dimensional structure of the Cu(II) site is pH-invariant within the range examined. Binding constants of ligand to enzyme Kb1 and Kb2 for 1:1 and 2:1 complex formation, respectively, were also determined through an analysis of the Rp values; it was found that Kb1 was larger than Kb2 irrespective of pH. (ABSTRACT TRUNCATED AT 250 WORDS)