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Childhood advanced lymphoblastic lymphoma (LBL) has a favorable outcome with an event-free survival (EFS) rate of over 80% in response to treatment strategies for acute lymphoblastic leukemia (ALL). However, no progress has been made in this outcome over the past 10 years.We conducted the first nationwide prospective study of childhood advanced LBL to assess the efficacy and safety of ALL-directed therapy with an intensified maintenance phase. We omitted local radiotherapy including prophylactic cranial radiotherapy except for patients with initial central nervous system disease. The total duration of the treatment was 24 months.For the 136 patients analyzed in this study, 5-year overall survival (OS) was 82.9% and 5-year EFS was 77.9%. Thirty events were observed and 14 occurred before the initiation of intensified maintenance phase. Of 14 events, nine were observed as mediastinal enlargement. There was no significant difference in outcome when stratified according to gender or by immunophenotype. The 5-year EFS according to clinical stage in patients with T-cell LBL (T-LBL) was 70.6% for stage III and 88.9% for stage IV (P = 0.037).Our first nationwide study provided about 80% cure rate with only one case of toxic death in childhood advanced LBL. However, our intensified maintenance therapy could not improve the survival outcome. There was a trend of better EFS in Japanese patients with T-LBL stage IV than T-LBL stage III.

We have investigated an off-center local oscillator of a guest atom in cage of clathrate compounds R3Pd20Ge6 ( R = La , Ce, Pr, Nd) and a filled skutterudite PrOs4Sb12 using ultrasonic measurements. The observation of ultrasonic dispersions in transverse C 44 mode of R3Pd20Ge6 and in transverse ( C 11 - C 12 ) / 2 mode of PrOs4Sb12 revealed the rattling of the off-center oscillator characterized by a relaxation time with Arrhenius-type temperature dependence. A low-temperature softening of C 44 in La3Pd20Ge6 below 3 K down to 20 mK and a softening of ( C 11 - C 12 ) / 2 in PrOs4Sb12 above the heavy Fermion superconducting transition indicate the charge fluctuation due to the degenerate off-center oscillators.

The development of reproductive organ tumors such as breast and prostate cancer often depends on the action of sex hormones. Nuclear sex hormone receptors are members of the nuclear hormone receptor superfamily and act as ligand-inducible transcription factors, controlling the expression of target genes. Nuclear receptors are considered to directly and indirectly interact with a number of nuclear co-regulatory complexes involved in chromatin remodeling and histone modification. Moreover, many intracellular signalings via cell membrane receptors are shown to modulate nuclear receptor-regulated transcription. We have shown that estrogen receptors (ER) associate with a number of nuclear complexes, one of which is a spliceosome complex. We recently found that this spliceosome complex interacts with phosphorylated ER by MAP kinase, generating a novel cross-talk of estrogen and growth factor signalings. We also observed that a dioxin receptor (AhR) is capable of associating with ER, resulting in modulation of ER transactivation function. From our findings we believe that development of estrogen-dependent breast cancer may be mediated through the other signaling pathways. To address the function of the androgen receptor (AR) in androgen-dependent prostate cancer, we established a transgenic mouse line expressing a human AR mutant that is found in androgen-independent prostate cancer patients. The hAR mutant mice, generated through a Cre-loxP system, developed hyperplasia in the prostates. Hypersensitivity of AR mutants to antagonists and endogenous steroid hormones may potentiate hormone-dependency in prostate cancer development.

A discrete variational-Xα (DV-Xα) method was applied to elucidate the formation of C–O–Si bridging bonds, produced when a silanol group of SiO2 comes close enough to react with a carboxyl group of indomethacin (IM). A decrease in the coordination number (CN) of oxygen atoms per silicon atom at the SiO2 surface increased the net charge (NC) of the silanolic hydrogen atom and decreased the bond overlap population (BOP) between the silanolic oxygen and hydrogen atoms. These changes favored the formation and stabilization of C–O–Si bridging bonds with simultaneous dehydration. The computational results agreed well with our previous experimental study of a ground indomethacin–SiO2 mixture to obtain a better solid dispersion of the drug.

The self-choice effect refers to the fact that self-chosen items are remembered better than experimenter-assigned items (Takahashi, 1991). The present study investigated the hypothesis that (a) response choice involves relational processing as activation of both target and context items, and (b) such activated context items are effective as potential retrieval cues for recall of target items. In the experiment, participants chose (choice condition) or were assigned (force condition) a target to remember for each trial. Prior to free recall of the target items, context words, related new words, or unrelated words were presented in a recognition task as potential retrieval cues. The results of a subsequent free recall test indicated that the incidental cues were more effective in the choice condition than in the force condition. Also, recognition resulted in a greater rate of successfully recognized context words at the cost of increasing falsely recognized related new words in the choice condition in comparison with the force condition. These results indicated that response choice activates context items at encoding, which operate as potential retrieval cues for recall of target items. Such cuing mechanisms operative in the self-choice effect are consistent with the multiple-cue theory proposed by Soraci et al. (1994; see also Soraci et al., 1999) for generative processing.

Dans le present article de revue, nous discutons les mecanismes de debut d'interaction entre un medicament et SiO 2 sous contraintes mecaniques, sur la base de changements dans les especes radicalaires, de formation de liaisons pontantes et de mise en ordre a courte distance. L'indomethacine (IM) a ete utilisee comme medicament representatif a cause de sa faible solubilite, et l'effet des interactions medicament-porteur sur la stabilite physique de l'IM amorphe a ete etudie. Nous montrons clairement que la stabilite de l'IM amorphe en presence de SiO 2 est plus grande pour les composites prepares par cobroyage que pour ceux obtenus par trempe de l'etat liquide. Le melange par cobroyage conduit a une interaction chimique specifique de l'IM avec SiO 2 . L'interaction chimique immobilise les molecules d'IM a l'interfaceravec le porteur, ce qui empeche la recristallisation. En utilisant un porteur binaire Mg(OH) 2 -SiO 2 , dans lequel une reaction mecanochimique rapide se produit, la stabilite de l'IM amorphe devient superieure a celle observee dans le melange avec SiO 2 seul. Les resultats d'une etude numerique sont en bon accord avec ceux de l'etude experimentale du melange broye indomethacine-silice.

In order to clarify the possible mechanisms underlying the inhibition of uterine tumorigenesis in rasH2 mice carrying a human prototype c-Ha-ras gene when treated with ethinylestradiol (EE), mice were given a single intraperitoneal injection of 120 mg/kg N-ethyl-N-nitrosourea (ENU), followed by 2.5 ppm EE for 6 weeks. Many genes involved in estrogen responses and cell proliferation in the uterus of rasH2 mice are activated by treatment with ENU followed by EE. These include genes associated with receptors such as estrogen receptor (ER) alpha, cell cycles such as cyclin E, cyclin dependent kinase (CDK) 4, CDK inhibitors, ubiquitin and smad3, and growth factors such as epidermal growth factor (EGF) receptor, transforming growth factor (TGF) beta, TGF beta receptor and insulin-like growth factor (IGF). In this study, the ENU+EE treated rasH2 mice demonstrated acceleration of estrogen decomposition and down-regulation of the expression of ER alpha. TGF beta, serine/threonine kinase and smad3, which are downstream of the TGF beta signaling pathway, were also down-regulated, indicating signal values such as CDK4 were down-regulated in the ENU+EE treated rasH2 mice. Ubiquitin which indicates CDK inhibitory metabolism was also down-regulated. Finally, several genes involved in growth factors such as EGF receptor, TGF beta receptor and IGF were also down-regulated. On the other hand, the ENU+EE treated ICR mice showed deceleration of estrogen decomposition and up-regulation of the expression of ER alpha, down-regulation of TGF beta, serine/threonine kinase, smad3, CDK4, ubiquitin, EGF receptor, TGF beta receptor and IGF, indicating that these genes appear to act as stimulants of cell proliferation and carcinogenesis. Therefore, we consider that these genes are key genes which are strongly involved in the inhibition of uterine carcinogenesis in ENU-initiated rasH2 mice treated with EE.

The fatigue of C/C composites was investigated in bending and shear modes. In bending, a large stress ratio resulted in a decrease in strength; the decrease became small without water present. However, a large ratio led to a decrease in Young's modulus, regardless of the presence of water. In shear, degradation in strength or fatigue life decreased with increasing the ratio. For specimens fatigue degraded in air, static strength in water decreased as compared with that in air. It is strongly suggested that fatigue degradation in C/C composites is promoted by a combination of stress corrosion and crack propagation promoted by a wedge effect.

As locally converted estrogen from testicular testosterone contributes to apparent androgen activity, the physiological significance of androgen receptor (AR) function in the beneficial effects of androgens on skeletal tissues has remained unclear. We show here that inactivation of AR in mice using a Cre-loxP system-mediated gene-targeting technique caused bone loss in males but not in females. Histomorphometric analyses of 8-week-old male AR knockout (ARKO) mice showed high bone turnover with increased bone resorption that resulted in reduced trabecular and cortical bone mass without affecting bone shape. Bone loss in orchidectomized male ARKO mice was only partially prevented by treatment with aromatizable testosterone. Analysis of primary osteoblasts and osteoclasts from ARKO mice revealed that AR function was required for the suppressive effects of androgens on osteoclastogenesis supporting activity of osteoblasts but not on osteoclasts. Furthermore, expression of the receptor activator of NF-κB ligand ( RANKL ) gene, which encodes a major osteoclastogenesis inducer, was found to be up-regulated in osteoblasts from AR-deficient mice. Our results indicate that AR function is indispensable for male-type bone formation and remodeling.

BACKGROUND: This study aimed to examine the contribution made by the change in mortality from malignant neoplasms to the life expectancy at birth, observed during the years 1965-1995 in Japan. METHODS: We used data on the population and number of deaths by cause, age and sex in 1965, 1975, 1985 and 1995. The contribution of different ages and causes of death to the change in life expectancy were examined with the method developed by Pollard. RESULTS: We found that, among all causes, the decrease of mortality from stomach cancer led to the greatest improvement in life expectancy for both sexes. On the other hand, negative contributions were seen with cancers of many sites, such as cancer of the intestine, liver and lung for males, and cancer of the intestine, gallbladder, lung and breast for females. Recently, the contributing years of all cancers have been negative because of the increase in mortality from malignant neoplasms. In addition, increase of death from malignant neoplasms in middle-aged and elderly people negatively influenced the life expectancy at birth. CONCLUSIONS: Female cancer influenced the improvement in life expectancy at birth. Cancer for males, however, contributed little to improvement of life expectancy at birth except for a little prolongation of life expectancy at birth during the years 1965-1975. To develop a public health policy, the contributing years to life expectancy at birth can be a useful indication in evaluating the impact of death from various diseases. It is necessary to analyze the contribution made by various causes of death to the changes of life expectancy at birth. J Epidemiol 2003;13:169-175.

States of interaction between indomethacin (IM) and polyvinylpyrrolidone (PVP) in an amorphous solid dispersion prepared by co-grinding were compared with those between IM and silica nanoparticles. Changes in the carbon chemical states of the solid dispersions were evaluated based on the chemical shift in the 13C-CP/MAS-NMR. Hydrogen bonds between the amide carbonyl of PVP particles and the carboxyl groups of IM molecules were formed by co-grinding. Despite the wide difference in carrier properties, the apparent equilibrium solubility (AES) of IM in the ground IM-PVP mixture was predicted by solid state NMR on the basis of the relationship previously established for IM with SiO(2). This indicates that AES is affected solely by the state of IM, irrespective of the carrier species, and despite carrier-dependent chemical interactions.

A composite of indomethacin (IM) and SiO 2 was prepared in a solid state by cogrinding. Dehydration was observed as a consequence of a chemical reaction between silanol groups of SiO 2 and carboxyl groups of IM. Several specific radical species found on separately ground SiO 2 disappeared preferentially after cogrinding as a result of their recombination. These chemical interactions under mechanical stress bring about a charge transfer, as confirmed by X-ray photoelectron spectroscopy, leading to Si–O–C bridging bond formation at the IM/SiO 2 interface.

To determine the clinical utility of thyroid ultrasonography in the diagnosis of congenital hypothyroidism (CH) before initiation of therapy, ultrasonographic images of the thyroid gland with a high-resolution transducer were obtained in 204 healthy infants aged from newborn to 12 months (Group A), and 174 infants suspected of having CH detected by neonatal mass screening (Group B). The thyroid gland was imaged by transverse scanning at the anatomic site of the thyroid gland. The maximal width of thyroid on the transverse section in the normal location was measured. By comparing with the normal thyroid gland size and location obtained from Group A, 174 infants of Group B were divided into four subgroups: 1) Normal in size (n = 117), 2) Enlarged (n = 33), 3) Small (n = 1) and 4) Invisible in the normal location (n = 23). They were compared with the final diagnoses based on the results of chemical laboratory data and scintigraphic findings. The sensitivity and the specificity for the presence or absence of the thyroid gland in the normal location were 96% (22/23) and 99% (150/151), respectively. Both subgroups of normal and enlarged sized gland included healthy infants (false positive), transient hyperthyrotropinaemia, transient hypothyroidism and CH due to dyshormonogenesis. We conclude that ultrasonography is useful for determining the presence or absence of the thyroid gland in the normal location, whereas normal and enlarged sized glands require further examination to complete the diagnosis.

Although mobile phones (MPs) have become important IT devices, there are few studies on the visibility of MPs for elderly people. Using six types of MPs, we analysed the reading performance among elderly people who read 11 numerics on each MP. The subjects were 130 people aged 18 to 86 years, including 60 people over 60 years of age. The subjects' visual functions of cataract cloudiness (CC) and near vision for a 50 cm distant target (NV) were measured. In a twoway ANOVA, two kinds of dependant variables, reading speed (RS) and the number of errors in reading (Error) were used for the subjects' reading performance. Two independent variables were taken from five variables. Each time one variable was fixed as the type of MPs. The other was taken as either age, CC, NV, individual history on MP operation or room illuminance (RI). Eventually, 10 ANOVAs were calculated. Significant differences were found in all ANOVAs except that for RI. We undertook a multiple logistic regression analysis. Independent variable...

The ecotropic viral integration site-1 gene (EVI1) encodes a zinc finger protein that functions as a transcriptional regulator of hematopoietic stem cell self-renewal and long-term multilineage repopulating activity.1,2 The mixed lineage leukemia gene (MLL) rearrangements [i.e. t(11q23)] occur at high frequency in pediatric acute myeloid leukemia (AML) patients with EVI1 overexpression,3 and EVI1 is a transcriptional target of MLL oncoproteins.4 EVI1 overexpression has been reported in up to 10% of patients with AML and is associated with an adverse prognosis. However, the prognostic value of EVI1 overexpression has been studied mostly in adult AML.5–9 Only two studies have examined EVI1 overexpression in pediatric AML, but a detailed analysis according to the type of leukemia was not performed because of the small sample size.3,10 Recent data from an international consortium, including those from our group, suggest that pediatric MLL-rearranged AML can be divided into certain risk groups on the basis of different translocation partners.11 However, clinical outcome data leading to risk stratification of the MLL-rearranged subgroups are still scarce and further investigation is necessary to identify new prognostic factors. Here, we retrospectively examined EVI1 expression levels and clinical outcomes of pediatric MLL-rearranged AML patients treated in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. After excluding patients with acute promyelocytic leukemia, Down syndrome, secondary AML, myeloid/natural killer cell leukemia and myeloid sarcoma, 485 AML patients were enrolled in the AML-05 study. Overall, 42 patients were excluded, mainly because of misdiagnosis. Details of the treatment schedules and risk stratification were described in previous publication.12 This study was conducted in accordance with the principles set down in the Declaration of Helsinki and was approved by the Ethics Committees of all participating institutions. All patients, or the patients’ parents/guardians, provided written informed consent. RNA obtained from diagnostic bone marrow samples was used to analyze the expression of EVI1 using a previously established EVI1 quantitative real-time polymerase chain reaction assay that covers the various EVI1 splice variants.7 Event-free survival (EFS) was defined as the time from the diagnosis of AML to the last follow up or the first event (failure to achieve remission, relapse, secondary malignancy, or any cause of death). In this study, most of the events were relapses (n=23) and the rest were deaths with sepsis (n=1) and acute respiratory distress syndrome (n=1). Overall survival (OS) was defined as the time from the diagnosis of AML to any cause of death. All tests were two-tailed and P

Little information is available on cytogenetic abnormalities and their prognostic importance in childhood mature B-cell non-Hodgkin lymphoma (B-NHL). We performed a review of 79 abnormal karyotypes in childhood B-NHL treated by a uniform protocol. Del(17p) was independently associated with significantly inferior event-free survival in Burkitt or Burkitt-like lymphoma. The adverse prognosis of MYC/8q24 rearrangement, +7q or del(13q), was not observed, which had been suggested as risk factors in FAB/LMB96. Our results imply the possible existence of a biological difference among ethnicities and should be useful to narrow down the gene causing poor prognosis in childhood B-NHL.

The clinical characteristics and prognostic relevance of acute myeloid leukaemia (AML) with myelodysplastic features remains to be clarified in children. We prospectively examined 443 newly diagnosed patients in a multicentre clinical trial for paediatric de novo AML, and found 'AML with myelodysplasia-related changes' (AML-MRC) according to the 2008 World Health Organization classification in 93 (21·0%), in whom 59 were diagnosed from myelodysplasia-related cytogenetics alone, 28 from multilineage dysplasia alone and six from a combination of both. Compared with 111 patients with 'AML, not otherwise specified' (AML-NOS), patients with 'AML-MRC' presented at a younger age, with a lower white blood cell count, higher incidence of 20-30% bone marrow blasts, unfavourable cytogenetics and a lower frequency of Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), NPM1 and CEBPA mutations. Complete remission rate and 3-year probability of event-free survival were significantly worse in 'AML-MRC' patients (67·7 vs. 85·6%, P < 0·01, 37·1% vs. 53·8%, P = 0·02, respectively), but 3-year overall survival and relapse-free survival were comparable with 'AML-NOS' patients. By multivariate analysis, FLT3-ITD was solely associated with worse overall survival. These results support the distinctive features of the category 'AML-MRC' even in children.

Sixty-two infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia (MLL-r ALL) were treated with the MLL03 protocol of the Japanese Pediatric Leukemia/Lymphoma Study Group: short-course intensive chemotherapy followed by early allogeneic hematopoietic stem cell transplantation (HSCT) within 4 months of the initial induction. The 4-year event-free survival and overall survival rates were 43.2% (95% confidence interval (CI)=30.7-55.1%) and 67.2% (53.8-77.4%), respectively. A univariate analysis showed younger age (

Background: Microtubule (MT) disorganization is related to cardiac disorders. To elucidate the mechanism by which disorganization of the MT network deteriorates cardiac function, the relationship between MT disorganization and mitochondrial permeability transition pore (mPTP) in cardiac myocytes was investigated. Methods and Results: The effects of MT stabilization (by paclitaxel) and MT disruption (by nocodazole) on mitochondrial membrane potential (ΔΨm) and the opening of mPTP were measured in permeabilized Sprague-Dawley rat myocytes. Both paclitaxel and nocodazole depolarized ΔΨm and opened mPTP. When isolated mitochondria were exposed to paclitaxel or nocodazole, there were no changes in ΔΨm. The effects of paclitaxel or nocodazole on ΔΨm depolarization and mPTP were inhibited by cyclosporin A. Treatment of myocytes with 0Ca+BAPTA or inhibition of sarcoplasmic reticulum (SR) Ca2+ uptake by thapsigargin prevented the effect of paclitaxel on mPTP, but not that of nocodazole. Inhibition of the mitochondrial Ca2+ uniporter by Ru360 did not alter the effect of paclitaxel on mPTP. Paclitaxel reduced the expression of the mitochondrial fusion protein, mitofusin-2, and induced mitochondrial fragmentation. Conclusions: Disruption of the MT network by nocodazole might destroy the MT-mitochondria connection and alter mitochondrial function. MT disorganization by paclitaxel could regulate mPTP through the outer mitochondrial membrane complex and the Ca2+-sensitive signaling pathway, which also interacts with the mitochondrial fusion protein, mitofusin-2. (Circ J 2014; 78: 1206–1215)

We analyzed the results of the clock drawing test (CDT) in patients with Alzheimer's disease (AD) by quantitative and qualitative methods to evaluate its significance for cognitive function screening. We administered the CDT and mini-mental state examination (MMSE) to a total of 156 AD patients, and CDT performance was scored quantitatively in accordance with the method by Freedman, while the CDT error types were qualitatively classified by Rouleau's method. We divided AD patients into three groups by their MMSE total score (A: 23 ≤, B: 18~22, C: ≤ 17). The mean total scores of CDT and MMSE in AD were 11.5 ± 3.4 and 19.8 ± 4.7, respectively, and the total CDT scores showed significant positive correlation with the total MMSE scores (r = 0.450). Fewer than 80% of subjects drew the clock correctly for 8 out of 15 sub-items, and fewer were able to correctly draw clock hands than could correctly draw numbers, contour or a center. In analysis of CDT qualitative error types, the most common error types were spatial and/or planning deficit (SPD) (28.2%), and conceptual deficit (CD) (23.7%), which suggested visuospatial impairments and semantic impairments play essential roles in AD patients' poor clock drawings. The frequency of CD and SPD error types significantly increased as severity of cognitive function worsened (p < 0.001, p < 0.05, respectively), and those of stimulus-bound response and perseveration had tendency to increase as severity of cognitive function. The present study suggests that CDT is a useful screening method not only for the impairment of cognitive function and the severity of cognitive dysfunction, but also for identification of specific cognitive function impairments in AD patients.

Modifying effects of scordinin, a biological active component in garlic, on diethylnitrosamine (DEN)- and phenobarbital (PB)-induced hepatocarcinogenesis were examined in rats. Male F344 rats, 5 weeks old, were divided into 8 groups. After a week, groups 1 - 5 were given DEN (100 mg / kg body weight, i.p.) once a week for 3 weeks, whereas groups 6 - 8 received vehicle treatment. Group 2 was given 600 ppm scordinin-containing diet in the initiation phase. From 4 weeks after the start of experiment, groups 3 and 5 were fed scordinin, and groups 1 - 3 and 7 received drinking water containing 500 ppm PB. Group 6 was given scordinin diet alone throughout the experiment (24 weeks). The incidences of hepatocellular adenoma and carcinoma were significantly smaller in group 3 than those in group 1 (P < 0.005 and P < 0.05, respectively). The average numbers of liver neoplasms in groups 2 and 3 were significantly smaller than in group 1 (P < 0.01 and P < 0.0001, respectively). Glutathione S-transferase placental form-positive foci were also significantly decreased by scordinin treatment in the initiation or promotion phase. Scordinin significantly decreased the mean number of nucleolar organizer regions' protein (AgNORs) / nucleus in hepatocellular adenoma and carcinoma. AgNORs / nucleus in the non-lesional area was also significantly decreased by scordinin treatment during the promotion phase. These results suggest that scordinin is a promising chemopreventive agent for liver neoplasia.

The self-choice effect is the phenomenon whereby self-chosen items are remembered better than experimenter-assigned items. This study examined whether the effect occurs when the choice is constrained by cuing, and whether the effect also occurs for unchosen items. In the experiment, 33 participants chose (choice condition) or were assigned (force condition) a target from three alternatives that were followed by a cue sentence as a criterion for the choice. Cue sentences corresponded to any of the three alternatives (free cuing) or to only one (constrained cuing). Participants then engaged in free recall of targets and subsequent recognition of all alternatives (chosen and unchosen items). Memory performance was enhanced by choice regardless of the constraints, but was also enhanced for unchosen items. These results indicate that “free choice” is not always critical for the self-choice effect, and that multiple cuing involving unchosen items is a plausible account for the retention advantage of choice procedures.

Hypocalcemia and hyperphosphatemia caused by PTH resistance are the only discernible abnormalities in pseudohypoparathyroidism type 1b (PHP-1b). Because of the selective resistance toward PTH, inactivating mutations in its receptor, the PTH/PTH-related peptide receptor (PTHR1), were thought to be responsible for PHP-1b. However, gene abnormalities responsible for PHP-1b have not been identified in the coding region and well conserved promoters (P1 and P2) of the PTHR1 gene. The purpose of the present study was to analyze the structure of the P3 promoter, the main promoter of the human PTHR1 gene in kidney, in patients with PHP-1b. Southern analysis of genomic DNA from lymphoblastoid cell lines of eight nonfamilial patients with PHP-1b revealed neither gross rearrangements nor methylation abnormalities in the P3 promoter region of the PTHR1 gene. Sequencing revealed no abnormalities in the P3 promoter region, although one patient was homozygous for an (AAAG)n polymorphic variant. In conclusion, despite the selective resistance toward PTH in the kidney, which mainly uses the PTHR1 P3 promoter, PHP-1b in eight cases is not associated with structural abnormalities in this promoter. This study also indicates that inactivation of the P3 promoter is not achieved by methylation as tested in patients’ genomic DNA from lymphoblastoid cell lines. The influence of alterations in the polymorphic A-rich repeat sequence on promoter activity warrants further study.

Fasting alters various hormonal and immune conditions. It has been reported that delayed type immune response to the injection of keyhole limpet hemocyanin was depressed by short-term fasting. In this study, we adopted the computer-assisted image analyzer for histopathological analysis and evaluated the infl uence of short-term fasting on allergic contact dermatitis induced by 2,4-dinitrofluorobenzene (DNFB). Mice were sensitized by painting of DNFB to the abdomen. After the sensitization, mice were challenged by DNFB painting to the ear. Fasting started 24 hour before (48-hour fasted group) or immediately after (24-hour fasted group) the challenging. Fasting without DNFB treatment did not induce remarkable change of ear thickness, ear tissue, serum albumin, serum total protein, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, or serum creatine phosphokinase. In contrast, fasting suppressed the increment of ear thickness in the DNFB-treated group in this study. We could also demonstrate, using the computerized image analyzer, that both lymphocyte infi ltration and the edema in the dermis were suppressed in fasted mice treated with DNFB. Further, edema in the dermis was inhibited more strongly in 48-hour fasted mice than in 24-hour fasted mice. These fi ndings indicate that short-term fasting induce histopathological changes in the state of contact dermatitis.

We examined clinical, endocrinological and molecular biological aspects of an estrogen-secreting adrenal carcinoma in an 18-month-old male to clarify the pathogenesis of this condition. An 18-month-old boy was referred for evaluation of progressive bilateral gynecomastia and appearance of pubic hair. The patient had elevated plasma estradiol (349 pg/ml) and testosterone (260 ng/dl) levels that completely suppressed FSH and LH levels, and was subsequently diagnosed with an adrenal tumor on the right side. After removal of a 300-g adenocarcinoma, gynecomastia regressed and essentially normal hormone levels were restored. Aromatase activity in the tumor tissue determined by the 3H-water method was 71.0-104.4 pmol/min/mg protein. High levels of aromatase protein and mRNA in the tumor tissue were also demonstrated, while neither aromatase activity nor protein was detected in normal adrenal glands. To investigate the regulation of aromatase expression in the adrenal carcinoma, we examined the usage of alternate promoters responsible for aromatase gene transcription. In the present case, the amounts of aromatase mRNA utilizing gonadal types of exon 1c (1.3) and 1d (II) were significantly higher than those that using other exon 1s. This result suggested that the utilization of a gonadal-type exon 1 might be involved in the over-production of aromatase in estrogen-secreting adrenal carcinoma.

A multiple-cue hypothesis was proposed by Soraci et al. (1994) to account for incongruous item generation effects. They reported a positive relationship between the number of cues at acquisition and subsequent recall for generation, but not read, conditions. The present experiments explored the role of cuing in congruous generation encoding contexts. In Experiments 1 and 2, no multiple cuing advantage was found across congruous generation encoding contexts when cues were directed at the same semantic referent. Experiments 3 and 4 demonstrated a recall advantage for multiple cues in congruous generation conditions only when both semantic referents of a homograph were cued. In contrast, Experiment 5, involving incongruous generation, demonstrated equivalent levels of recall for redundant and variable multiple cuing conditions. These data indicate that the original multiple-cue hypothesis should be modified to include the critical role that generative processing has in promoting the utilization of multiple referents (i.e., potential response candidates) in recall.

Design and numerical analysis of an X-band femtosecond electron linear accelerator (linac) is presented. We aim to generate a 100 fs (full width at half maxium: FWHM) electron single bunch with more than 1 nC at the X-band femtosecond linac. The simulation of electron dynamics including magnetic pulse compression is carried out by using PARMELA and SUPERFISH. It is found that the 700 ps (tail-to-tail) electron emission from a 150 kV thermionic gun can be bunched and compressed to 100 fs (FWHM) electron single bunch with the charge of 1 nC which gives 10 kA. We plan to use one high power X-band klystron which can supply 60 MW with more than 200 ns pulse duration. The flatness of plateau of the RF pulse should be 0.2% for stable ultrashort bunch generation. The influence of the klystron voltage fluctuation on the accelerating voltage is quantitatively evaluated and the vacuum design is also done. We have confirmed the feasibility of the linac from viewpoints of state-of the-art technologies.

The effects of sardine fish oil or corn oil on diethylnitrosamine (DEN)-induced hepatocarcinogenesis were investigated in male F344 rats. Starting at 5 weeks of age, animals were divided into 11 groups and fed 23.5% corn oil (HCO) (groups 1 and 7) or 5% corn oil (LCO) (groups 2 and 8), 22.5% sardine oil + 1% corn oil (FO) semipurified diet (groups 3 and 9) or basal diet (CE-2) (groups 4-6, 10 and 11). At 6 weeks of age, all animals except the vehicle-treated groups were given DEN (200 mg/kg body weight, i.p. once weekly for 3 weeks). One week after the final exposure to DEN, groups 1-3 were changed to the basal diet, and groups 4-6 were switched to the HCO, LCO or FO diet, respectively. Animals in groups 1-3 and 10 were given drinking water containing 0.05% phenobarbital (PB). Liver sections from the animals at the termination of the experiment (24 weeks) were doubly stained for glutathione S-transferase placental form (GST-P) and silver-stained nucleolar organizer regions (AgNORs). The multiplicity of hepatocellular neoplasms of group 1 was significantly larger than that of group 2 or 3. The number of GST-P-positive foci of group 2 or 3 was significantly smaller than that of group 1. Among the groups fed the experimental diets in the postinitiation phase (groups 4-6), no significant difference was found in the incidence of liver tumors. AgNORs values of the enzyme-altered foci in rats of the HCO diet groups were larger than those of the other diet groups. These results indicate that the enhancing effect of a high dose of corn oil in hepatocarcinogenesis is mainly present during the initiation phase but not during postinitiation phase, and fish oil rich in polyunsaturated omega-3 fatty acids could inhibit DEN-induced hepatocarcinogenesis in rats.

We have measured Raman spectra of La 3 Pd 20 Ge 6 and La 3 Pd 20 Si 6 single crystals from 4 K to room temperature. For both crystals, all Raman-active modes have been found without additional modes. Thus, there is no evidence that La atoms locate on off-center positions in the cages. By a comparison with La 3 Pd 20 Si 6 , two anomalous results have been observed only in La 3 Pd 20 Ge 6 . One is a large broad peak due to the second order Raman scattering below 140 cm - 1 . The other is that the energy of the lowest-energy T 2 g mode, which is the vibration of the La(2) atoms, decreases with decreasing temperature. Since the latter behavior is also found in the clathrate compounds A 8 Ga 16 Ge 30 ( A = Ba , Sr , Eu ) , we believe that this behavior is universal for thermal motion of weakly bound guest atoms to cages.

We have carried out an ultrasonic measurement to investigate an off-center motion of a rare-earth ion in clathrate compounds R 3 Pd 20 Si 6 and R 3 Pd 20 Ge 6 . In R 3 Pd 20 Ge 6 , an elastic constant C 44 shows an ultrasonic dispersion around 10–30 K. This is caused by thermally activated rattling of the rare-earth ion over an anharmonic potential in the cage. In addition, the C 44 of La 3 Pd 20 Ge 6 exhibits a remarkable softening proportional to 1 / T below 3 K down to 20 mK. This result indicates the tunneling state of the rare-earth ion through the potential barrier. On the other hand, the C 44 of La 3 Pd 20 Si 6 and Ce 3 Pd 20 Si 6 shows no ultrasonic dispersion indicating the absence of the rattling.

BACKGROUND AND OBJECTIVE: To determine the efficacy of the pedicle internal limiting membrane (ILM) transposition flap technique for refractory macular holes (MHs) in which the inverted ILM flap technique cannot be performed. PATIENTS AND METHODS: The pedicle ILM flap transposition technique was conducted by transconjunctival microincision vitrectomy. The authors attempted to peel the remaining ILM inferior from the MH to create an ILM flap. This ILM was still attached to the retina at the upper part of the MH and covered the MH. Finally, fluid-gas exchange was performed. After surgery, patients remained face-down for 1 week. This procedure was performed in two eyes. RESULTS: There were no adverse events, and MHs were closed successfully in both study eyes. CONCLUSION: The pedicle ILM flap transposition technique has the potential to improve functional and anatomical outcomes in patients with refractory MHs. [ Ophthalmic Surg Lasers Imaging Retina . 2015;46:1045–1046.]

Activating mutations of the extracellular calcium (Ca2+e)-sensing receptor (CaR) gene, mostly in its extracellular domain, can cause both familial and sporadic hypoparathyroidism. We report a Japanese family with severe hypoparathyroidism with pretreatment serum calcium (Ca) levels of 4.9–5.9 mg/dL. The proband presented with a seizure at 6 days of age. Her older brother and mother, who had also experienced seizures and tetany, respectively, likewise had hypoparathyroidism. A heterozygous missense mutation substituting a cysteine for the phenylalanine normally present at codon 788 (F788C) was identified in the CaR’s fifth transmembrane domain and was shown to cosegregate with the disease. The mutation was absent in DNA from 50 control subjects. Analysis of the functional properties of the mutant receptor was carried out in transiently transfected HEK293 cells loaded with fura-2 by assessing Ca2+e-evoked increases in the cytosolic calcium concentration (Ca2+i). There was a leftward shift in the concentrati...

This study was designed to investigate the chronic cardiotoxic potential of SM-5887 and a possible deteriorating effect of SM-5887 on low-grade cardiotoxicity pre-induced by doxorubicin in beagle dogs. In the chronic treatment, beagle dogs of each sex were given intravenously once every 3 weeks, either a sublethal dose of doxorubicin (1.5 mg/kg) or SM-5887 (2.5 mg/kg). The experiment was terminated 3 weeks after the ninth dosing. Animals which received over six courses of doxorubicin demonstrated the electrocardiogram (ECG) changes, decrease of blood pressure and high-grade histopathological cardiomyopathy, while animals which were terminally sacrificed after the SM-5887 administration did not show any changes in ECG, blood pressure and histopathological examinations. To examine a possibly deteriorating cardiotoxic effect of SM-5887, low-grade cardiomyopathy was induced in dogs by four courses of doxorubicin (1.5 mg/kg). Nine weeks after pre-treatment, dogs were given four courses of either doxorubicin (1.5 mg/kg) or SM-5887 (2.5 mg/kg) once every 3 weeks. The low-grade cardiotoxic changes were enhanced by the additional doxorubicin treatment. On the contrary, the SM-5887 treatment did not progress the grade of cardiomyopathy. In conclusion, SM-5887 does not have any potential of chronic cardiotoxicity and deteriorating effect on doxorubicin-induced cardiotoxicity in dogs.

Modifying effects of irsogladine maleate (IRG) on diethylnitrosamine (DEN)-induced hepatocarcinogenesis were examined in male F344 rats. Six-week-old rats were divided into 8 groups. Groups 1 through 4 were given a single i.p. injection of DEN (200 mg/kg body weight) at the start of the experiment, whereas groups 5 through 8 received a single i.p. injection of saline as the vehicle treatment. Groups 1 and 8 were kept on the basal diet and distilled water throughout the experiment (36 weeks). Groups 2 and 7 were exposed to 500 ppm phenobarbital (PB) in the drinking water, starting one week after the carcinogen or vehicle treatment. Groups 3 and 5 were fed the diet mixed with 125 ppm IRG from one week after DEN or vehicle treatment. Groups 4 and 6 were given 125 ppm IRG-containing diet and drinking water with 500 ppm PB after the carcinogen or vehicle treatment. Liver neoplasms developed in groups 1 (1/15 rats, 7%) and 2 (14/14 rats, 100%). However, no liver tumors were found in rats of groups 3 through 8. Incidence and average number of liver neoplasms in group 4 (0/14 rats, 0%) were less than those in group 2 (P < 0.0001). The number of glutathione S-transferase placental form (GST-P)-positive liver cell foci in group 3 or 4 was significantly smaller than that in the appropriate control (P < 0.01, P < 0.001, respectively). The average and unit areas of these foci in group 4 were also significantly smaller than those in group 2 (P < 0.001, P < 0.05, respectively). These results suggest that IRG could be a chemopreventive agent for rat liver carcinogenesis.

To examine whether oxfendazole has tumour-promoting activity, a total of 100 male Fisher 344 rats were initiated with a single ip injection of 100 mg/kg of diethylnitrosamine (DEN) or given saline vehicle alone and starting 1 wk later given diet containing 500, 250, 100, 10 or 0 ppm of oxfendazole for 8 wk. Sub-groups of five rats each from the DEN plus 250 and 0 ppm groups were killed after wk 1 of oxfendazole treatment and the remaining animals at wk 8. At the termination relative liver weights were significantly increased in the DEN-initiated and non-initiated groups treated with 250 ppm and 100 ppm or more, respectively, compared with the corresponding controls values. Light microscopical examination showed centrilobular hepatocellular hypertrophy in all animals receiving 100 ppm or more. Electron microscopy also revealed marked increases in smooth endoplasmic reticulum in hepatocytes of the DEN plus 500 ppm group. Furthermore, induction of cytochrome P-450 (CYP) 1A1/2, 2B1/2 or 4A1 was observed in the DEN plus 100 ppm group, that of CYP 1A1/2 being most marked. A similar change in CYP 1A1/2 was seen in the DEN plus 10 ppm group. The numbers and areas of connexin 32 (Cx32)-positive spots per hepatocyte were also significantly decreased in a dose-dependent manner. Similar changes in liver weights, P-450 isozymes and Cx32 immunohistochemistry were already evident in the DEN plus 250 ppm group at wk 1. The number of placental form glutathione S-transferase positive single cells was significantly increased in the DEN-initiated groups treated with 250 ppm or more. The results therefore strongly suggest that oxfendazole exerts liver tumour promotion potential.

Purpose Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (Δ Ψ m ) depolarization, exhibited attenuated insulin signaling and 2-deoxy- d -glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H 2 O 2 ), they increased DRP1 expression and mitochondrial fragmentation, resulting in Δ Ψ m depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H 2 O 2 -induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the Δ Ψ m depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance.

Previous Japanese studies of childhood B-cell non-Hodgkin lymphoma (B-NHL) have shown a favorable outcome, though the study size was too small to effectively assess the efficacy and safety of treatment for childhood B-NHL.We performed a nation-wide prospective B-NHL03 study to assess the efficacy and safety of short-pulse intensive chemotherapy for children with B-NHL. They were stratified into four treatment groups according to disease stage, tumor resectability and bone marrow/CNS involvement: Group 1 with all resected stage I/II, Group 2 with non-resected stage I/II, Group 3 with stage IIICNS-negative stage IV, and Group 4 with CNS-positive stage IVBurkitt leukemia. Treatment duration was 2 courses for Group 1, 4 courses for Group 2, and 6 courses for Groups 3 and 4, respectively. CNS irradiation was omitted in all patients.The follow-up time ranged from 0.8 to 88 months, with a median of being 45 months. For 321 patients analyzed in this study, overall survival and event-free survival (EFS) at 4 years was 92.7% and 87.4%, respectively. The 4-year EFS according to treatment group were 94% for Group 1 (n = 17), 98% for Group 2 (n = 103), 84% for Group 3 (n = 111), and 78% for Group 4 (n = 90). There was no significant difference in outcome by histology. Therapy-related death occurred in three patients in remission.Our nationwide large-scale study resulted in a cure rate above 90% with1% toxic death in childhood B-NHL.

AIM The purpose of this study was to evaluate whether physical activities reduce the risk of cognitive decline in community-dwelling elderly. We investigated correlations between cognitive functions at baseline and physical activities, correlations between cognitive functions at baseline and cognitive decline over 4 years, as well as correlations between physical activity at baseline and cognitive decline over 4 years. METHODS At baseline, 2,431 community-dwelling elderly completed the cognitive screening by telephone (TICS-J), and answered the questionnaires about physical activities. Of these, 1,040 subjects again completed the TICS-J over 4 years. Physical activities contained moving ability, walking frequency, walking speed, the exercise frequency. RESULTS At baseline, 870 elderly (age 75.87±4.96 (mean±SD) years, duration of education 11.05±2.41) showed normal cognitive functions and 170 (79.19±6.22, 9.61±2.23) showed cognitive impairment. The total TICS-J score was significantly higher in cognitive normal subjects compared with that of cognitive impaired subjects (36.02±1.89, 30.19±2.25, respectively, p

The Japanese government recommended in 2000 that women planning pregnancy should take 400 μg of folic acid daily to decrease the risk of having an infant with spina bifida. We aimed to identify risk factors for the occurrence of spina bifida and to evaluate how the prevalence rate has altered over the past 3 decades.Subjects comprised 360 women who gave birth to spina bifida-affected offspring and 2333 women who gave birth to offspring without spina bifida between 2001 and 2012. A self-administered questionnaire was used to collect data, which were analyzed by multiple logistic regression models. The prevalence rate of spina bifida was obtained through data provided by international and domestic organizations.Four variables were significantly associated with the increased risk of having newborns afflicted with spina bifida: not taking folic acid supplements (odds ratios [OR], 2.50; 95% confidence interval [CI], 1.72-3.64), presence of spina bifida patients within third-degree relatives (OR, 4.26; 95% CI, 1.12-16.19), taking anti-epileptic drugs without folic acid (OR, 20·20; 95% CI, 2.06-198.17), and low birth weight in the newborns ≤ 2500 g (OR, 4.21; 95% CI, 3.18-5.59). The prevalence rate of spina bifida has remained 5 to 6 per 10,000 total births and has not shown any decreasing trend over the past 11 years.Four risk factors were identified among Japanese women. Because recommendations and information have not decreased the occurrence of spina bifida, the Japanese government should implement mandatory food fortification.