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Acute myocardial infarction (AMI) remains one of the most serious heart diseases and elucidation of its pathogenesis and advances in treatment strategies have been desired. In 2009, to understand the status of AMI in Fukushima Prefecture for improving treatment outcomes, a new AMI registration survey system was conducted throughout the prefecture. A total of 1,556 cases were registered in the initial 2 years from 2009 to 2010. The hospital-based overall incidence of AMI in Fukushima Prefecture was 37.9 people per population of 100,000 per year. Mortality from AMI within 30 days of onset was 10.2%. We report herein the actual situation of AMI onset and treatment in Fukushima Prefecture based on the initial results of the survey.

Excess treatment reduction including anthracyclines results in higher incidence of relapse in core binding factor acute myeloid leukemia in children

We hypothesized that assessment of 3D wall motion tracking method is possible to detect small change of systolic function and myocardial risk area by 3D adenosine stress echocardiography inpatients with ischemic heart disease (IHD). We examined 39 vessel areas by 3D adenosine stress

The physiological and beneficial actions of vitamin D in bone health have been experimentally and clinically proven in mammals. The active form of vitamin D [1α,25(OH)2D3] binds and activates its specific nuclear receptor, the vitamin D receptor (VDR). Activated VDR prevents the release of calcium from its storage in bone to serum by stimulating intestinal calcium absorption and renal reabsorption. However, the direct action of VDR in bone tissue is poorly understood because serum Ca2+ homeostasis is maintained through tightly regulated ion transport by the kidney, intestine, and bone. In addition, conventional genetic approaches using VDR knockout (VDR-KO, VDR−/−) mice could not identify VDR action in bone because of the animals' systemic defects in calcium metabolism. In this study, we report that systemic VDR heterozygous KO (VDR+/L−) mice generated with the Cre/loxP system as well as conventional VDR heterozygotes (VDR+/−) showed increased bone mass in radiological assessments. Because mineral metabolism parameters were unaltered in both types of mice, these bone phenotypes imply that skeletal VDR plays a role in bone mass regulation. To confirm this assumption, osteoblast-specific VDR-KO (VDRΔOb/ΔOb) mice were generated with 2.3 kb α1(I)-collagen promoter-Cre transgenic mice. They showed a bone mass increase without any dysregulation of mineral metabolism. Although bone formation parameters were not affected in bone histomorphometry, bone resorption was obviously reduced in VDRΔOb/ΔOb mice because of decreased expression of receptor activator of nuclear factor kappa-B ligand (an essential molecule in osteoclastogenesis) in VDRΔOb/ΔOb osteoblasts. These findings establish that VDR in osteoblasts is a negative regulator of bone mass control.

A new predictive toxicokinetics model was developed to estimate subacute toxicity (target organs, severity, etc.) of non-congeneric industrial chemicals, where the chemical structures and physico-chemical properties are only available. Thus, a physiological pharmacokinetics model, which consists of blood, liver, kidney (these were experimentally found as major toxicological targets), muscle and fat compartments, was established to simulate the chemical concentrations in organs/tissues with pharmacokinetic parameters by means of Runge-Kutta-Gill algorithm. The pharmacokinetic parameters, i.e. absorption rate, absorption ratio, hepatic extraction ratio of metabolism and renal clearance were calculated by using separately established Quantitative Structure-Pharmacokinetics Relationship equations. The developed predictive model was then applied to simulations of 43 non-congeneric industrial chemicals. The chemical concentrations in organs/tissues after single oral administration were simulated, and their maximum concentrations (Cmax's) and area under the concentration-time curves (AUC's) were calculated. Fast Inverse Laplace Transform was newly applied for the purpose of simulation of 28-day repeated dose toxicity. Simulated concentrations of 28 days repeated dose were, however, found to be the same as those of simple repetitions of a single administration per day because of the short half-lives of non-congeneric industrial chemicals. A comparison of subacute toxicity data with Cmax's and AUC's in a single dose scenario suggested that the organs/tissues with relatively high concentrations of tested chemical substances were the most sensitive targets within a chemical. Chemical concentrations in liver, for instance, were correlated with the severity of hepatotoxicity among the chemicals. It was also suggested that to improve and widen the present approach, data of metabolite and reactivity of non-congeneric industrial chemicals to organs/tissues, receptors, etc. should be incorporated into the model.

Modifying effects of chlorophyllin (CHL) on the diethylnitrosamine (DEN)-phenobarbital (PB) hepatocarcinogenesis model were examined in rats. Five-week-old male F344 rats were divided into 8 groups. Groups 1 through 5 were given i.p. injections of DEN (100 mg/kg body weight) once a week for 3 weeks beginning one week after the start of the experiment, while groups 6 through 8 received vehicle treatment. Groups 1, 2, 3 and 7 received drinking water with 500 ppm PB from one week after the end of carcinogen or vehicle treatment. CHL-containing diet (2000 ppm) was given to group 2 during the initiation phase and to groups 3 and 5 during the promotion and the post-initiation phase, respectively. Group 6 was given the experimental diet alone throughout the experiment (24 weeks). Liver neoplasms were present in DEN-treated groups and PB treatment promoted liver tumorigenesis. The incidences of adenoma in groups 2 and 3 were significantly smaller than in group 1 (P < 0.05 and P

The effect of ethanol (EtOH) on esophageal cell proliferation and the development of esophageal cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in shrews were investigated. Sequential histological examination was done, and cell proliferation was assessed by BrdU labeling. At 5 weeks of age, animals were given tap water, 2% EtOH, 50 ppm MNNG, or 50 ppm MNNG plus 2%, 5% or 10% EtOH in the drinking water. Administration of 10% and 5% EtOH simultaneously with MNNG caused death in 40% (10/25) within 4 days and in 20% (6/30) within 7 days respectively, whereas other treatment were well tolerated with no sudden deaths. Administration of 2% EtOH for 30 weeks caused a 2-fold increase, and that of MNNG caused a 4.5-fold increase in the proliferation index of the basal cells of the esophagus compared with control shrews, and MNNG plus 2% EtOH caused a 5.5-fold increase. In MNNG-treated shrews, with or without 2% EtOH administration, sequential histological examination of esophageal tissue revealed a similar change; dysplasia appeared at 30 weeks of age, squamous cell carcinoma occurred at 35 weeks of age, and the depth of invasion extended to adventitia at 45 weeks of age. These finding indicate that treatment with 2% EtOH promoted the proliferation of esophageal basal cells but did not alter the tumor induction period and did not have tumor-promoting activity. EtOH per se was not carcinogenic; no tumors were seen in shrews not administered MNNG.

“Single dose detailed toxicity study” in rats was conducted with 6 chemical substances to establish a predicting system of subacute toxicity of non-congeneric industrial chemicals. In the detailed examinations, new and previously reported biological parameters were developed and utilized for the establishment and confirmation of the correlations for both qualitative and quantitative prediction of target organs and effects in repeated dose toxicity studies of non-congeners; the new parameters were concerned with liver, kidneys and blood and the established relating equations for prediction had a correlation coefficient of 0. 83 (liver), 0.49 (kidneys) and 0. 94 (blood), while the old parameters effectively confirmed the previous correlations. The serial changes in the study gave a biological explanation to the established relationships between acute and subacute toxicities in terms of extrapolation.

Predicting equations of subacute toxicity were developed by analyzing rat acute and subacute toxicity data of 56 chemicals of various structures. Minimum or 10% effect level in acute or subacute toxicity was estimated as a “biological parameter”. Good regression equations were established between the geometrical means (“combined parameters' of any two of the parameters of acute and subacute toxicities and introduction of log P to the equations improved the correlations with a statistically significant multiple regression coefficient. The lowest predicted effect level of the subacute toxicity, which is selected from the data calculated by the above several correlations, can predict the upper limit of the no observed effect level.

A study was conducted to determine the mode of action for promoting effect of large amounts of vitamin A (VA) on cell proliferation of thyroid proliferative lesions induced by thiourea (TU) (Mitsumori et at, Cancer Letter 103: 19-31, 1996). Groups of male F344 rats (16/group) received 0.1% TU in water (TU group), 0.1% VA in diet (VA group), both 0.1% TU in water and 0.1% VA in diet (TU+VA group) or distilled water and basal diet (control group) for 4 weeks. Increased weights of thyroids (absolute and relative), liver (absolute and relative) and pituitary (relative), decreased serum T4 levels, and decreased thyroidal iodine uptake, and organification were observed in TU and TU+VA groups, as compared to the control group. Thyroidal iodine organification was also decreased in VA group. However, there were no differences in these parameters between TU and TU+VA groups. No treatment related effects were noted in serum T3 and TSH. No remarkable differences were observed in the histopathological findings of thyroids, liver, and pituitary between TU and TU+VA group, although diffuse follicular cell hyperplasia was induced in these groups. The results in the present study suggest that the enhancement effect of VA on thyroid proliferative lesions may not be attributable to the modification of thyroidal iodine uptake.

We investigated the effects of nifedipine on cyclic GMP turnover and the pertinent enzyme activities in cultured coronary smooth muscle cells (SMC). Nifedipine at high concentrations slightly decreased basal soluble guanylate cyclase activity and inhibited the action of sodium nitroprusside (SNP) but had no effect on the particulate form of the enzyme. In contrast, nifedipine inhibited cyclic GMP hydrolysis by directly inhibiting the partially purified calmodulin-stimulated isoform of phosphodiesterase (type I PDE) with IC50 of 4.2 microM. Nifedipine > or = 1.0 microM enhanced cyclic GMP accumulation in response to 1.0 microM SNP, although nifedipine alone exerted no influence on cyclic GMP levels. Enhancement of cyclic GMP accumulation by nifedipine in response to SNP was not affected by BAY K 8644, a calcium channel agonist. These properties may be shared by other dihydropyridines since nicardipine and nisoldipine also inhibited type I PDE with similar IC50. However, some other structurally unrelated calcium channel blockers, diltiazem and verapamil, had little effect on cyclic nucleotide hydrolysis or on cyclic GMP accumulation in response to SNP. Nifedipine may synergistically enhance cyclic GMP accumulation in response to nitric oxide (NO)-releasing agents by directly inhibiting type I PDE in coronary SMC. Such effects of nifedipine may partly contribute to coronary vasodilation and prevention of coronary spasm in patients with ischemic heart disease.

Background. A number of studies have indicated that the ki-67 proliferation index is of important prognostic significance for a variety of neoplasias. It was the aim of this study to investigate whether any correlation exits between the MIB-1 proliferation index and various clinicopathologic parameters in squamous cell carcinomas of the esophagus from 72 patients (20 women: median age, 64 years; range, 45–79 years; and 52 men: median age, 61 years; range, 43–77 years). Methods. Proliferative activity was determined using an immunohistochemical method with monoclonal antibody MIB-1 (ABC method), for tumor samples obtained from individuals who underwent esophagectomy in the period from 1983 to 1991. The percentage proliferation index (PI) was calculated as the number of positive cells divided by the total number of cells examined. Thirty-nine patients (54%) died of recurrence of esophageal cancer, with a median survival span of 15 months (range, 1–58 months). Thirty-three patients (46%) were still alive at the time of this study; their median follow up was 57 months (range, 40–98 months). Results. Significant differences between proliferative index values were recorded for the following parameters: survival rate, P < 0.0001; presence of lymph node metastasis, P < 0.05; size of the primary esophageal lesion, P < 0.01; proliferation pattern of the tumor, P < 0.01; and age of the patients, P < 0.05. No correlation was found regarding histologic differentiation, clinical stage, location of the lesion, intraepithelial cancerous spread, lymphatic and blood vessel invasion, and sex of the patients. Conclusion. The MIB-1 proliferation index may be a powerful prognostic marker for patients with squamous cell carcinomas of the esophagus. Cancer 1995;76:358–66.

Mechanical activation increased the surface basicity of the alkaline earth hydroxides in the order Sr(OH) 2 > Ca(OH) 2 > Mg(OH) 2 , as determined by titration, temperature-programmed, desorption, and FT-IR. The increase and the difference in the basicity between the hydroxides became more significant in the case of grinding Me (OH) 2 -SiO 2 mixtures, as a result of mechanochemical interactions between the ingredients. Bidentate adsorption of CO 2 , found exclusively on the ground mixture with SiO2, is only explained by the formation of new - Me -O-Si- bonding. This indicates the incipient formation of alkaline earth silicates as a result of charge transfer during grinding.

This paper deals with a newly developed underwater displacement sensor utilizing the acoustic resonant frequency of water in a submerged pipe. Both ends of the pipe are closed. A speaker to generate sound is fixed on the end of the pipe with the reflector at the other end. A piezoelectric ceramic is used as a speaker. Sweeping signal is radiated from the speaker to the water column in the pipe. The sound pressure takes the largest value at the resonant frequency. The displacement of the reflector which is inserted from the other end of the pipe by the plunger, corresponds to the length of the water column. The displacement of the reflector has good correspondence to the resonant frequency of the water column. It is found from the experiment that it is possible to measure accurately underwater displacement using this sensor.

Mature T cell lymphoma has been noted for poor prognosis when compared with B cell lymphoma, even in the pre-rituximab era. To confirm this difference, a retrospective cohort study was conducted. One hundred-and nineteen patients with mature T cell lymphoma and 568 patients with diffuse large B cell lymphoma (DLBCL) who did not receive rituximab as first induction were studied. Overall survival (OS) was worse for patients with international prognostic index (IPI) scores indicating low-risk mature T cell lymphoma than for those with DLBCL (3-year OS 87 % vs. 58 %, P = 0.001), but not in other risk groups. Prognosis of mature T cell lymphoma was significantly poorer in the IPI low-risk group, as compared with DLBCL.

A 73-year-old man was hospitalized for unstable angina pectoris with no history of myocardial infarction. After undergoing percutaneous coronary intervention, left ventriculography incidentally revealed a cavity in the anterior wall, and echocardiography found the cavity wall to be dyskinetic. Myocardial contrast echocardiography revealed that the wall of the cavity was surrounded by myocardial tissue with low perfusion. Furthermore, radial strain in the wall of the cavity was low. Myocardial scintigraphy showed a localized defect on the anterior wall. The patient was finally diagnosed as true aneurysm after asymptomatic and localized myocardial infarction, and has since been followed up by echocardiography in the outpatient clinic.

The aims of the present study were to investigate the effectiveness of exercise intervention provided by a medical support team specializing in lifestyle-related diseases in the treatment of elderly lower extremity osteoarthritis and to examine the influence of bodyweight decrease on changes in the evaluation indexes.Participants were 61 patients (57 women and 4 men, aged 68.3 ± 9.6 years) with lower extremity osteoarthritis (109 total diseased joints) and either one or more of the following diseases: obesity, metabolic syndrome and type 2 diabetes. Indexes relating to metabolic diseases, orthopedic disorders, lifestyle activity level and health-related quality of life (HRQOL) were obtained before and after exercise intervention.The numbers of patients with obesity, metabolic syndrome, type 2 diabetes, gonarthrosis and coxarthrosis were 56, 49, 32, 56 and 9, respectively. The mean intervention period was 4.7 ± 1.6 months (2-10.8 months). Indexes relating to metabolic diseases and orthopedic disorders, activity level and HRQOL were all significantly improved after intervention (P0.05). Bodyweight decreased by 10.3% and showed a correlation with other evaluated items. Five explanatory variables were extracted through multiple regression analysis that bodyweight reduction rate was set as the criterion variable: changes of bodyweight, body mass index, percent body fat, glycated hemoglobin and total energy expenditure per bodyweight.The exercise intervention provided by our medical support team clearly improved indexes relating to metabolic diseases and orthopedic disorders. In addition, decreased bodyweight was related to improvements in metabolic factors, motor function and HRQOL.

The Image Processor for Analytical Pathology (IPAP), is a computer-based image analysis instrument which uses current technology to provide valuable information to the pathologist. Our own studies using the IPAP system are focussed on the fields of tumor pathology and toxicologic pathology. The spectrum of methods for the characterization of histologic patterns in these fields consists of karyometric and histometric measurements. This paper describes the hardware configuration of the IPAP and the software system which has been developed to allow a flexible and interactive analysis of microscopical images with minimal computer training and experience. Some examples are given to illustrate the possibilities of the IPAP.

Prostate cancer development is associated with hyperactive androgen signaling. However, the molecular link between androgen receptor (AR) function and humoral factors remains elusive. A prostate cancer mouse model was generated by selectively mutating the AR threonine 877 into alanine in prostatic epithelial cells through Cre-ER T2 –mediated targeted somatic mutagenesis. Such AR point mutant mice ( AR pe-T877A/Y ) developed hypertrophic prostates with responses to both an androgen antagonist and estrogen, although no prostatic tumor was seen. In prostate cancer model transgenic mice, the onset of prostatic tumorigenesis as well as tumor growth was significantly potentiated by introduction of the AR T877A mutation into the prostate. Genetic screening of mice identified Wnt-5a as an activator. Enhanced Wnt-5a expression was detected in the malignant prostate tumors of patients, whereas in benign prostatic hyperplasia such aberrant up-regulation was not obvious. These findings suggest that a noncanonical Wnt signal stimulates development of prostatic tumors with AR hyperfunction.

Specific sugar ligands which bind to rat L-selectin (LECAM-1, lymphocyte homing receptor)-IgG chimera were investigated by thin-layer chromatography-binding assay and ELISA. Rat L-selectin-IgG bound to native sulfated glycolipids such as sulfatide (I 3 SO 3 -GalCer), seminolipid, SM3(II 3 SO 3 -LacCer), SB2(III 3 SO 3 ,II 3 SO 3 -Gg3Cer), SB1a (IV 3 SO 3 ,II 3 SO 3 -Gg4Cer). The binding activity of the SM2 (II 3 SO 3 -Gg3Cer) carrying the internal sulfated Gal was very low, indicating that non-reducing terminal SO 3 H-3Galβ1- structure is essential for the binding. The reactivity of sulfatide was higher than that of sialyl Le x [Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glcβ1-Ceramide] either in the presence of 1 mM Ca 2+ or 1 mM Ca 2+ and 5 mM EGTA. All the non-fucosylatedgangliosides including ganglio-series and lacto-series type I and II chains tested gave a negative reaction. Neutral glycosphingolipids tested were all negative. Binding assay using synthetic sulfatide analogs indicated that the L-selectin-binding to its sulfated sugar ligands is position specific and depends on the number of the sulfate group, i.e., (SO 3 ) 3 -3,4,6Gal- > (SO 3 ) 2 -3,6Gal- > SO 3 -3Gal- > SO 3 -3Glc- > SO 3 -6Gal- > SO 3 -2Gal-. Lower reactivity of the chimera to SO 3 -3Glc- rather than SO 3 -3Gal- indicates that the chimera recognizes the configuration of hydroxyl group linked to the 4 carbon atom of the pyranose ring in galactose.

The distribution of glutathione S-transferase (placental form; GST-P) and the c-myc gene product in rat hepatic preneoplastic lesions induced by diethylnitrosamine (DEN) and clofibrate was examined immunohistochemically. An in vivo medium-term assay system (4) was used to study the effects of chemical hepatocarcinogenesis. Rats initially received a single intraperitoneal dose (200 mg/kg) of DEN, and after week 2,1% clofibrate in diet for consecutive days. The rats were subjected to partial hepatectomy at week 3 and sacrificed at weeks 8, 20 and 30

Chronic illnesses are common among elderly people, and may considerably affect to their quality of life (QOL). We investigated the impact of chronic conditions on QOL among community-dwelling elderly people, and the stability of QOL over time.A total of 2,762 community-dwelling elderly persons (men: 47.0%, age 76.7±5.8 [mean±SD]) completed postal QOL questionnaires twice over 4 years. Chronic illnesses were selected from the following 9 conditions: cerebrovascular disease, hypertension, heart disease, cancer, diabetes mellitus, bone fracture, chronic digestive disease, chronic respiratory disease, and the diseases of joints or muscles. The QOL questionnaire was developed based on the QOL components proposed by Lawton, and consisted of 6 subscales: daily activity, health satisfaction, human support satisfaction, economic state satisfaction, symptoms of depression, and positive mental attitude. The subjects were divided into 3 groups regardless of the presence of chronic illnesses. QOL subscale scores were compared among the 3 groups, and fluctuations over 4 years were also evaluated.The baseline QOL scores showed significant differences among the 3 groups, especially regarding health satisfaction, but not in satisfaction with human support. There were significant differences among the 3 groups in fluctuations over 4 years in health satisfaction, daily activity, and positive mental attitude.Chronic illnesses have a negative impact on the QOL of elderly people, and also influence fluctuations in QOL over time. Degrees of impacts differed according to each QOL subscale. Therefore, evaluation of QOL in community-dwelling elderly needs multi-dimensional assessment.

For many antibodies, each antigen-binding site binds to only one antigen molecule during the antibody's lifetime in plasma. To increase the number of cycles of antigen binding and lysosomal degradation, we engineered tocilizumab (Actemra), an antibody against the IL-6 receptor (IL-6R), to rapidly dissociate from IL-6R within the acidic environment of the endosome (pH 6.0) while maintaining its binding affinity to IL-6R in plasma (pH 7.4). Studies using normal mice and mice expressing human IL-6R suggested that this pH-dependent IL-6R dissociation within the acidic environment of the endosome resulted in lysosomal degradation of the previously bound IL-6R while releasing the free antibody back to the plasma to bind another IL-6R molecule. In cynomolgus monkeys, an antibody with pH-dependent antigen binding, but not an affinity-matured variant, significantly improved the pharmacokinetics and duration of C-reactive protein inhibition. Engineering pH dependency into the interactions of therapeutic antibodies with their targets may enable them to be delivered less frequently or at lower doses.

Primary central nervous system lymphoma (PCNSL) related to acquired immunodeficiency syndrome (AIDS) is a lethal disorder, but the recent application of highly active antiretroviral therapy (HAART) has significantly improved prognosis. This retrospective cohort study of AIDS-related PCNSL examined the actual clinical outcomes and prognostic variables affecting overall survival (OS) in the HAART era. Twenty-three newly diagnosed AIDS-related PCNSL at 12 regional centre hospitals for HIV/AIDS in Japan between 2002 and 2008 were consecutively enrolled. The estimated 3-yr OS rate of the entire cohort was 64% (95%CI, 41.0-80.3%). Whole brain radiation therapy (WBRT) had an independent positive impact on survival (WBRTor=30 Gy vs. others, P = 0.02). Nine of 10 patients with a good performance status (PS) (0-2) remained alive with complete response, whereas 10 (77%) of 13 of those with a poor PS (3-4) died mostly after a short period. The estimated 3-yr OS rate of the groups with a good and poor PS was 100% and 38% (95%CI, 14-63%), respectively (P = 0.01). Leukoencephalopathy (gradeor= 2) developed in 21% of those that survived more than 12 months after radiation. The patients receiving a curative intent radiation dose (or=30 Gy) of WBRT achieved prolonged survival while maintaining a good quality of life in the HAART era, especially among patients with a favourable PS.

A 73-year-old male in a persistent vegetative state underwent percutaneous coronary intervention (PCI) for unstable angina with multiple-vessel stenosis. The maximum dose pharmaceutical therapy was ineffective in controlling his symptoms. The goal of the procedure was to alleviate the patient's severe chest pain and vomiting with minimal invasion and risk. The procedure was effective despite treating only the culprit artery. Symptoms disappeared immediately after PCI and the patient remained attack free for 12 months. With the consent of the patient's family and support of medical staff, elective single-vessel PCI can be a practical and effective treatment option for refractory angina in patients with impaired consciousness.

To examine the mechanism and toxicological significance of thyroidal tumor observed slightly in a long-term rat study with diethofencarb (isopropyl 3, 4-diethoxycarbanilate), male Sprague-Dawley rats were fed diethofencarb in diets at concentrations of 0, 5, 000 or 20, 000 ppm for 3 months. Examinations mainly for thyroid functions including thyroid uptake of &lt125&gtI, serum thyroid hormone and thyroid stimulating hormone (TSH) level, hepatic UDP-glucuronyltransferase (UDP-GT) activity and histopathological examination in thyroid were performed at week 13. Decreases of body weights and food consumptions were observed at and above 5, 000 ppm. Under these conditions, decrease of serum free T4 and increase of serum TSH level were observed only at 20, 000 ppm, concurrently with liver weight increase at and above 5, 000 ppm and increase of hepatic UDP-GT activity at 20, 000 ppm. However, no compound related effects were noted in thyroid weight, thyroid uptake of &lt125&gtI and gross or histopathological examination in thyroid. These results indicate that the administration of diethofencarb leads to an increase in UDP-GT activity and acceleration of thyroid hormone excretion from the liver. The acceleration causes a decrease in serum free T4 level, triggering the feedback mechanism of the pituitary gland, promotion of TSH release and consequently an increase in serum TSH level. Thus, the slightly higher incidence of thyroid follicular cell tumors observed in the chronic and oncogenicity study with non-genotoxic diethofencarb is considered to be caused by these weak pituitary-thyroid hormonal imbalances. The toxicological significance in humans is extremely low according to the well established facts that the chronic TSH stimulatin would not induce thyroid tumors in humans and humans may be less sensitive than rats in regard to the response to goitrogenic stimuli.

We evaluated the developmental prognosis of 31 infants born to mothers with autoimmune thyroiditis. Four of the babies developed transient neonatal hypothyroidism. Their mothers all had low thyroid hormone concentrations during pregnancy. Neonatal thyroid function tended to correlate with maternal thyroid function at delivery in babies born to mothers with Graves';disease who were taking antithyroid drugs. Since severe fetal hypothyroidism sometimes results in neurological damage, it is important to maintain normal maternal thyroid function during pregnancy.

C-type natriuretic peptide (CNP) plays a critical role in endochondral ossification through guanylyl cyclase-B (GC-B), a natriuretic peptide receptor subtype. Cartilage-specific overexpression of CNP enhances skeletal growth and rescues the dwarfism in a transgenic achondroplasia model with constitutive active mutation of fibroblast growth factor receptor-3. For future clinical application, the efficacy of CNP administration on skeletal growth must be evaluated. Due to the high clearance of CNP, maintaining a high concentration is technically difficult. However, to model high blood CNP concentration, we established a liver-targeted CNP-overexpressing transgenic mouse (SAP-CNP tgm). SAP-CNP tgm exhibited skeletal overgrowth in proportion to the blood CNP concentration and revealed phenotypes of systemic stimulation of cartilage bones, including limbs, paws, costal bones, spine, and skull. Furthermore, in SAP-CNP tgm, the size of the foramen magnum, the insufficient formation of which results in cervico-medullary compression in achondroplasia, also showed significant increase. CNP primarily activates GC-B, but under high concentrations it cross-reacts with guanylyl cyclase-A (GC-A), a natriuretic peptide receptor subtype of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP). Although activation of GC-A could alter cardiovascular homeostasis, leading to hypotension and heart weight reduction, the skeletal overgrowth phenotype in the line of SAP-CNP tgm with mild overexpression of CNP did not accompany decrease of systolic blood pressure or heart weight. These results suggest that CNP administration stimulates skeletal growth without adverse cardiovascular effect, and thus CNP could be a promising remedy targeting achondroplasia.

It has become important for elderly to live better rather than to live longer. There have been many reports about quality of life (QOL) of the elderly, but we have no knowledge about the relation between the QOL and the cognitive function. We investigated the relationship between the QOL and the cognitive function among community-dwelling elderly.A total of 12,059 community-dwelling elderly were invited to join a cognitive screening study by telephone (TICS-J) combined with a mailed QOL questionnaire. Among them, 1,920 subjects (age 71.87+/-5.50 (mean+/-SD) years old, duration of education 11.08+/-2.61 years) who completed both TICS-J and QOL questionnaire were actually measured. TICS-J was administered by the previously reported method, and the QOL questionnaire was developed based on the component of QOL proposed by Lawton, and consisted of 6 subscales (daily activity, satisfaction with health, satisfaction with human support, satisfaction with economic state, symptoms of depression, and positive mental attitude). Correlations were analyzed among the scores of TICS-J, age, duration of education, and scores on each QOL subscale. Multiple linear regression analysis was conducted after QOL subscale scores, adjusting for gender, age, and duration of education, were entered as dependent variables.Four out of 6 subscales scores of QOL showed significant differences between men and women. All QOL subscale scores showed significant differences between the two groups in the TICS-J scores. Partial correlations were seen among TICS-J scores and each QOL subscale score. Multiple linear regression analysis revealed significant influence of cognitive function by TICS-J on QOL subscales scores.Cognitive function was considered to have more influence on QOL scores than gender or age. TICS-J and the QOL questionnaire in this study were useful to evaluate the outcome of welfare in community-dwelling elderly.

The purpose of this study was to elaborate the relationship between the (13)C CP/MAS NMR spectra and the recrystallization behavior during the storage of troglitazone solid dispersions. The solid dispersions were prepared by either the solvent method or by co-grinding. The recrystallization behavior under storage conditions at 40 degrees C/94% RH was evaluated by the Kolmogorov-Johnson-Mehl-Avrami (KJMA) equation. Solid dispersions prepared by the solvent method or by prolonged grinding brought about inhibition of the nucleation and the nuclei growth at the same time. No differences in the PXRD profiles were found in the samples prepared by the co-grinding and solvent methods, however, (13)C CP/MAS NMR showed significant differences in the spectra. The correlation coefficients using partial least square regression analysis between the PXRD profiles and the apparent nuclei-growth constant or induction period to nucleation were 0.1305 or 0.6350, respectively. In contrast, those between the (13)C CP/MAS NMR spectra and the constant or the period were 0.9916 or 0.9838, respectively. The (13)C CP/MAS NMR spectra had good correlation with the recrystallization kinetic parameters evaluated by the KJMA equation. Consequently, solid-state NMR was judged to be a useful tool for the prediction of the recrystallization behavior of solid dispersions.

Eric J. Grant et al. raised three issues concerning our paper “Hiroshima survivors exposed to very low doses of A-bomb primary radiation showed a high risk for cancers” [1]. Their proposed title was “Radiation unlikely responsible for high cancer rates among distal Hiroshima A-bomb survivors”. However, in response, we suggest that a better title would be “Risk analysis in LSS without using an unexposed group is responsible for the apparent low cancer rates among distal Hiroshima A-bomb survivors”. We discuss the reasons for this proposal here.

Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation. Oral methotrexate (MTX) has anti-inflammatory efficacy but is associated with severe adverse events. Based on the rationale that a conjugation of HA and MTX would combine the efficacy of the two clinically evaluated agents and avoid the risks of MTX alone, we designed HA-MTX conjugates in which the MTX connects with the HA through peptides susceptible to cleavage by lysosomal enzymes. Intra-articular injection of our HA-MTX conjugate (conjugate 4) produced a significant reduction of the knee swelling in antigen-induced arthritis rat, whereas free MTX, HA or a mixture of HA and MTX showed no or marginal effects on the model. The efficacy of conjugate 4 was almost the same as that of MTX oral treatment. Conjugate 4 has potential as a compound for the treatment of osteoarthritis.

A 36-year-old male was diagnosed with acute inferior myocardial infarction (MI). Emergent coronary angiography (CAG) revealed an occlusive lesion in the distal segment of the right coronary artery (RCA). The proximal and distal sites of the lesion were treated with a bare-metal stent (BMS) and a sirolimus-eluting stent (SES), respectively. Nine days later, he underwent elective percutaneous coronary intervention (PCI). Two SESs were implanted for the stenotic lesion in the left anterior descending artery (LAD), in addition to one SES for the mid-stenotic lesion in the left circumflex artery (LCX). Nine months after PCI, follow-up CAG revealed no restenosis at any stent-implanted site. Two years and 4 months after PCI, he was admitted to our hospital because of acute anterior MI. Emergent CAG revealed total thrombotic occlusion in the in-stent proximal site of LAD. Moreover, thrombotic lesions were also observed in in-stent sites: in both BMS of RCA and SES of LCX. He underwent intracoronary aspiration thrombectomy and plain old balloon angioplasty for LAD using intra-aortic balloon pumping. PCI for the thrombotic lesions in RCA and LCX was not performed. Seventeen days after the stent thrombosis, CAG revealed the complete disappearance of thrombi in LAD, LCX, and RCA.

Textual information can be sent as graphic images without being coded in the broadband digital network. By using graphic text, characters or symbols with unsupported fonts can be displayed. Graphical e-mail systems in mobile phones for sending digital photographs are useful in sending graphic text. We researched the visibility of graphic text on the liquid crystal displays in mobile phones comparing with that of font in the mobile phones, by measuring the variables of reading time and visual distance. We also recorded the number of errors, and subjects evaluated the visibility. Graphic text prepared in the JPEG format had nearly the same visibility of the original font. However, it must be noted that visibility deteriorates as the character size become smaller, and as the user become older. We also mention about the possibility of multilingual disaster information system with mobile phones as an application of the graphic text. Graphic text enables easy display of multilingual information by ordinary types of mobile phones which does not support multilingual characters.

Using a multi-touch display on an iPod touch mobile multimedia player, an evaluation experiment was conducted to determine the most legible size for characters displayed on screens of mobile terminals. Subjects enlarged the characters by pinch-out (pinch opening) and/or reduced them by pinch-in (pinch closing) on a multi-touch display with more than one finger, and adjusted to the sizes of alphanumeric or Japanese characters to be the most legible. The characters were displayed positively (black characters on a white background) or negatively (white characters on a black background) using graphic text on the iPod touch. The adjusted sizes of characters and viewing distances were measured and visual angles were calculated. The influence of the positive or negative image display mode and the age of subjects on these legibility parameters is described.

The purpose of this study was to clarify the effect on visual function of gazing at stereoscopic images on a head mounted display (HMD). We measured visual accommodation during stereoscopic viewing while using a HMD by using our original instrument of measurement. The presented image was shown 3-dimensionally on an HMD set up at a visual distance of 3 cm. A spherical object moved back and forth toward and away from the observer in a 10 sec cycle. While the subjects were gazing at the 3D image with both eyes, the lens accommodation in the right eye was measured and recorded. Accommodation to the virtual objects was shown during the viewing of stereoscopic images of 3D computer graphics, but was not shown when the images were displayed without appropriate binocular parallax. It is suggested that stereoscopic moving images on HMD induced the visual accommodation by the expansion and contraction of the ciliary muscle, which is synchronizing with convergence.

Often, people travelling in ships, trains, aircraft, and cars tend to experience motion sickness. It has been reported that even users of virtual environments and entertainment systems experience motion sickness. This visually induced motion sickness (VIMS) is known to be caused by sensory conflict, which is the disagreement between vergence and visual accommodation while observing stereoscopic images. VIMS can be measured by psychological and physiological methods. The simulator sickness questionnaire (SSQ) is a well-known method that is used herein for verifying the occurrence of VIMS. We also quantitatively measure the sway of the centre of gravity of the human body before and during exposure to several types of movies. During the measurement, subjects are instructed to maintain the Romberg posture for the first 60 s and a wide stance (with midlines of the heels 20 cm apart) for the next 60 s. The centre of gravity is projected on a plane that is parallel to the ground. The body sway is recorded as a stabilogram on the plane. According to previous research, a stochastic process is regarded as a mathematical model that generates stabilograms. We propose a method to obtain stochastic differential equations (SDEs) as a mathematical model of the body sway on the basis of the stabilogram. While there are several minimal points of the temporally averaged potential function involved in the SDEs, the stereoscopic images decrease the gradient of the potential function. We have succeeded in estimating the decrease in the gradient of the potential function by using an index called sparse density.

Copoly(β-stearyl l -aspartate-β-benzyl l -aspartate) with various degrees of stearylation was synthesized and secondary and higher ordered structure in solid state was examined from the standpoint of composition and temperature of the copolyaspartates. Copolyaspartate with degree of stearylation 30% caused the reverse transformation, from right-handed α helix to left-handed α helix. The transition from α helix to β form was observed at higher temperature for all copolyaspartates studied. The transitions of helix sense and α helix to β form were irreversible. Copolyaspartate with degree of stearylation > 20% could furthermore cause an intramolecular side chain crystallization of a long alkyl chain. The side chain crystal of such a copolyaspartate melted but a helix backbone was still stable. The helix surrounded by a molten long side chain which plays a role as a solvent could be considered for construction of a thermotropic liquid crystalline phase. Copolyaspartate with a long alkyl side chain was compared with copolyglutamate and the difference of helix stability and side chain crystalline part was interpreted in terms of the competitive hydrogen bonding between NH groups in the backbone and CO groups in the side chain formed in the copolyaspartate.

A 61-year-old man was referred for cardiac investigation because embolism was suspected to be the cause of the sudden onset of severe pain in his right leg after a surgical procedure. The electrocardiogram revealed no atrial fibrillation. Transthoracic echocardiography demonstrated a tumor-like echo at the anterior mitral leaflet, and transesophageal echocardiography documented a mass 13x9mm in size, attached by a stalk to the left atrial side of the anterior mitral leaflet. The other parts of the mitral valve appeared to be intact. At emergency surgery, the mass was located in the center of the left atrial side of the anterior mitral leaflet. It mimicked a myxoma and had a stalk arising from the anterior leaflet. After resection of the mitral valve mass, catheter thrombo-embolectomy was performed and several long pieces of fresh thrombus were removed. On histological examination, the mass consisted of fresh thrombus tissue. No cellular component or myxoma tissue was documented. The distal embolus also consisted of fresh thrombus tissue. This is the first case of a thrombus of the intact mitral valve without atrial fibrillation.

The purpose of this study was to evaluate whether the Telephone Interview for Cognitive Status in Japanese (TICS-J) is accepted among community-dwelling elderly, to examine the correlations among gender, age or the duration of education and the TICS-J, as well as to grasp the subjects with probable cognitive impairment.A total of 12,059 community-dwelling elderly were invited to join the cognitive screening by the TICS-J, among which 3,482 responded, of these we were actually able to measure 2,620 and found out the educational back ground of the 2,431. They counted 1,186 men (age 72.3+/-5.7 (mean+/-SD) years old, duration of education 11.4+/-2.9 years) and 1,245 women (72.4+/-5.8, 10.3+/-2.2). The TICS-J was administered according to the TICS manual. The TICS-J consisted of orientation concerning name, time and place, counting backward from 20 to 1, remembering a word list, 7 serial subtractions, naming of verbal descriptions, repetition, recent memory, praxis and opposites. The subjects were divided into two groups by the duration of education (less than 11 years, or 11 years or more), or four groups by age (65-69, 70-74, 75-79 and 80 years old or more).There were no significant differences of total TICS-J scores between men and women, 34.3+/-3.5 and 34.4+/-3.6, respectively. The mean total score of the high education group (35.3+/-3.0) was significantly higher than that of the low education group (33.3+/-3.8). Moreover, the averages of the total scores decreased according to age increase. The number of the subjects who showed the total TICS-J scores below the cut-off point of 33 was 564 (23.2%).There was no difference between men and women with the average total score of the TICS-J, however, there were correlations between ages and extent of education and their average total scores. The TICS-J is useful to assess the cognitive function of the community-dwelling elderly.

Background: Intravenous myocardial contrast echocardiography (MCE) at rest and during vasodilator stress is a reliable bedside technique for assessment of myocardial perfusion in patients with coronary artery disease. The aim of this study is to evaluate diagnostic accuracy of myocardial perfusion abnormalities using MCE at rest in patients with acute coronary syndrome (ACS). This study is the first MCE multicenter trial for the evaluation of ACS in Japan. Methods: We performed triggered MCE at rest in 102 patients (mean age: 65 ± 11 years) with suspected ACS. We obtained 1:1 and 1:6 end-systolic triggered MCE images at four- and two-chamber views. We detected myocardial ischemia by the appearance of myocardial perfusion abnormalities (defect or reduction) in 1:1 end-systolic triggered MCE image. We assessed the appearance of regional wall motion abnormality (RWMA) at the same time. Quantitative coronary angiography was performed in all patients within 1 week (2.6 ± 2.2 days) after MCE. Results: Eighty-four of 102 (82%) patients were diagnosed ACS (unstable angina: 70 patients; non-ST-segment elevation myocardial infarction: 11 patients; ST-segment elevation myocardial infarction: 3 patients) and demonstrated significant coronary artery stenosis (stenosis = or >75%) that required coronary revascularization therapy. The sensitivity, specificity, and accuracy of myocardial perfusion abnormality by MCE at rest for diagnosing ACS were 79%, 86%, and 83%, respectively. On each coronary artery, the sensitivity, specificity, and accuracy of MCE for diagnosing ACS were 85%, 71%, and 79% in the left anterior descending artery; 70%, 92%, and 84% in the left circumflex artery; 77%, 89%, and 84% in the right coronary artery, respectively. The sensitivity, specificity, and accuracy of RWMA for diagnosing ACS were 49%, 90%, and 71%, respectively, and the sensitivity of MCE for diagnosing ACS was significantly higher than that of RWMA. Conclusion: Intravenous myocardial contrast echocardiography at rest without stress examination is a feasible noninvasive method for accurate diagnosis of ACS. In this multicenter study, MCE at rest improved the diagnostic accuracy of echocardiography for diagnosing ACS.

Objectives The aim of this study was to compare the risk for cancers of A-bomb survivors in the ongoing life span study (LSS) with unexposed groups consisting of the entire populations of Hiroshima prefecture and neighboring Okayama prefecture. Methods The subjects consisted of the Hiroshima group reported in LSS report 12 (LSS-H group) and a control group (the entire populations of Hiroshima and Okayama-HPCG and OPCG, respectively). We estimated the expected number of deaths due to all causes and to cancers of various causes among the exposed survivors of the Hiroshima bombing in the LSS report 12 who died in the follow-up interval at ages similar to those of people in Hiroshima and Okayama prefectures who were aged 0-34 years at the time of the bombing in 1945. We compared the standardized mortality ratio (SMR) of the LSS-H group to that of the HPCG and OPCG (SMR-H and SMRO, respectively). Results Even at low and very low dose categories, the SMR-H and SMR-O were significantly high for all deaths, all cancers, solid cancers, and liver cancers in male subjects, and for uterus and liver cancers in female subjects, respectively. The results show that, if the dose estimations of the dosimetry system 1986 (DS86) are correct, there are significantly increased risks of cancer among even survivors exposed to the very low dose level. Conclusions The dose assumptions of DS86 have been criticized for underestimating doses in areas distant from the hypocenter. The contribution of residual radiation, ignored in LSS, and that of neutrons, underestimated by DS86, is suggested to be fairly high.

Objective To clarify the associations of periodontal damage and tooth loss with atherogenic factors among diabetic patients. Methods We examined the correlations of age, sex, smoking, oral hygiene score, blood pressure, body mass index, and blood chemical data with the mean depth of periodontal pockets or the number of remaining teeth. Patients One hundred outpatients with type 2 diabetes aged 29 to 77 years. Results The mean depth of periodontal pockets was significantly associated with smoking, oral hygiene score, and HbA1c; the Spearman correlation coefficients (r) were 0.220, 0.417, and 0.260, respectively. Age, oral hygiene score, and HbA1c were inversely correlated with the number of remaining teeth (r=-0.306, -0.287, and -0.275, respectively). Serum total cholesterol was significantly correlated with the mean depth of pockets after adjustment for smoking, oral hygiene score, and HbA1c (r=0.211; P=0.044), while serum HDL cholesterol tended to be negatively associated with depth (r=-0.202; P=0.055). Serum HDL cholesterol was also associated with an increased number of teeth, which remained significant after adjustment for age, oral hygiene score, and HbA1c (r=0.202; P=0.048). The estimated glomerular filtration rate was significantly and positively correlated with the number of teeth in the univariate analysis, although consideration of the potential confounding factors somewhat weakened the association (r=0.186; P=0.069). Conclusions We may expect better management of oral health in diabetic patients with control of dyslipidemia in addition to blood glucose.

BACKGROUND The relationships between flow reserves in coronary and peripheral circulation and their modification by statin therapy have not been assessed in the same patients, especially females. METHODS AND RESULTS To assess the effect of pravastatin on both circulation, in 20 postmenopausal female patients with hypercholesterolemia but a low probability of coronary artery disease, the forearm blood flow reserve (FBFR) using the plethysmographic method and coronary flow velocity reserve (CFVR) by Doppler echocardiography were measured before, 4 and 8 weeks after starting the pravastatin and/or diet therapy. At baseline, CFVR and FBFR had a positive linear correlation (r=0.63, p