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Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the MeCP2 gene for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circular RNA (circRNA) and transcribed-ultraconserved region (T-UCR) populations in a mouse model of the disease reveals widespread dysregulation and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of hippocampal samples from affected individuals confirms abnormal levels of several cytoskeleton-related proteins together with key alterations in neurotransmission. Importantly, the glutamate receptor GRIA3 gene displays altered biogenesis in affected individuals and in vitro human cells and is influenced by expression of two ultraconserved RNAs. We also describe post-transcriptional regulation of SIRT2 by circRNAs, which modulates acetylation and total protein levels of GluR-1. As a consequence, both regulatory mechanisms converge on the biogenesis of AMPA receptors, with an effect on neuronal differentiation. In both cases, the noncoding RNAs antagonize MeCP2-directed regulation. Our findings indicate that noncoding transcripts may contribute to key alterations in Rett syndrome and are not only useful tools for revealing dysregulated processes but also molecules of biomarker value., Graphical abstract, circRNAs and T-UCRs identify convergent pathways in mouse and human models of Rett syndrome. GRIA3 biogenesis is altered in affected individuals and human cells influenced by two ultraconserved RNAs. SIRT2 is post-transcriptionally regulated by circRNAs. Noncoding RNAs antagonize MeCP2-directed regulation, highlighting the potential of noncoding RNAs (ncRNAs) as biomarkers in Rett syndrome.

To identify Lysinibacillus strains with the potential to function as plant biostimulants, we screened 10 previously isolated Lysinibacillus strains from the rhizosphere and soil for their plant growth-promoting (PGP) effects. In vitro tests showed that all strains produced indole-3-acetic acid. In primary screening, the PGP effects of these strains were assessed on spinach seedlings grown on Jiffy-7 pellets; strains GIC31, GIC41, and GIC51 markedly promoted shoot growth. In secondary screening, the PGP efficacies of these three strains were examined using spinach seedlings grown in pots under controlled conditions. Only GIC41 exerted consistent and significant PGP effects; therefore, it was selected for subsequent experiments. The results of 6-week glasshouse experiments revealed that GIC41 markedly increased shoot dry weight by ca. 12–49% over that of the control. The impact of fertilization levels on the PGP efficacy of GIC41 was investigated using pot experiments. The application of a specific level of fertilizer was required for the induction of sufficient PGP effects by this strain. The phylogenetic ana­lysis based on the 16S rDNA sequence identified GIC41 as L. xylanilyticus. Collectively, these results show the potential of strain GIC41 to function as a plant biostimulant.

Background: In pancreatic cancer clinical practice guideline 2016, it is recommended to perform pathological diagnosis as much as possible, but priorities and algorithms for diagnostic methods have not yet been established. In recent years, EUS-FNA has become mainstream as a method of collecting tissues from pancreatic disease, but the effect of EUS-FNA on surgical results and prognosis has not been clarified.Aims: To evaluate the diagnostic ability of EUS-FNA and preoperative diagnosis affects surgical outcome and prognosis of pancreatic cancer.Methods: Between January 2005 and June 2017, 293 patients who had surgical resection for pancreatic cancer were retrospectively evaluated. The interested outcomes were diagnostic ability of EUS-FNA and the influence for surgical result and prognosis.Results: The diagnostic sensitivity of EUS-FNA was 94.4%, which was significantly higher than ERCP (45.5%) (pp=0.001). Patients were divided into FNA group (N=160) and non-FNA group (N=133) for each preoperative diagnostic method. In the study of surgical curability R0 between two groups, there was no significant difference in FNA group: 65.0% (104/160) and non-FNA group: 64.7% (86/133), (p=1.000). In the prognostic study, the total of 256 patients with curability R0 or R1, the recurrence rate was 54.3% (70/129) in the FNA group and 57.4% (73/127) in non-FNA group. Moreover peritoneal dissemination occurred 34.3% (24/70) in the FNA group and 21.9% (16/73) in the non-FNA group, neither of which showed significant difference. The median survival time of FNA group and non-FNA group were 955 days and 799 days, respectively, and there was no significant difference between the two groups (Log rank p=0.735). In the Cox proportional hazards model examining factors influencing prognosis, staging, curability and adjuvant chemotherapy were dominant factors, but preoperative diagnostic method(EUS-FNA) itself was not.Conclusions: As a preoperative examination of pancreatic cancer, EUS-FNA was shown to be a safe procedure with high diagnostic ability. It was considered to be the first choice without the influence of surgical curability, postoperative recurrence, peritoneal dissemination and prognosis.

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .).

© The Author(s) 2019. Published by Oxford University Press on behalf of Kazusa DNA Research Institute. Brassica rapa L. is an important vegetable and oilseed crop. We investigated the distribution of the histone mark tri-methylation of H3K27 (H3K27me3) in B. rapa and its role in the control of gene expression at two stages of development (2-day cotyledons and 14-day leaves) and among paralogs in the triplicated genome. H3K27me3 has a similar distribution in two inbred lines, while there was variation of H3K27me3 sites between tissues. Sites that are specific to 2-day cotyledons have increased transcriptional activity, and low levels of H3K27me3 in the gene body region. In 14-day leaves, levels of H3K27me3 were associated with decreased gene expression. In the triplicated genome, H3K27me3 is associated with paralogs that have tissue-specific expression. Even though B. rapa and Arabidopsis thaliana are not closely related within the Brassicaceae, there is conservation of H3K27me3-marked sites in the two species. Both B. rapa and A. thaliana require vernalization for floral initiation with FLC being the major controlling locus. In all four BrFLC paralogs, low-temperature treatment increases H3K27me3 at the proximal nucleation site reducing BrFLC expression. Following return to normal temperature growth conditions, H3K27me3 spreads along all four BrFLC paralogs providing stable repression of the gene.

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Objectives/Hypothesis: To reveal the treatment utility of xenon phototherapy around the stellate ganglion for chronic tinnitus unresponsive to oral medications. Study design: Outcome research. Methods: Subjects were 24 patients (13 men, 11 women, mean age: 66 years) with chronic tinnitus unresponsive to oral medications and 8 patients (5 men, 3women; mean age: 66 years) in the control group. Xenon phototherapy around the stellate ganglion (XPSG) was performed bilaterally for 10 minutes once monthly up to once weekly. At 3 months after the start of xenon phototherapy, treatment outcome was evaluated using the Tinnitus Handicap Inventory (THI) and a Numerical Rating Scale (NRS). Results: No adverse effects of xenon phototherapy were observed. THI and NRS score were correlative. Wilcoxon’s signed rank test revealed a significant improvement in THI (p

© 2015 The Authors. Chinese cabbage (Brassica rapa L. var. pekinensis) is an important vegetable in Asia, and most Japanese commercial cultivars of Chinese cabbage use an F1 hybrid seed production system. Self-incompatibility is successfully used for the production of F1 hybrid seeds in B. rapa vegetables to avoid contamination by non-hybrid seeds, and the strength of self-incompatibility is important for harvesting a highly pure F1 seeds. Prediction of agronomically important traits such as disease resistance based on DNA markers is useful. In this dataset, we identified the S haplotypes by DNA markers and evaluated the strength of self-incompatibility in Chinese cabbage inbred lines. The data described the predicted disease resistance to Fusarium yellows or clubroot in 22 Chinese cabbage inbred lines using gene associated or gene linked DNA markers.

Since the first demonstration of the Virtual Robot Competition, USARSim has been used as the simulation interface and environment. The underlying simulation platform, Unreal Engine, has seen three major upgrades (UT2004, UT3 and UDK). These upgrades required a whole new USARSim simulator to be built from scratch. Yet, between those versions the USARSim interface has not been modified, which made USARSim a stable platform for more than 10 years. This stability allowed developers to concentrate on their control and perception algorithms. This paper describes a new prototype of the USARSim interface; implemented as plugin to Gazebo, the simulation environment native to ROS. This plugin would facilitate a shift of the maintenance of the simulation environment to the Open Source Robotics foundation and attract new teams to the Virtual Robot Competition.

Background PRKAR1A gene encodes the type 1A regulatory subunit of protein kinase A. The mutation of this gene causes Carney complex which is an autosomal dominant multiple neoplasia syndrome characterized by spotty pigmentations, endocrine overactivity and cardiac myxoma. We hypothesized that cardiac myxoma may be associated with PRKAR1A gene mutation and determined whether mutation in the PRKAR1A gene is the cause of familial and sporadic cardiac myxoma. Methods We studied seven patients (three males and four females) with cardiac myxoma. Two of them had familial cardiac myxoma complicated with Carney complex. The other five patients were characterized as sporadic cardiac myxomas. We analyzed the PRKAR1A gene of all patients by the polymerase chain reaction (PCR)–single-strand conformation method, followed with direct sequence analysis. Results We identified a novel mutation (494delTG) in exon 4A of the PRKAR1A gene in the patients with Carney complex. A 16-year-old proband had a left atrial myxoma, pituitary adenoma and skin pigmentation. His father also had left atrial myxoma and skin pigmentation. In contrast, no mutations in the PRKAR1A gene were identified in the other five patients with sporadic cardiac myxomas. Conclusions These results suggest that mutation of the PRKAR1A gene may be associated with familial cardiac myxoma in Carney complex but may not be associated with sporadic cardiac myxoma.

Summary Background Bowen's disease in the genital area is generally considered to be caused by mucosal high-risk human papillomaviruses (HPVs). However, the detection rate and spectrum of HPVs in extragenital Bowen's disease are various and it is not clear to what extent HPV is involved in its pathogenesis. Objectives To assess the degree of association of HPV in extragenital cases by examining detection rates, types, quantities and localization of HPV. Methods A polymerase chain reaction (PCR) approach that we had previously established, which can give sensitive detection of a broad range of HPVs from cutaneous [including epidermodysplasia verruciformis-related HPVs (EV-HPVs)] to mucosal HPVs, was applied to samples from 41 patients with extragenital Bowen's disease and normal skin samples from 48 individuals. Semiquantitative L1-PCR and tyramide-based in situ hybridization (ISH) were also employed for positive cases. Results HPVs belonging to the mucosal high-risk group were detected in three patients with Bowen's disease (7%; two HPV 16 and one HPV 33), with 101−103 copy equivalents per diploid amount of cellular DNA. They were distributed among most nuclei of tumour cells but in none of the cells of adjacent normal skin. HPVs belonging to the cutaneous group were detected in two patients (5%; HPV 27 and HPV 76) at 10−2−10−3 copy equivalents, the same level as in a normal skin specimen positive for type 23 EV-HPV. No positive signals were observed by ISH. Conclusions HPVs belonging to the mucosal high-risk group may participate in the development of extragenital Bowen's disease.

Brugada Syndrome and Sodium Channel Blockade. Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel a subunit, which can lead ventricular fibrillation and sudden death. Inattentive use of antiarrhythmic drugs potentially triggers fatal cardiac arrhythmias through further reduction of sodium current (I N a ). We studied the molecular mechanism underlying a case of Brugada syndrome that showed no response to a class Ic antiarrhythmic drug. Molecular genetic studies of a patient with Brugada syndrome identified a novel mutation in SCN5A, which causes substitution of serine for asparagine (N406S) in S6 of domain I (IS6). The provocation test with pilsicainide, a class Ic antiarrhythmic drug, failed to exacerbate ST-segment elevation in this case. Electrophysiological analyses of the N406S-mutant channel expressed together with the β1 subunit in HEK293 cells showed that the voltage dependence of activation was positively shifted by 16 mV and that intermediate inactivation was enhanced. Whereas tonic block by pilsicainide was not changed in the N406S channel, use-dependent block by pilsicainide was almost completely abolished, consistent with the clinical findings of the negative provocation test. In contrast, the N406S channel showed stronger use-dependent block by quinidine than the wild-type channel. We demonstrate a novel Brugada mutation N406S, which is associated with the discordant effects on blocking actions of antiarrhythmic drugs as well as the multiple channel gating defects. We emphasis that an antiarrhythmic drug may exert unpredicted effects in patients with channel mutations.

Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha-subunit, and potentially leads to ventricular fibrillation and sudden death. We report a case of a novel SCN5A mutation associated with Brugada syndrome. A 51-year-old man suffered from recurrent nocturnal syncopal attacks due to polymorphic ventricular tachycardia. His electrocardiogram showed ST-segment elevation in V1-V3 leads, but there was no evidence of structural heart disease. DNA sequence analysis of SCN5A in this patient revealed a missense mutation (R282H) in the S5-pore region of domain I. This mutational change was not present in 100 healthy Japanese controls. In the patient's family, a 36-year-old brother had died suddenly. Genetic analysis identified two other carriers of the R282H mutation, who had ST-segment elevation and slightly increased QRS widths, but they experienced no syncopal episodes or ventricular fibrillation. Electrophysiological investigation of the R282H mutant channel expressed in cultured cells showed a severe reduction in sodium current density and a mild positive shift of activation curve. R282H did not enhance intermediate inactivation. Single-channel conductance of R282H was slightly decreased compared with WT. The electrophysiological characteristics of the R282H channel are suggested to be closely related to the clinical phenotype of Brugada syndrome.

Objective: The aim of this study was to investigate whether the bioequivalence range applied world-wide, 80 - 120%, ensures the clinical equivalence. We investigated the relationship between variations of AUC and C m a x and those of AUEC based on a direct link model using a simulation technique. Methods: A one-compartment pharmacokinetic model and a sigmoid E m a x pharmacodynamic model were used. Regarding the influence of AUC variation on AUEC variation, the total clearance value was changed from 80% to 120%. Regarding the influence of C m a x variation on AUEC variation, C m a x was changed from 80% to 120% under a constant AUC value estimated from zero to four elimination half-lives of a drug. Results: In the case that Υ, shape factor, is less than 1, irrespective of the ratio of EC 5 0 to C m a x , AUEC is within the acceptable range as long as AUC and C m a x are within the acceptable range for bioequivalence, BE. In the case that Υ is more than 1, and C m a x is lower than EC 5 0 , AUEC may fail within the acceptable range in the case that AUC and C m a x are within the acceptable range for BE. Conclusion: These results suggest that 20% difference for BE does not always ensure the clinical equivalence for all drugs.

Background: Hypertrophic cardiomyopathy (HCM) is caused by mutations in the genes that encode sarcomeric proteins. Although some patients with HCM have shown dilated cardiomyopathy (DCM)-like features, the relationship between genotype and histologic findings is not well known. Hypothesis: Family members with the same gene mutation may show the same histopathologic changes and clinical manifestations. Methods: Siblings with HCM caused by an Arg92Trp mutation in the cardiac troponin T gene, showing DCM-like features, were examined. Results: The patients were a 69-year-old woman and her 57-year-old brother who both died from congestive heart failure. Their autopsies revealed the same histopathologic findings in the heart. The anterior walls and interventricular septa of their hearts were replaced with extensive fibrosis and showed thinning. Myocyte hypertrophy, disarray, and thickened medial walls of the intramural coronary arteries were found. On electron microscopy, the number of mitochondria was seen to be increased and they formed many clusters. Conclusions: Patients with HCM caused by an Arg92Trp mutation in the cardiac troponin T gene may have the same histopathologic findings, whichmay result in DCM-like features.

Objective: To evaluate the relation between QT variables and disproportion of left ventricular wall hypertrophy in patients with hypertrophic cardiomyopathy. Design: Retrospective analysis of the results of echocardiography and electrocardiography. Setting: University hospital (tertiary referral centre). Patients: 70 patients with hypertrophic cardiomyopathy were divided into four groups according to the distribution of left ventricular wall hypertrophy on cross sectional echocardiography: group A—hypertrophy confined to the interventricular septum; group B—hypertrophy confined to the interventricular septum and left ventricular anterior wall; group C—hypertrophy confined to the interventricular septum, left ventricular anterior wall, and lateral free wall; group D—hypertrophy involving all portions of the left ventricle. Main outcome measures: QT intervals and QT dispersion in precordial six lead ECGs. Results: There were no significant differences in the maximum left ventricular wall thickness among the four groups, and maximum and minimum QTc intervals also did not differ. QTc dispersion was increased significantly in groups A and B compared with groups C and D. Dispersions of the interval from the J point to the end of the T wave (JTc dispersions) in groups A and B were also increased significantly compared with groups C and D. By linear regression analysis, QTc and JTc dispersions correlated with the ratio of the interventricular septal thickness to left ventricular posterior wall thickness (p = 0.0152 and p = 0.0075, respectively). Conclusions: QT dispersion may be affected by not only electrical inhomogeneity but also by morphological inhomogeneity of the left ventricle in patients with hypertrophic cardiomyopathy.

Background: Patients with hypertrophic cardiomyopathy (HCM) associated with a deletion of lysine 183 (K183del) in the cardiac troponin I (cTnI) gene suffer sudden cardiac death at all ages. However, the correlation between QT variables and sudden cardiac death in these patients remains uncertain. Hypothesis: We evaluated the correlation between QT variables and sudden cardiac death and/or ventricular tach-yarrhythmia (SCD/VT) in patients with HCM associated with the cTnI mutation. Methods: We analyzed 10 probands with HCM associated with the cTnI gene K183del and their family members. The subjects were divided into three groups: Group A (n = 7), mutation carriers with SCD/VT; Group B (n = 16), mutation carriers without SCD/VT; Group C (n = 24), no mutation carriers. QT intervals were corrected using Bazett's formula. Results: Maximum QTc and corrected QT dispersion were significantly longer in Groups A and B than in Group C. However, there were no differences in either parameter between Groups A and B. On the contrary, the peak-to-end interval of T wave/QT interval in V5 (Tpe) in Group A was significantly longer than that in Groups B and C. Logistic regression analysis revealed that Tpe was a good clinical predictor for SCD/VT in patients with HCM in this study. Conclusions: These results suggest that Tpe rather than QT dispersion may be one of the best predictors for SCD/VT in patients with HCM associated with the K183del mutation in the cTnI gene.

Background: In patients with essential hypertension (HT), proportional (symmetric) left ventricular hypertrophy (LVH) is common. In contrast, hypertrophic cardiomyopathy (HCM) is characterized by disproportional LVH and, in particular, asymmetric septal hypertrophy (ASH); however, some hypertensive patients also develop ASH. It has not been determined whether such cases represent a distinct type of hypertensive LVH or HCM combined with hypertension. Hypothesis: The study was undertaken to evaluate sympathetic activity in the interventricular septum in patients with HT and ASH or in patients with HCM. Methods: The patients were evaluated by I–123 metaiodobenzylguanidine (MIBG) and thallium-201 (201Tl) single-photon emission computed tomography (SPECT), respectively. They were divided into three groups: patients with essential HT and symmetric septal hypertrophy (Group A), patients with HT and ASH (Group B), and patients with HCM and ASH (Group C). Results: Compared with the lateral wall, early uptake of MIBG in the septum was significantly higher in Group B than in Group A, but not significantly different between Groups A and C. Compared with the lateral wall, early uptake of 201Tl in the septum did not differ among the three groups. No significant difference in the MIBG clearance in the lateral wall was seen among the three groups. By contrast, MIBG clearances in the septum and apex were significantly greater in Group C than in Groups A and B. There was an inverse correlation between systolic thickening and MIBG clearance in the septum. Conclusion: These findings suggest that sympathetic activity in the septum differs between patients with HT and ASH and patients with HCM.

Fas/Apo-1 (CD95)-Fas ligand (FasL) system has been implicated in the suppression and stimulation of immune responses. We examined the induction of antitumor immunity with neuroblastoma Neuro-2a cells transfected with FasL cDNA (Neuro-2a+FasL). Neuro-2a+FasL cells expressed FasL on the cell surface and secreted soluble FasL. Histologic and flow cytometric analyses revealed that Neuro-2a+FasL cells caused neutrophils to infiltrate into the injected site, resulting in strong inflammation. Neutrophil infiltration was inhibited by treatment with anti-FasL mAb and did not occur in Fas-deficient lpr mice. Normal syngeneic mice rejected Neuro-2a+FasL cells after the inflammation and acquired tumor-specific protective immunity. CD8+ T cells were responsible for the antitumor immunity. Neuro-2a+FasL cells formed tumors after far longer latency compared with mock-transfected Neuro-2a+Neo cells in nude mice, and immune competent mice rejected Neuro-2a cells but not sarcoma S713a cells when they were injected with Neuro-2a+FasL cells in a mixture. These results suggest that neutrophils attracted through the Fas-FasL system may impair tumor cells by inflammation at the initial step, followed by development of CD8+ T cell-dependent tumor-specific antitumor immunity, leading to complete eradication of tumor cells. Importantly, the treatment with Neuro-2a+FasL cells exhibited therapeutic efficacy against growing tumors.

123I-labelled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) is a modified long-chain fatty acid that shows some beta-oxidation. Some basic aspects of this fatty acid, including myocardial uptake, distribution, clearance and differences from 201 Tl myocardial perfusion, have yet to be evaluated. An average of 150 MBq of 123 I-9MPA was injected intravenously into 16 patients with coronary artery disease. Planar images were obtained 45, 120 and 240 min post-injection, and single photon emission tomography (SPET) was performed at the initial (5 min), middle (45 min) and late (120 min) phases after injection. Myocardial uptake and clearance were evaluated by planar imaging, and a segmental comparison between 123 I-9MPA and reinjection or resting 201 Tl was performed on the SPET images. 123 I-9MPA showed good uptake between 5 and 60 min, but a severe decrease was seen after 120 min in three (19%) patients. The heart-to-mediastinum ratio was 1.68 ± 0.19, 1.55 ± 0.19 and 1.40 ± 1.40 at 45, 120 and 240 min, respectively. The washout rate after background subtraction was 28% for 45 min to 2 h and 47% for 45 min to 4 h. The segmental comparison (n = 182) between 123 I-9MPA and 201 Tl showed complete agreement of 72, 75 and 65% at 10, 45 and 120 min, respectively. The grading of the uptake of 123 I-9MPA was less than that of 201 Tl in 20-30% of the segments, indicating myocardial fatty acid metabolic impairment relative to perfusion. The regional clearance from 5 to 120 min in the reduced-count region was lower than that in the normal region (28 ± 7% vs 36 ± 8%, P < 0.01). All 123 I-9MPA SPET images showed good contrast if the data were acquired within 60 min. Based on the clearance of 123 I-9MPA from the myocardium, imaging within 120 min is desirable. A mismatch of fatty acids and perfusion was seen in one-quarter of patients, and differential regional clearance may be clinically significant and should be investigated.

In order to understand nature of building blocks of galaxies in the early universe, we investigate "genuine irregular galaxies (GIGs)" in the nearby universe. Here, GIGs are defined as isolated galaxies without regular structures (spheroid, bulge, disk, bar, spiral arm, and nucleus). Using the results of two excellent studies on galaxy morphology based on the Sloan Digital Sky Survey (SDSS), we obtain a sample of 66 irregular galaxies. We carry out new classification of them into GIGs and non-GIGs which have regular structure or show evidence for galaxy interaction, by using the SDSS Data Release 10 images. We then find that a half of these irregular galaxies (33/66) are GIGs and obtain an unambiguous sample of 33 GIGs for the first time. We discuss their observational properties by comparing them with those of elliptical, S0, spiral galaxies, and irregular galaxies without the GIGs. We find that our GIGs have smaller sizes, lower optical luminosities, bluer rest-frame optical colors, lower surface stellar mass densities, and lower gas metallicity than normal galaxies. All these properties suggest that they are in chemically and dynamically younger phases even in the nearby universe., Comment: submitted to the Astrophysical Journal on 21st October, 2013

AIMS: To investigate collagen remodelling in the interstitium of the heart in patients with diabetes. METHODS: Immunohistochemical study of the biopsied myocardium using type specific anticollagen antibodies (I, III, IV, V, VI) was performed in 12 patients with non-insulin dependent diabetes mellitus and six non-diabetic patients. There was no history of hypertension or coronary artery stenosis in any of the patients. RESULTS: Noticeable accumulations of collagen types I, III, and VI in the myocardial interstitium were recognised in both groups, but little accumulation of types IV or V was found. Types I and III mainly stained in the perimysium and perivascular region, while type VI predominantly stained in the endomysium. There was no disease specific accumulation of collagen in diabetes mellitus. The percentage of total interstitial fibrosis in the myocardium was significantly higher in the diabetic group than in the control group (p < 0.05). Although the percentages of collagen types I and VI did not differ between the two groups, the percentage type of III was significantly higher in the diabetic group than in the controls (p < 0.01). CONCLUSIONS: Collagen remodelling mainly as a result of an increase in collagen type III in the perimysium and perivascular region, occurs in the hearts of patients with diabetes.

To determine whether asymmetrical septal hypertrophy (ASH) in patients with essential hypertension (HT) is a type of hypertensive left ventricular (LV) hypertrophy or hypertrophic cardiomyopathy (HCM) combined with HT, we investigated a group of 7 hypertensive patients with ASH compared with 12 HCM patients and 10 healthy controls using radionuclide angiography and right ventricular endomyocardial biopsy. The LV time-volume curve and its first and second derivative curves were constructed from cardiac output and time-activity curves constructed by combined forward and reverse-gating from the R wave. The LV wall thickness and ejection fraction were significantly greater in both the HT and HCM groups than in the control group, whereas there were no differences in these indices between the HT and HCM groups. Rapid filling volume index and rapid filling fraction showed significantly lower values in the HCM group than in the control group (p < 0.005). In contrast to the HCM group, these indices in the HT group did not differ from those in the control group. The time to peak filling rate was prolonged in the control, hypertension, and HCM groups in increasing order. Histopathological study revealed a higher incidence of myocardial cell disarray in the HCM than in the HT group. The above results suggest that ASH in hypertensive patients is a type of hypertensive LV hypertrophy.

Summary: The current situation of bovine virus diarrhoea-mucosal disease (BVD-MD) virus infections is briefly reviewed, with special reference to problems arising from fetal infection in the Hokkaido district, a northern island of Japan. The results of some investigations on BVD-MD virus carried out in Japan are also described. Although bovine congenital anomalies caused by BVD-MD virus and mucosal disease may be late sequelae to fetal infection and occur sporadically, it appears that their incidence and importance in the Hokkaido district have increased in recent years. The results of antigenic characterisation of the recent isolates and serologic survey on bovine sera suggested that BVDMD viruses with various antigenic properties are widespread among cattle in the district. There is also a possibility that clinical manifestations in infected cattle may differ with the antigenicity of the viruses. In addition, the virological investigations on experimental and naturally occurring mucosal disease suggested that persistently infected cattle are populations at high risk of developing mucosal disease. The antigenic homology of non-cytopatho genic persistent virus and cytopathogenic virus is probably an important factor in the pathogenesis of mucosal disease.

Thyroid carcinoma usually is characterized by a nonfunctioning or "cold" nodule depicted on the Tc-99m scan. Twelve patients with functioning "hot" thyroid nodules underwent thyroidectomy (nine hemithyroidectomies, two nodulectomies, and one subtotal thyroidectomy). Histologic examination revealed that five patients (42%) had malignant nodules (papillary carcinoma in two and follicular carcinoma in three). Of the seven patients with benign nodules, five had follicular adenoma and two had adenomatous hyperplasia. TI-201 scanning (early and delayed) was performed at the same time as Tc-99m scanning. Only one of the seven benign nodules showed accumulation on the delayed TI-201 scan, whereas all five malignant nodules showed accumulation. The delayed TI-201 scan is useful for the differentiation of benign from malignant nodules that show accumulation of Tc-99m pertechnetate.

Konno T, Shimizu M, Ino H, Fujino N, Hayashi K, Uchiyama K, Kaneda T, Inoue M, Masuda E, Mabuchi H (Kanazawa University, Kanazawa, Japan). Phenotypic differences between electrocardiographic and echocardiographic determination of hypertrophic cardiomyopathy in genetically affected subjects. J Intern Med 2005; 258: 216-224. Objectives. In the molecular era, two types of phenotypic differences are recognized between electrocardiography (ECG) and echocardiography in hypertrophic cardiomyopathy (HCM); ECG abnormalities in carriers without left ventricular hypertrophy (LVH), and normal ECG patterns in carriers with LVH. The goal of this study was to evaluate the diagnostic value of ECG for detecting carriers without LVH, and also to assess normal ECG patterns in carriers with LVH from the genetic standpoint of HCM. Setting. A matched case-control study in a university hospital and general hospitals in Japan. Patients and design. ECG and echocardiographic findings were analysed in 173 genotyped subjects (107 genetically affected, 66 unaffected) from families with disease-causing mutations in four genes. Results. ECG abnormalities were found in 18 (54.5%) of 33 nonhypertrophic carriers, but only nine (13.6%) of 66 noncarriers (P < 0.001). For detecting nonhypertrophic carriers, ST-T abnormalities showed the highest accuracy amongst the three major ECG criteria. In contrast, normal ECG patterns were found in eight (10.8%) of 74 carriers with LVH. The sensitivity of ECG for detecting carriers with LVH in families with the cardiac myosin-binding protein C, cardiac troponin T and cardiac troponin I gene mutations was 83%. 88% and 94% respectively. Conclusion. These findings suggest that ECG may have favourable diagnostic value even for detecting nonhypertrophic carriers. Furthermore, diagnostic value of ECG may differ according to the genes involved. Our data may contribute to interpretation of phenotypic differences between ECG and echocardiography from the viewpoint of molecular genetics of HCM.

Deranged oxidative metabolism is a property of many tumour cells. Oxidation of the deoxynucleotide triphosphate (dNTP) pool, as well as DNA, is a major cause of genome instability. Here, we report that two Y-family DNA polymerases of the archaeon Sulfolobus solfataricus strains P1 and P2 incorporate oxidized dNTPs into nascent DNA in an erroneous manner: the polymerases exclusively incorporate 8-OH-dGTP opposite adenine in the template, and incorporate 2-OH-dATP opposite guanine more efficiently than opposite thymine. The rate of extension of the nascent DNA chain following on from these incorporated analogues is only slightly reduced. These DNA polymerases have been shown to bypass a variety of DNA lesions. Thus, our results suggest that the Y-family DNA polymerases promote mutagenesis through the erroneous incorporation of oxidized dNTPs during DNA synthesis, in addition to facilitating translesion DNA synthesis. We also report that human DNA polymerase eta, a human Y-family DNA polymerase, incorporates the oxidized dNTPs in a similar erroneous manner.

Spontaneous damage to DNA as a result of deamination, oxidation and depurination is greatly accelerated at high temperatures. Hyperthermophilic microorganisms constantly exposed to temperatures exceeding 80 degrees C are endowed with powerful DNA repair mechanisms to maintain genome stability. Of particular interest is the processing of DNA lesions during replication, which can result in fixed mutations. The hyperthermophilic crenarchaeon Sulfolobus solfataricus has two functional DNA polymerases, PolB1 and PolY1. We have found that the replicative DNA polymerase PolB1 specifically recognizes the presence of the deaminated bases hypoxanthine and uracil in the template by stalling DNA polymerization 3-4 bases upstream of these lesions and strongly associates with oligonucleotides containing them. PolB1 also stops at 8-oxoguanine and is unable to bypass an abasic site in the template. PolY1 belongs to the family of lesion bypass DNA polymerases and readily bypasses hypoxanthine, uracil and 8-oxoguanine, but not an abasic site, in the template. The specific recognition of deaminated bases by PolB1 may represent an initial step in their repair while PolY1 may be involved in damage tolerance at the replication fork. Additionally, we reveal that the deaminated bases can be introduced into DNA enzymatically, since both PolB1 and PolY1 are able to incorporate the aberrant DNA precursors dUTP and dITP.

Background: The relationship between the extent of myocardial interstitial fibrosis, the percentage of each type of collagen, and cardiac function in patients with hypertrophic cardiomyopathy (HC) has not been established. Hypothesis: The study aimed to establish that increases in some types of collagen may correlate with cardiac dysfunction. Methods: Mallory-Azan staining and immunohistochemical staining by the avidin-biotin-complex (ABC) method using anticollagen antibodies were performed on the myocardial biopsy specimens in 35 patients with HC, and the percentage and type of collagen present was determined. Left ventricular (LV) function was evaluated by cardiac catheterization and ventriculography. Results: The percentage of myocardial interstitial fibrosis correlated highly with indices of LV diastolic and systolic function. The amount of type III collagen correlated significantly with the peak negative dp/dt, the rapid filling volume/ stroke volume, and the ejection fraction (EF). Significant correlations also were noted between the amount of type VI collagen and peak negative dp/dt, peak positive dp/dt, and EF. Type I collagen did not correlate with any of the LV function indices, and type IV collagen correlated only with peak ejection rate. Type V collagen did not accumulate substantially in the myocardial interstitium. Conclusions: The progression of myocardial interstitial fibrosis in the HC heart adversely impacts both the diastolic and systolic function of the LV. Increases in the percentage of type in and VI collagen correlate with cardiac dysfunction.

Of pediatric patients with purulent meningitis seen at the institutions listed in the title page of this paper between 1986 and 1994, 93 patients treated with antibiotics and dexamethasone (DXM) were compared with 91 patients treated with antibiotics alone. The patients receiving antibiotics with dexamethasone achieved overall improvement in inflammatory symptoms and signs and cerebrospinal fluid findings and became afebrile significantly earlier than those receiving antibiotics alone. However, some of the patients became febrile again. The secondary fever rate for the DXM group was much higher than that for the antibiotic alone group (p0.0001). In most of the rebounded cases, the body temperature rose above 38 degrees C and remained elevated for 2-4 days. Cerebrospinal fluid (CSF) was cultured daily in 54 and 32 patients receiving antibiotics with and without DXM, respectively. Although this study was not a controlled study in a strict sense, these patients compared. In both groups, the CSF became mostly culture-negative within 48 hours. In a few patients receiving DXM, however, it became culture-negative after 72 hours or longer. DXM caused an adverse effect in a patient with meningitis caused by Streptococcus pneumoniae. The adverse effect was mild gastrointestinal bleeding, which recovered spontaneously. From the findings described above, the use of DXM combined with antibiotic therapy was considered to accelerate the relief from fever and improvement of inflammatory symptoms and signs and CSF findings. The body temperature rose again in more than half of the patients receiving DXM, but fell to normal spontaneously without treatment. The elevation doubtlessly could not be distinguished from recurrence of the meningitis itself or complications. It seems to be likely that no treatment but careful observation is required even if the fever recurs as far as the CSF findings showed favorable progress with excelluent general conditions. When DXM is given, it is essential that CSF tests and culture are repeated during the early stages and the progress is monitored carefully.

A 58 year old man with a history of cerebral infarction was admitted to hospital with chest discomfort and dyspnoea. He had no history of precordial chest discomfort. Angiography and left ventriculography showed that coronary fistulas connected the coronary sinus with the left circumflex and right coronary arteries. His coronary sinus did not communicate with the right atrium, draining instead into a persistent left superior vena cava. Angiography showed a mass, suspected to be a thrombus, in the coronary sinus. Transoesophageal echocardiography confirmed the presence of a mass in the atrioventricular groove. The mass was removed at surgery and proved to be a cavernous haemangioma. Keywords: coronary fistulas; persistent left superior vena cava; cavernous haemangioma; coronary sinus

Expression of the cdc2 gene is induced steeply at the G1-S-phase boundary. The previous analysis of promoter elements that confer inducibility revealed the enhancer at positions -276 to -265. Enhancer activity is suppressed by the upstream sequence that seems to contain the silencer. The silencer element was analyzed by fusing several oligonucleotides covering the silencer region upstream of the enhancer in the cdc2 promoter-luciferase construct. Oligonucleotide IV, which suppressed enhancer activity, was further dissected by the introduction of base substitutions and by forming the DNA-protein complexes with quiescent rat cell extract. The silencer element, AAGTAGTAAAAATA, was finally identified at positions -374 to -360, which resembles the enhancer sequencer but contains extra internal AG residues. Silencer complexes were formed with the quiescent cell extract, whereas the amounts of the complexes decreased with the progression of the cell cycle, and nearly no complexes were formed with the late G1 cell extracts. Conversely, the enhancer complex begins to be formed after late G1. Among the three silencer complexes, the formation of the slowest-migrating complex (complex III) was inhibited by the enhancer sequence, suggesting that a common factor interacts with both the silencer and enhancer. These results suggest that the conversion of complex formation from the silencer to the enhancer site regulates the induction of cdc2 promoter activity at the G1-S-phase boundary.

Left ventricular function during exercise and recovery was investigated in patients with angina pectoris, ST segment depression during exercise and angiographically normal coronary arteries (syndrome X) using a continuous left ventricular function monitor with cadmium telluride detector (CdTe-VEST). Fourteen patients with syndrome X and 14 patients with atypical chest pain without ST segment depression during exercise and normal coronary arteries (control group) performed supine ergometric exercise after administration of 740-925 MBq of technetium-99m labelled red blood cells, and left ventricular function was monitored every 20 s using CdTe-VEST. Left ventricular ejection fraction (EF) response was impaired (or = 5% increase from rest to peak exercise) in 11 or 14 patients with syndrome X but in none of the control patients. Resting EF was similar in the two groups (62.1% +/- 6.7% in patients with syndrome X, 61.9% +/- 6.2% in controls); however, EF increase from rest to peak exercise was lower in syndrome X (-3.1 +/- 9.5% vs 14.7% +/- 7.4%, P0.001). After cessation of exercise, all patients showed rapid EF increase over baseline and this EF overshoot was lower (19.3% +/- 8.3% vs 26.4% +/- 7.3%, P0.001) with the time to EF overshoot longer (114 +/- 43 s vs 74 +/- 43 s, P0.05) in patients with syndrome X. Thus, in patients with syndrome X, left ventricular dysfunction was frequently observed during exercise in spite of normal epicardial coronary arteries.

X-ray diffraction illustrates that a two-dimensional smectic liquid crystal is formed in a melting pro- cess of an anisotropic, incommensurate monolayer of n-propanol physisorbed on graphite. In this phase a hydrogen-bonded head-to-head association of molecules is arranged in rows with their long axes on average normal to the row. Parallel to the rows, there is only short-range translational order of the molecules

OBJECTIVE--To investigate left atrial chamber stiffness and its influence on left atrial and left ventricular functions in hypertrophic cardiomyopathy. DESIGN--Prospective study. SETTING--Department of internal medicine in a university teaching hospital. PATIENTS--Five control subjects, six patients with essential hypertension, and 11 patients with hypertrophic cardiomyopathy. INTERVENTIONS--Measurement of left atrial pressure by a tip micromanometer and of real-time left atrial volume from left atrial cineangiograms. MAIN OUTCOME MEASURE--Left atrial stiffness constant determined by fitting the ascending limb of the v loop of the left atrial pressure-volume relation to an exponential curve. RESULTS--The mean (SD) left atrial chamber stiffness constant was significantly larger in patients with hypertrophic cardiomyopathy than in controls (0.063 (0.018) v 0.041 (0.006), p < 0.05) and was correlated with left ventricular wall thickness (r = 0.560, p < 0.01). Left atrial reservoir volume (left atrial emptying volume before atrial contraction) was significantly smaller in patients with hypertrophic cardiomyopathy than in the controls (7.3 (2.1) v 12.5 (4.4) ml/m2, p < 0.01) and was inversely correlated with the left atrial chamber stiffness constant (r = -0.598, p < 0.01). The cardiac index was inversely correlated with the left atrial chamber stiffness constant (r = -0.542, p < 0.01). CONCLUSIONS--Left atrial chamber stiffness was increased in patients with hypertrophic cardiomyopathy and this affected the left atrial reservoir function. This may in turn have affected cardiac output.

OBJECTIVE--To investigate the relation between regional myocardial sympathetic nerve activity and the electrocardiographic and cardiac functional changes in hypertrophic cardiomyopathy. DESIGN--A retrospective study to compare the findings of myocardial scintigraphy with iodine-123 metaiodobenzylguanidine (MIBG) and the serial electrocardiographic changes. SETTING--Myocardial scintigraphy was performed with iodine-123 MIBG and thallium-201 and single photon emission computed tomography (SPECT) in the division of nuclear medicine of Kanazawa University Hospital. Both SPECT studies were performed within a week. PATIENTS--22 patients with hypertrophic cardiomyopathy classified according to their serial electrocardiographic changes--namely, 15 patients with an increase in or the appearance of a negative T wave (group A) and seven patients with a conduction disturbance or a decrease in or disappearance of the negative T wave (group B). The mean follow up period was 45 (range 12-143) months. RESULTS--Group B showed a high rate of decreased activity or defects in MIBG uptake compared with group A (p less than 0.005). The areas of decreased activity or defects corresponded with the hypertrophied portion of the left ventricular wall. Although the early myocardial uptake (MIBG: thallium ratio) was similar in both groups, the mean (SD) MIBG clearance rate was significantly higher (p less than 0.05) in group B (0.25 (0.17)) than in group A (0.10 (0.15)). CONCLUSION--Abnormalities of regional myocardial sympathetic nerve activity may be important in patients with hypertrophic cardiomyopathy and suspected progression of myocardial damage.

In diabetes mellitus, the development of myocardial injury secondary to hypertension and coronary arteriosclerosis poses a major clinical problem. In addition, this issue has been the focus of great interest and it has been demonstrated that the existence of myocardial injury is not attributable to hypertension or coronary arteriosclerosis. It has also been reported in various pathological studies that even in the diabetic heart without hypertension and coronary artery lesions, various histological changes such as myocyte hypertrophy, perivascular fibrosis, and interstitial fibrosis are present (1–3). On the other hand, the existence of functional abnormalities such as left ventricular systolic and diastolic dysfunction has also been reported (4–12). It is, however, not yet clear which pathological changes account for these functional disturbances in the diabetic heart. To clarify this point we investigated the relation between systolic and diastolic function and the myocardial histological findings in diabetic patients.

Myocardial interstitial fibrosis is an important microscopic feature of hypertrophic cardiomyopathy. To determine whether interstitial fibrosis of the myocardium in hypertrophic cardiomyopathy and essential hypertension differ in quality or quantity, and to determine whether fibrosis affects cardiac function directly, we measured the percentage of fibrosis in patients of both categories and compared the severity of fibrosis with several cardiac functions. Left and right ventricular endomyocardial biopsies were performed in 25 patients with essential hypertension and in 19 patients with hypertrophic cardiomyopathy. Interstitial fibrosis was classified into four different microscopic types, and the percentage of total and of each type was calculated using the point-counting method. Although the percentage of total fibrosis was similar between the two groups, the type of fibrosis was different. There was no correlation between the percentage of total fibrosis and the mean size of myocytes in either group. Although there was a significant correlation between the percentage of total fibrosis and the thickness of the interventricular septum in hypertrophic cardiomyopathy, such correlation was lacking in hypertension. There was no correlation between the percentage of total fibrosis and the ejection fraction, cardiac index, or left ventricular end-diastolic pressure in either group. We concluded that the amount of myocardial interstitial fibrosis in hypertrophic cardiomyopathy is no greater than that in essential hypertension, but the type of fibrosis is different. Furthermore, in subjects in whom the ejection fraction is normal or only slightly decreased, fibrosis does not influence global cardiac functions.