Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions

Prostaglandin E1 (PGE1), known pharmaceutically as alprostadil, has vasodilatory properties and is used widely in various clinical settings. In addition to acute vasodilatory properties, PGE1 may exert beneficial effects by altering protein expression of vascular cells. PGE1 is reported to be a potent stimulator of angiogenesis via upregulation of VEGF expression, which is under the control of the transcription factor hypoxia-inducible factor 1 (HIF-1). However, the molecular mechanisms behind the phenomenon are largely unknown. In the present study, we investigated the mechanism by which PGE1 induces HIF-1 activation and VEGF gene expression in human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs), both vascular-derived cells. HUVECs and HASMCs were treated with PGE1 at clinically relevant concentrations under 20% O2 conditions and HIF-1 protein expression was investigated. Expression of HIF- 1α protein and the HIF-1-downstream genes were low under 20% O2 conditions and increased in response to PGE1 treatment in both HUVECs and HASMCs in a dose- and time-dependent manner under 20% O2 conditions as comparable to exposure to 1% O2 conditions. Studies using EP-receptor-specific agonists and antagonists revealed that EP1 and EP3 are critical to PGE1-induced HIF-1 activation. In vitro vascular permeability assays using HUVECs indicated that PGE1 increased vascular permeability in HUVECs. Thus, we demonstrate that PGE1 induces HIF- 1α protein expression and HIF-1 activation under non-hypoxic conditions and also provide evidence that the activity of multiple signal transduction pathways downstream of EP1 and EP3 receptors is required for HIF-1 activation

Prevalence and cumulative incidence of autism spectrum disorders and the patterns of co-occurring neurodevelopmental disorders in a total population sample of 5-year-old children.

BackgroundsWhether there is a true increase in autism spectrum disorder (ASD) frequency or not remains unclear. Additionally, the rates of co-existing neurodevelopmental disorders (NDD) in a total population sample has not been fully examined before. Therefore, using a total population sample in Japan, we aimed to estimate the prevalence and cumulative incidence of autism spectrum disorder (ASD) annually, to determine whether there is a true increase in ASD prevalence by estimating the cumulative incidence of ASD annually, and to examine the rates of co-existing neurodevelopmental disorders (NDD).MethodIn this cross-sectional sequential design study, all 5-year-old children in the catchment area underwent the screening annually from the year 2013-2016. Screen-positive children were invited to participate in a comprehensive assessment, including child and parent interview, behavioral observation, and cognitive and motor function testing. All cases were reviewed by a multidisciplinary research team.ResultsCaregivers of 3954 children returned the screening, among which 559 children underwent the assessment with 87 children receiving an ASD diagnosis. Adjusted ASD prevalence was 3.22% (95% confidence interval (CI) 2.66-3.76%). The male to female ratio of the crude prevalence was 2.2:1. The cumulative incidence of ASD up to 5 years of age for the total study years was 1.31% (95% CI 1.00-1.62%). A generalized linear model revealed no significant linear trends in 5-year cumulative incidence over the study years. Only 11.5% of children had ASD alone; the remaining 88.5% were found to have at least one co-existing NDD.LimitationsModest sample size for a total population study.ConclusionsOur findings demonstrate the stability of the 5-year cumulative incidence of ASD, implying no true rise in ASD incident cases over the 4-year study period in the study catchment area. High rates of co-existing NDDs reflect the importance of investigating broad developmental challenges in children with ASD

Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model

This report shows that interleukin (IL) 17–producing T helper type 17 (Th17) cells predominantly express CC chemokine receptor (CCR) 6 in an animal model of rheumatoid arthritis (RA). Th17 cells induced in vivo in normal mice via homeostatic proliferation similarly express CCR6, whereas those inducible in vitro by transforming growth factor β and IL-6 additionally need IL-1 and neutralization of interferon (IFN) γ and IL-4 for CCR6 expression. Forced expression of RORγt, a key transcription factor for Th17 cell differentiation, induces not only IL-17 but also CCR6 in naive T cells. Furthermore, Th17 cells produce CCL20, the known ligand for CCR6. Synoviocytes from arthritic joints of mice and humans also produce a large amount of CCL20, with a significant correlation (P = 0.014) between the amounts of IL-17 and CCL20 in RA joints. The CCL20 production by synoviocytes is augmented in vitro by IL-1β, IL-17, or tumor necrosis factor α, and is suppressed by IFN-γ or IL-4. Administration of blocking anti-CCR6 monoclonal antibody substantially inhibits mouse arthritis. Thus, the joint cytokine milieu formed by T cells and synovial cells controls the production of CCL20 and, consequently, the recruitment of CCR6+ arthritogenic Th17 cells to the inflamed joints. These results indicate that CCR6 expression contributes to Th17 cell function in autoimmune disease, especially in autoimmune arthritis such as RA

Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ): Part 2. Endorsement of the alternative item

AbstractBackgroundA new self-administered questionnaire as an outcome measure for patients with cervical myelopathy was drawn up in Part 1 (Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire, JOACMEQ). Because a question with regard to driving a car (C-41) was not suitable for this patient group, the authors composed an alternative question related to neck motion (C-41-2). The purposes of the present study were to perform a secondary survey on patients with cervical myelopathy and to statistically analyze the responses to validate the JOACMEQ, and also to determine if it was possible to convert item C-41 to the alternative question.MethodsA member of the Subcommittee on Low Back Pain and Cervical Myelopathy Evaluation from each hospital administered the questionnaire to more than 50 patients with cervical myelopathy in each hospital. The questionnaire consisted of 25 questions, 24 of which were extracted in the primary survey. The authors statistically examined whether it was possible to convert question C-41 to C-41-2.ResultsThree hundred and sixty-eight patients with cervical myelopathy were enrolled in the present study. No questions elicited no answer or “I am not sure” in more than 5% of patients except question C-41. There were no questions that the patients answered with difficulty. There was no tendency that was concentrated on one option as an answer to questions. There was a high correlation between questions C-41 and C-41-2. Spearman’s correlation coefficient and κ value showed that there was high coincidence between the two questions C-41 and C-41-2. It is possible to convert the question C-41 to the alternative question C41-2.ConclusionThe questionnaire has sufficient reliability for clinical use. It is possible that the JOACMEQ will prevail and become a global standard to evaluate outcomes in patients with cervical myelopathy

Japanese Orthopaedic Association Back Pain Evaluation Questionnaire. Part 3. Validity study and establishment of the measurement scale: Subcommittee on Low Back Pain and Cervical Myelopathy Evaluation of the Clinical Outcome Committee of the Japanese Orthopaedic Association, Japan

AbstractBackgroundThe Japanese Orthopaedic Association decided to revise the JOA score for low back pain and to develop a new outcome measure. In February 2002, the first survey was performed with a preliminary questionnaire consisting of 60 evaluation items. Based on findings of that survey, 25 items were selected for a draft of the JOA Back Pain Evaluation Questionnaire (JOABPEQ). The second survey was performed to confirm the reliability of the draft questionnaire. This article further evaluates the validity of this questionnaire and establishes a measurement scale.MethodsThe subjects of this study consisted of 355 patients with low back disorders of any type (201 men, 154 women; mean age 50.7 years). Each patient was asked to fill in a self-administered questionnaire. Superficial validity was checked in terms of the completion rate for filling out the entire questionnaire. Factor analysis was then performed to evaluate the validity of the questionnaire and establish a measurement scale.ResultsAs a result of the factor analysis, 25 items were categorized into five factors. The factors were named based on the commonality of the items: social function, mental health, lumbar function, walking ability, and low back pain. To establish a measurement scale for each factor, we determined the coefficient for each item so the difference between the maximum factor scores and minimum factor scores was approximately 100. We adjusted the formula so the maximum for each factor score was 100 and the minimum was 0.ConclusionsWe confirmed the validity of the JOA Back Pain Evaluation Questionnaire and est ablished a measurement scale

Two Roles of Debt and Optimal Capital Structure

"This paper examines the optimal capital structure of the firm when debt has the roles of both ""reducing-free-cash"" and ""reorganization"". Under one reorganization process, we show that the optimal financing policy for the firm is to choose debt seniority structure (between junior and senior debt) as well as to determine the debt level as a whole.

Mobile monitoring along a street canyon and stationary forest air monitoring of formaldehyde by means of a micro gas analysis system

A micro-gas analysis system (μGAS) was developed for mobile monitoring and continuous measurements of atmospheric HCHO. HCHO gas was trapped into an absorbing/reaction solution continuously using a microchannel scrubber in which the microchannels were patterned in a honeycomb structure to form a wide absorbing area with a thin absorbing solution layer. Fluorescence was monitored after reaction of the collected HCHO with 2,4-pentanedione (PD) in the presence of acetic acid/ammonium acetate. The system was portable, battery-driven, highly sensitive (limit of detection = 0.01 ppbv) and had good time resolution (response time 50 s). The results revealed that the PD chemistry was subject to interference from O3. The mechanism of this interference was investigated and the problem was addressed by incorporating a wet denuder. Mobile monitoring was performed along traffic roads, and elevated HCHO levels in a street canyon were evident upon mapping of the obtained data. The system was also applied to stationary monitoring in a forest in which HCHO formed naturally via reaction of biogenic compounds with oxidants. Concentrations of a few ppbv-HCHO and several-tens of ppbv of O3 were then simultaneously monitored with the μGAS in forest air monitoring campaigns. The obtained 1 h average data were compared with those obtained by 1 h impinger collection and offsite GC-MS analysis after derivatization with o-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBOA). From the obtained data in the forest, daily variations of chemical HCHO production and loss are discussed

Conservation Laws in Higher-Order Nonlinear Optical Effects

Conservation laws of the nonlinear Schr\"{o}dinger equation are studied in the presence of higher-order nonlinear optical effects including the third-order dispersion and the self-steepening. In a context of group theory, we derive a general expression for infinitely many conserved currents and charges of the coupled higher-order nonlinear Schr\"{o}dinger equation. The first few currents and charges are also presented explicitly. Due to the higher-order effects, conservation laws of the nonlinear Schr\"{o}dinger equation are violated in general. The differences between the types of the conserved currents for the Hirota and the Sasa-Satsuma equations imply that the higher-order terms determine the inherent types of conserved quantities for each integrable cases of the higher-order nonlinear Schr\"{o}dinger equation