新規TLR9リガンドK3－SPGを用いたin situワクチン療法は長期間持続する全身性免疫応答を誘導し、全身または局所免疫療法と相乗効果を示す

京都大学新制・課程博士博士(医学)甲第24139号医博第4879号新制||医||1060(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 森信 暁雄, 教授 上野 英樹, 教授 金子 新学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

AKARI infrared imaging of reflection nebulae IC4954 and IC4955

We present the observations of the reflection nebulae IC4954 and IC4955 region with the Infrared Camera (IRC) and the Far-Infrared Surveyor (FIS) on board the infrared astronomical satellite AKARI during its performance verification phase. We obtained 7 band images from 7 to 160um with higher spatial resolution and higher sensitivities than previous observations. The mid-infrared color of the S9W (9um) and L18W (18um) bands shows a systematic variation around the exciting sources. The spatial variation in the mid-infrared color suggests that the star-formation in IC4954/4955 is progressing from south-west to north-east. The FIS data also clearly resolve two nebulae for the first time in the far-infrared. The FIS 4-band data from 65um to 160um allow us to correctly estimate the total infrared luminosity from the region, which is about one sixth of the energy emitted from the existing stellar sources. Five candidates for young stellar objects have been detected as point sources for the first time in the 11um image. They are located in the red S9W to L18W color regions, suggesting that current star-formation has been triggered by previous star-formation activities. A wide area map of the size of about 1 x 1 (deg^2) around the IC4954/4955 region was created from the AKARI mid-infrared all-sky survey data. Together with the HI 21cm data, it suggests a large hollow structure of a degree scale, on whose edge the IC4954/4955 region has been created, indicating star formation over three generations in largely different spatial scales.Comment: 23 pages, 7 figures, accepted for publication in PASJ AKARI special issu

Crystalline Silicate Feature of the Vega-like star HD145263

We have observed the 8-13 $\mu$m spectrum (R$\sim$250) of the Vega-like star candidate HD145263 using Subaru/COMICS. The spectrum of HD145263 shows the broad trapezoidal silicate feature with the shoulders at 9.3 $\mu$m and 11.44 $\mu$m, indicating the presence of crystalline silicate grains. This detection implies that crystalline silicate may also be commonly present around Vega-like stars. The 11.44 $\mu$m feature is slightly shifted to a longer wavelength compared to the usual 11.2-3 $\mu$m crystalline forsterite feature detected toward Herbig Ae/Be stars and T Tauri stars. Although the peak shift due to the effects of the grain size can not be ruled out, we suggest that Fe-bearing crystalline olivine explains the observed peak wavelength fairly well. Fe-bearing silicates are commonly found in meteorites and most interplanetary dust particles, which originate from planetesimal-like asteroids. According to studies of meteorites, Fe-bearing silicate must have been formed in asteroidal planetesimals, supporting the scenario that dust grains around Vega-like stars are of planetesimal origin, if the observed 11.44 $\mu$m peak is due to Fe-bearing silicates.Comment: accepted for Publication in ApJ

Activin–like kinase–3 activity is important for kidney regeneration and reversal of fibrosis

Molecules associated with TGF-β superfamily such as BMPs and TGF-β are key regulators of inflammation, apoptosis and cellular transitions. Here, we demonstrate that the BMP receptor activin–like kinase 3 (Alk3) is elevated early in response to kidney injury and its deletion in the tubular epithelium leads to enhanced TGF-β1 / Smad3 signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3 mediated signaling. Structure–function analysis of Alk3 / BMP / BMPRII ligand–receptor complex coupled with synthetic organic chemistry led us to construct a library of small peptide agonists of BMP signaling that function via Alk3 receptor. One such peptide agonist, THR–123, suppressed inflammation, apoptosis epithelial–to–mesenchymal transition program, and reversed fibrosis in mouse models of acute and chronic injury. Combining THR–123 and angiotensin–converting enzyme inhibitor, captopril, exhibited additive therapeutic benefit in controlling fibrosis. Our studies demonstrate that BMP signaling agonists constitute a new line of therapeutic agents with a potential utility in the clinic to induce regeneration, repair and reverse fibrosis

Effects of Therapeutic Hypothermia for Neuroprotection from the Viewpoint of Redox Regulation

Redox regulation has recently been recognized as an important factor in acute illnesses as well as in chronic diseases. It has also become a target for neuroprotection in acute intensive care. Despite its well-known therapeutic effects, therapeutic hypothermia has recently been re-evaluated for its potential use in emergency and critical care medicine. Hypothermia is an undesirable physiological condition that can increase oxidative stress and decrease anti-oxidative potency. However, many studies have shown that under ischemia/reperfusion conditions, therapeutic hypothermia actually suppresses enhanced oxidative stress and maintains or increases anti-oxidative potency. This review provides an overview and outlook for the future of therapeutic hypothermia for neuroprotection from the perspective of redox regulation in patients with post-cardiac arrest syndrome and traumatic brain injury

A new variety of Thismia hexagona Dancak, Hrones, Koblova et Sochor (Thismiaceae) from Sabah, Borneo, Malaysia

Thismia hexagona Dančák, Hroneš, Koblová et Sochor was recently reported from Brunei Darussalam. It is characterized by its unique yellow and brown coloration and sharply hexagonal flower annulus. Here, we also report its discovery during a botanical expedition in the Maliau Basin Conservation Area, Sabah, Borneo, Malaysia. The Malaysian individuals differ from the original description of T. hexagona in the opening angle and size of the perianth lobes. We therefore propose it as a new variety, T. hexagona var. grandiflora Tsukaya, M. Suleiman & H. Okada var. nov. Detailed morphological characters are provided

Quality of life and physical/psychosocial factors in children and adolescents with orthostatic intolerance

Background　Orthostatic intolerance (OI), which is common in children and adolescents, negatively impacts their quality of life (QOL) due to physical symptoms that limit work, school, and daily activities. The purpose of this study is to explore the association of physical and psychosocial factors with QOL scores in children and adolescents with OI. Methods　A cross sectional observational study was conducted. The study participants included 95 Japanese pediatric patients of age 9-15 years who were diagnosed with OI from April 2010 to March 2020. The QOL scores and the QOL T-scores of children with OI assessed using the KINDL-R questionnaire at the initial visit were compared with conventional normative data. The associations of physical and psychosocial factors with the QOL T-scores were examined using multiple linear regression. Results　Pediatric patients with OI had significantly lower QOL scores than healthy children in both elementary (50.7 +/- 13.5 vs. 67.9 +/- 13.4, p Conclusions　These results suggest that the assessment of QOL, including both physical and psychosocial aspects, especially school factors, needs to be implemented earlier in children and adolescents with OI

Einfluss von Phosphodiesterase 5-Inhibitoren auf die Escherichia coli Hämolysin und Lipopolysaccharid vermittelte Kardiodepression am isolierten Rattenherzen

Durch Mikroorganismen, wie Bakterien, Viren oder Pilze kommt es zu Primärinfektionen, in deren Folge sich eine Sepsis entwickeln kann. Die häufigsten Sepsisverursacher sind Bakterien, wobei der Tatsache, dass das Krankheitsbild der Sepsis nicht an die Anwesenheit intakter Bakterien in der Zirkulation gebunden ist sondern die hämatogene Streuung sezernierter Exotoxine und endotoxinhaltiger Zellfragmente zur Induktion einer Sepsis ausreichen, besondere Bedeutung beigemessen werden muss. Die während einer Sepsis auftretenden kardiovaskulären Veränderungen tragen entscheidend zur Induktion des septischen Multiorganversagens sowie des septischen Schocks bei. Es ist dem Herzen im Zuge einer akuten septischen Kardiomyopathie häufig nicht möglich, seine Pumpleistung so zu erhöhen, wie es zur Aufrechterhaltung eines adäquaten Blutdrucks bei stark erniedrigtem systemischem Widerstand nötig wäre. Die septische Kardiomyopathie kann durch die Wirkung kardiodepressiver Zytokine wie TNF-alpha und Il-1beta hervorgerufen werden; daneben sind Mikrozirkula-tionsstörungen innerhalb des Myokards, welche auch ohne globale Minderperfusion zu einer hypoxisch bedingten Pumpinsuffizienz führen können, als mögliche Ursache anzusehen. Zyklische Nukleotide stellen dabei einen wichtigen Bestandteil in der Regulation von koronarer Vasomotorik und kardialer Kontraktilität dar, überdies spielen sie auch eine Rolle in der Pathophysiologie der Sepsis. Die vorliegende Arbeit behandelt die Frage, ob Phosphodiesterase (PDE5) -Inhibitoren den kardiodepressiven Effekt gram-negativer Bakterien respektive deren Endo- und Exotoxinen zumindest teilweise aufheben und so zu einem günstigeren Verlauf der Sepsis beitragen können. Dazu wurden isolierte Rattenherzen mit Escherichia coli Hämolysin (ECH) und Lipopolysaccharid (LPS) perfundiert. Die dadurch generierte Kardiodepression sowie Vasokonstriktion im Koronargefäßsystem sollten mit Hilfe von Sildenafil und Zaprinast inhibiert werden, was partiell gelang. Desweiteren wurde durch die Aufarbeitung von Ventrikelpräparaten eine verminderte Freisetzung kardio-depressiver Mediatoren, insbesondere von TNF-alpha und Cysteinyl-Leukotrienen (Cys-LT), nachgewiesen. Eine Beeinflussung der Genexpression hingegen konnte nicht gezeigt werden. Für die LPS-Versuche stellt sich der protektive Effekt folgendermaßen dar: Der durch die PDE5-Inhibitoren erhöhte cGMP-Spiegel führt zu einer koronaren Vasodilatation, welche Mikrozirkulationsstörungen vorbeugt, was zur Verbesserung der Myokardversorgung und einer verminderten Freisetzung von TNF-alpha führt. Durch diese zeitige Intervention in die teilweise selbstunterhaltenden Mechanismen können der TNF-alpha abhängige kardiodepressive Effekt, aber auch die Aktivierung der cNOS/iNOS, des Sphingomyelinasesignalwegs, der freien Radikalliberation und der Apoptose antagonisiert werden. Im Falle der ECH-Versuche steht ebenfalls die vasodilatative Wirkung der PDE5-Inhibitoren im Koronargefäßsystem im Vordergrund. Diese beruht sowohl auf einer prolongierten cGMP Wirkung als auch auf einer herabgesetzten Cys-LT Liberation. Die verbesserte Perfusion verhindert die sich selbstunterhaltende, ischämisch bedingte Cys-LT Freisetzung und verringert so eine weitere Erhöhung des koronaren Gefäßwiderstandes. Infolge der Senkung des koronaren Gefäßwiderstandes wird die Kardiodepression nahezu vollständig aufgehoben. Die gewonnenen Ergebnisse deuten auf ein protektives Potential der PDE5-Inhibitoren bezüglich der septischen Kardiomyopathie hin.Microorganisms like bacteria, viruses and fungi cause primary infections, which can lead to sepsis. In fact, sepsis is primarily caused by bacteria. Induction of septicemia is not dependent on the presence of intact bacterial organisms in the blood circulation. Hematogenic spreading of secreted bacterial exotoxins as well as cellular fragments containing endotoxins can also lead to sepsis. Cardiovascular alterations due to sepsis crucially contribute to multiple organ dysfunction syndrome and to septic shock. The heart of septic patients is frequently unable to increase cardiac output adequately to compensate the systemic fall in blood pressure. On the one hand septic cardiomyopathy can be induced by cardiodepressive cytokines like TNF-alpha or Il-1beta and on the other hand by microcirculatory dysfunctions within the myocardium, which even without global ischemia may lead to a decreased cardiac output due to hypoxia. Cyclic nucleotides play an important role in coronary vasoconstriction and cardial depression and also in pathophysiology of sepsis. The present study investigates in how far the phosphodiesterase (PDE5) inhibitors Sildenafil and Zaprinast could be able to inhibit the cardiodepressive effect of gram–negative bacteria and their endo- and exotoxins respectively, which then could lead to an improvement of the prognosis. Isolated rat hearts were perfused with Escherichia coli hemolysin (ECH) and lipopolysaccharides (LPS) respectively which lead to cardiodepression and coronary vasoconstriction. After treatment with Sildenafil and Zaprinast respectively this effect could be partially decreased. Analysis of samples gained from ventricular tissue revealed a decreased liberation of cardiodepressive mediators, such as TNF-alpha and cysteinyl-leukotrienes (Cys-LT). Alterations in gene expression could not be shown. The protective effect of the PDE5-inhibitors in the LPS perfused rat hearts can be explained in the following way: PDE5-inhibitor elevate the cGMP levels which lead to coronary vasodilatation inhibiting microcirculatory dysfunction. This improves myocardial supply and decreases TNF-alpha liberation. The early intervention in the partially self engaging mechanisms inhibit the TNF-alpha dependent cardiodepressive effect, activation of the cNOS/iNOS in the sphingomyelinase signaling pathway, free radical liberation and apoptosis. The main effect of PDE5-inhibotor treatment on ECH perfused hearts is a coronary vasodilatation due to a prolonged cGMP impact and a decreased Cys-LT liberation. PDE5-inhibitors decrease self engaging, ischemic induced Cys-LT liberation, which in the end leads to a minimized increase in coronary vascular resistance. Due to the decrease of the coronary resistance cardiodepression can be abolished nearly completely. All results gained in this study recommend a beneficial potential of PDE5-inhibitors in septic cardiomyopathy