可溶性Flt-1産生低下は、心筋リモデリングおよび心不全増悪に寄与する

Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti–placental growth factor–neutralizing antibody prevented pressure overload–induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart.博士（医学）・乙第1384号・平成28年11月24日© 2016 American Heart Association, Inc.The definitive version is available at " https://doi.org/10.1161/HYPERTENSIONAHA.116.07371

ヒト口腔粘膜受容器からの感覚入力による随意性嚥下の促進効果

Both voluntary and reflex components are involved in normal swallowing. Swallowing depends on the bulbar central pattern generator (CPG). Therefore, the relationship between the voluntary component (central input) and reflex component (sensory input) may be important to understand the central mechanisms for deglutition. There are water receptors, mechanoreceptors (tactile receptors and deep mechanoreceptors) and taste receptors in the oral mucosa. In this study, the role of sensory receptors in voluntary swallowing was investigated. Twenty healthy volunteers (mean±SD, 28.9±9.7 years) were enrolled in this study. A fine tube was inserted into the pharyngolaryngeal region (PL) or the tongue base (TB). Stimulating solution at room temperature was delivered into the PL or the TB through this tube. Each subject was instructed to repeat swallowing as fast as possible. EMG activity was recorded from suprahyoid muscles during swallowing. The swallowing interval (SI) between two consecutive swallows in each infusion was measured. SIs were shorter in the case of water infusion into the PL than in the case of water infusion into the TB, suggesting that water receptors are localized in the PL. Infusion of 0.15M NaCl into the PL prolonged SI, because 0.15M NaCl inhibits water receptors. However, infusion of 0.15M NaCl into the TB shortened SI, suggesting that excitation of Na^+taste receptors can facilitate voluntarily swallowing. SI with resting saliva infusion into the PL was almost the same as that with water infusion, suggesting that resting saliva can excite water receptors. In the weak mechanical stimulation (infusion rate of 0.2ml/min), SIs varied greatly from subject to subject. Therefore, the variation in SI cannot be explained by difference in sensitivity of the mucosal receptors among subjects. It appears that the ability of CPG to perform repetitive voluntary swallowing varies greatly in subjects. The strong mechanical stimulation (infusion rate of 5.0ml/min) did not influence SI in a subject showing short SI with the weak stimulation, but it shortened SI in a subject showing long SI. This suggests that excitation of oral mucosal receptors strongly compensates for difficulty in swallowing in subjects showing a long SI

Epidemiological survey of tick-borne encephalitis virus infection in wild animals on Hokkaido and Honshu islands, Japan

The first human case of tick-borne encephalitis (TBE) in Japan was recorded in southern Hokkaido in 1993 and was followed by four further cases in southern, central, and northern Hokkaido during 2016-2018. However, the distribution of TBE virus (TBEV) foci in Japan is unclear. Therefore, here, we serologically examined raccoons (Procyon lotor), sika deer (Cervus nippon), and wild boars (Sus scrofa) as sentinels of TBEV infection in Hokkaido and in Fukushima and Tochigi Prefectures in Honshu. A total of 1,649 serum samples collected between 2003 and 2018 were screened by enzyme-linked immunosorbent assay using subviral particles and confirmed using the virus neutralization test. In raccoons, the seroprevalence of TBEV was 5.9% (39/662 samples) in central Hokkaido in 2003-2005 and 0.8% (3/368 samples) in eastern Hokkaido in 2010-2018, revealing the presence of TBEV foci in these areas. In addition, 0.5% (2/414) of deer sampled in eastern Hokkaido in 2010-2017 and 2.4% (1/42) of deer sampled in Tochigi Prefecture in 2016-2018 were seropositive. On Honshu, seropositive rodents have previously been detected only in Shimane Prefecture. Therefore, the detection of seropositive animals in Tochigi Prefecture may indicate the widespread distribution of TBEV foci throughout Japan. TBEV and viral genes were not detected in 507 ticks collected in the same area of eastern Hokkaido where seropositive animals were found, reemphasizing the value of using serological examination of wild animals as a tool for revealing unknown TBE risk areas. Our findings also indicate that raccoons may be particularly useful sentinels