odontogenic infection of Porphyromonas gingivalis (P.g.), a major periodontal pathogen, exacerbates pathological progression of non-alcoholic steatohepatitis (NASH). In this study, we aimed to clarify the detailed mechanism in which P.g. induced hepatic stellate cells (HSCs; key effector cells in liver fibrosis) activation. In the liver of high fat diet-induced NASH mouse model with P.g. odontogenic infection, immunolocalization of P.g. was detected. The number of hepatic crown-like structure, which was macrophage aggregation and related to liver fibrosis, was drastically increased and fibrosis area was also increased through upregulating immunoexpression of Phosphorylated Smad2 (key signaling molecule of TGF-β1) and Galectin-3. P.g.-secreted trypsin-like enzyme [gingipain; an activator of protease-activated receptor 2 (PAR2)] stimulated HSC proliferation and differentiation through Smad and ERK signaling induced by TGF-β1 produced from HSCs with P.g.-infection. Further, Galectin-3 produced from HSCs with P.g. infection and P.g.-derived LPS/lipoprotein stimulation stabilized TGFβ-receptor II resulting in increasing sensitivity for TGF-β1, finally leading to HSC differentiation via activating Smad and ERK signaling. In addition to them, hepatocytes (main component cells of liver) contributed to HSC activation through TGF-β1 and Galectin-3 production in paracrine manner. Collectively, P.g.-odontogenic infection exacerbates fibrosis of NASH by HSC activation through TGF-β1 and Gal-3 production from HSCs and hepatocytes.Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatic disease caused by obesity including simple steatosis and non-alcoholic steatohepatitis (NASH). The morbidity rate of NAFLD is high, up to 30% in Western countries, with increasing the number of NAFLD patients because of the increase of obesity 1-3 . Most NAFLD patients indicate simple steatosis, which is a reversible condition, but 10-20% of simple steatosis progresses to NASH, which is presented as inflammation with hepatocyte degeneration followed by hepatic fibrosis 3 . As some of the NASH cases eventually result in liver cirrhosis and cancer, it is a critical health problem requiring adequate prevention and early therapeutic intervention 2,4 . The mechanisms for the development and progression of NASH are extremely complicated. Recently, it was reported that fat deposition, inflammation and fibrosis in NASH are simultaneously caused by many factors such as up-regulation of free fatty acids (FFA), oxidation stress, cytokines and bacterial lipopolysaccharide (LPS) 5 .Porphyromonas gingivalis (P.g.) is a main periodontal pathogen. Periodontitis caused by P.g. is a well-recognized risk factor for many systemic diseases such as cardiovascular disease, preterm birth, diabetes mellitus, and rheumatoid arthritis 6-9 . P.g. can enter the blood circulation from periodontal disease sites and disseminate into the whole body and it can be detected in the distant organs including liver 6,7,10,11 . Furusho et al. reported that P.g.-odontogenic infect...

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Sonographic ONSD measurement is a simple, rapid technique to assess the neurological prognosis after cardiac arrest.

Autophagic recycling of cell parts is generally termed as the opposite of cell death. Here, we explored the relation between cell death and autophagy by examining granulosa cell layers that control oocyte quality, which is important for the success of fertilization. Granulosa cell layers were collected from infertile women and morphologically divided into four types, viz., mature (MCCs), immature (ICCs), and dysmature cumulus cells (DCCs), and mural granulosa cells (MGCs). Microtubule-associated protein light chain 3 (LC3), which is involved in autophagosome formation, was expressed excessively in DCCs and MGCs, and their chromosomal DNA was highly fragmented. However, autophagy initiation was limited to MGCs, as indicated by the expression of membrane-bound LC3-II and autophagy-related protein 7 (ATG7), an enzyme that converts LC3-I to LC3-II. Although pro-LC3 was accumulated, autophagy was disabled in DCCs, resulting in cell death. Our results suggest the possibility that autophagy-independent accumulation of pro-LC3 proteins leads to the death of human granulosa cells surrounding the oocytes and presumably reduces oocyte quality and female fertility.

PurposeThis study aimed to evaluate the effect of advanced paternal age on pregnancy outcomes and sperm parameters following intrauterine insemination (IUI). We used IUI data rather than assisted reproductive technology data, which might mask the effects of sperm impairments.MethodsWe retrospectively analyzed 1576 IUI cycles in women under 40 years old between April 2012 and May 2016 at the National Center for Child Health and Development in Japan. The main outcomes were clinical pregnancy and live birth.ResultsThe mean male age was significantly lower in cycles that resulted in pregnancy compared with those without pregnancy (38.0 vs 39.1 years; P < 0.001), with a similar trend for live‐birth cycles. However, there was no relationship between advanced paternal age and pregnancy outcomes after adjusting for confounding factors and correlations within patients using generalized estimating equations, and the age of the female partner was the only factor affecting pregnancy rate. Furthermore, advanced paternal age had no effect on sperm parameters.ConclusionsAdvanced paternal age alone does not adversely affect pregnancy or live‐birth rates or sperm parameters following IUI.