Preeclampsia (PE) is a multisystem disorder that contributes to maternal and fetal mortality and morbidity worldwide. It is characterized by de-novo hypertension and proteinuria or other maternal organ damage after 20 weeks of gestation. Evidence suggested that endogenous digitalis-like factor (EDLF) contributes to the pathogenesis of PE, and that the potential source of EDLF is the placenta. EDLF can inhibit the sodium pump (SP) specifically and may lead to hypertension, it has also been associated with hypoxia, oxidative stress and other abnormalitites present in PE.We studied whether normal human placenta responded to SP inhibition casued by EDLF with a change in abundance of lipids in the placental cytosol, and whether there was a characteristic set of lipid changes that could serve as a signature for EDLF exposure if there were such changes. Placenta tissues from 20 normal pregnancies were incubated for 48 hr in the presence and absence of ouabain, a widely studied EDLF, followed by tissue homogenization, lipid extraction, and the study of lipids using a mass spectrometery (MS) based lipidomics approach. 1207 lipidomic markers were surveyed by paired Student t-test, among which 26 markers had significantly different abundances between cases and control at the FDR=0.05 level. A set of 8 lipidomic markers were selected by a statistical model built with a sparse partial least squares discriminant analysis method (sPLS-DA) and a bootstrap procedure. All eight markers were then chemically characterized and partially identified using tandem MS. These markers might be used to identify placentas that have been previously exposed to EDLF in return.Endogenous peptides and small proteins might contribute to the pathophysiology of various diseases. Therefore, we investigated the potential peptidomic profile of placenta tissues in response to EDLF exposure as well. Placenta tissues from 20 normal pregnancies were incubated for 25 hr with and without the addition of ouabain, followed by homogenization, protein depletion, and the study of the peptides by a LC-MS based peptidomics approach. 275 peptidomic markers were evaluated by Student t-test. A set of 8 markers was chosen using a logistic regression model build with the Akaike information criterion (AIC). However, no peptidomics markers or set of markers showed specific, statististically significantly different changes in abundances between cases and controls after applying a false discovery rate (FDR) correction or using more conservative methods to overcome over-fitting. Using an optimal sPLS- DA, cross-validation studies and logistic regression models, we also found that the addition of any peptidomic marker to the previously selected lipidomic profile was unlikely to help identify placentas that had been exposed to EDLF.Alzheimer's disease (AD) is the most common form of dementia and the number of AD cases worldwide is currently estimated to be 36 million. The exact pathogenesis of AD remainsiielusive and available therapeutic strategies can only delay its progession temporarily. Several hypotheses have been proposed regarding the pathophysiology of AD and the beta-amyloid (Aβ) hypothesis is considered the core mechanism. However, the majority of studies concerning AD, or AD biomarkers specifically, have ignored a potentially important variable that is gender, despite reported gender differences in the risk of developing AD, the risk factors, clinical symptoms and CSF biomarkers of the disease, among many other aspects.We analyzed data obtained from a previous study of diagnostic serum lipid biomarkers for AD with the consideration of potential gender difference. Firstly, we studied the interaction between gender and disease stage using analysis of variance (ANOVA) and analysis of covariance (ANCOVA). Lipid markers that showed statistically significant interaction were selected after applying a FDR correction. Secondly, using a lasso logistic regression model with binary classification (control vs. all AD stages), we identified gender-specific markers and found different coefficient estimates for different genders as well. Lastly, we build a new ordinal model with the addition of a gender-specific marker using a Bayesian lasso probit ordinal regression model. The predictive performance of the new model was found to be statistically significantly better than the previous model which was built without the consideration of gender.In conclusion, we successfully discovered, chemically characterized lipidomic markers indicative of EDLF exposure in placenta and detected gender-specific lipid markers for AD.

Background: Airway fibroblasts have become a critical addition to all facets of structural lung tissue changes such as in human asthma and chronic obstructive pulmonary disease, but little is known about their role in the equine recurrent airway obstruction, a disease that resembles to the human asthma. Since the equine bronchial fibroblasts (EBF) have not been isolated and characterized yet, the use of defined medium was investigated. Results: Primary EBF were cultured on non-collagen coated flasks without serum or in the presence of feta bovine serum (FBS) or horse serum (HS) or in serum depleted medium. EBF cultured in serum-free basal media and those serum deprived were not able to proliferate and even exhibited considerable cell death. In media containing FBS or HS, proliferation of the cells was reproducible between different primary cultures and cells demonstrated expression of vimentin. Large variations were found in the ability of FBS and HS to support growth and differentiation of EBF in monolayer culture. Indications of growth-promoting actions, increasing passage number as well as maintaining fibroblast morphology were found rather in FBS than in HS. EBF culturing in HS needed longer doubling and confluence time. The protein content of the cell pellets was higher in EBF cultured in medium containing HS than FBS. Alpha-smooth muscle actin seemed to be less expressed in EBF cultured in medium containing FBS than those in HS. Conclusions: In sum, serum addition to basal EBF medium enhanced EBF differentiation into myofibroblasts, and these findings are useful to develop in vitro fibroblast culture models that mimic in vivo physiological processes and to study airway disease mechanisms and remodeling.:Background; Results; Discussion; Conclusions

Toll-like receptor 4 (TLR4), a key member of the TLR family, has been well characterized by its function in the induction of inflammatory products of innate immunity. However, the involvement of TLR4 in a variety of apoptotic events by an unknown mechanism has been the focus of great interest. Our investigation found that TLR4 promoted apoptotic signalling by affecting the glycogen synthase kinase-3β (GSK-3β) pathway in a serum-deprivation- induced apoptotic paradigm. Serum deprivation induces GSK-3β activation in a pathway that leads to subsequent cell apoptosis. Intriguingly, this apoptotic cascade is amplified in presence of TLR4 but greatly attenuated by β-arrestin 2, another critical molecule implicated in TLR4-mediated immune responses. Our data suggest that the association of β-arrestin 2 with GSK-3β contributes to the stabilization of phospho-GSK-3β, an inactive form of GSK-3β. It becomes a critical determinant for the attenuation of TLR4-initiated apoptosis by β-arrestin 2. Taken together, we demonstrate that the TLR4 possesses the capability of accelerating GSK-3β activation thereby deteriorating serum-deprivation-induced apoptosis; β-arrestin 2 represents an inhibitory effect on the TLR4-mediated apoptotic cascade, through controlling the homeostasis of activation and inactivation of GSK-3β.

Cancer treatments including chemotherapy and radiotherapy treat cancer by targeting rapidly dividing cells. Although these forms of treatment damage rapidly dividing cancer cells, they are also toxic to the cells of the gastrointestinal tract, leading to inflammation of the mucosal layer (mucositis) and causing nausea, vomiting, diarrhea, and abdominal pain. Improvement in symptoms may allow patients to have better performance status permitting ongoing treatment and possibly a better prognosis. This article describes the pathophysiology of chemotherapy-induced mucositis and includes 3 case reports of treatment of mucositis with serum bovine immunoglobulin.

The late second and early third decades of life are critical periods for bone health due to the attainment of peak bone mass during this time, yet little is known about relationships between lifestyle factors and bone health among young-adult females. Therefore, anthropometric, body composition, and nutritional variables were examined in relation to bone mineral density (BMD) and biochemical markers of bone turnover in a group of 60 healthy, young-adult females aged 18 to 25 years. Body weight, body mass index (BMI), fat-free soft tissue mass (FFST), and fat mass had statistically significant and positive associations with BMD. Mean daily dietary protein, magnesium, and iron intakes had statistically significant and negative associations with BMD. A second study compared dietary intake, BMD, and biochemical markers of bone turnover in young-adult females with chronic dieting habits to nondieters. Anthropometric and body composition variables between chronic dieters and nondieters were not statistically different; however, chronic dieters had statistically significantly lower average daily dietary intakes of energy, macronutrients, and selected micronutrients compared to nondieters. Chronic dieters had statistically significantly higher whole body (WB) BMD compared to nondieters. Moderate effects were observed for WB, lumbar spine, trochanter, and total proximal femur BMD such that chronic dieters possessed greater BMD compared to nondieters. It appears that among young-adult females, total body weight, particularly FFST mass, has an important association with BMD. Although nutritional inadequacies among young-adult females raise concerns, overconsumption of nutrients may increase the likelihood of nutrient-nutrient interactions that may have a less than optimal impact on BMD. Future investigations of dietary intake and BMD among young-adult females are warranted. / Master of Science

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24800号 / 医博第4992号 / 新制||医||1067(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 伊藤 貴浩, 教授 波多野 悦朗, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The dichotomy between type 1 and 2 conventional DCs under steady-state conditions is well defined. Bosteels et al. demonstrate that, upon inflammation, cDC2s acquire a hybrid inf-cDC2 phenotype, sharing phenotype, gene expression, and function with cDC1s and monocyte-derived cells, to optimally boost CD4 and CD8 immunity via Fc receptors.