ランダム化比較試験によるエドキサバン投与下におけるTKA後DVT発生に対するフットポンプの有効性

長崎大学学位論文 [学位記番号]博（医歯薬）甲第986号 [学位授与年月日]平成29年9月20

Geology and Sedimentary Environments of the Pleistocene Setana Formation in the Kuromatsunai District, Southwestern Hokkaido, Japan

The Pleistocene Setana Formation is exposed along the axial zone of the Kuromatsunai district, southwestern Hokkaido Island, and is divided into the Nakasato Conglomerate Member and Soebetsu Sandstone Member. The Nakasato Conglomerate Member consists of medium- to coarsegrained sandstone that accumulated in shoreface, delta, and channel systems. This member is correlated with the overlapping interval between the CN13b calcareous nannofossil zone and the Neogloboquadrina pachyderma (s) / Neogloboquadrina incompta planktonic foraminiferan zone, which indicates an age of 1.2-1.0 Ma. The Soebetsu Sandstone Member is made up of sandy siltstone to very fine-grained sandstone and includes several beds of shell concentrations. This member is correlated with the CN14a calcareous nannofossil zone and is thought to range in age from 1.0-0.6 Ma. The Setana Formation contains abundant and well-preserved molluscs, bryozoans, and planktonic and benthic foraminifera. Paleoclimatic reconstructions based on the molluscan and planktonic foraminiferan faunas, and on oxygen isotope ratios from planktonic foraminifera, indicate that the basal part of the Nakasato Sandstone Member was deposited during a cooler climate than that of the present Kuromatsunai district, while the lower and middle parts of the Soebetsu Sandstone Member were deposited when the climate was warmer than at present. The Setana Formation, together with other Pleistocene deposits in Japan, has the potential to become a model system for studies on the effects of climatic change on the composition and diversity of assemblages of benthic marine animals; on how community-level parameters modulate these effects; on the responses of individual taxa to climatic change; and on comparison of various proxies used to assess paleoclimate and climatic change.International Symposium, "The Origin and Evolution of Natural Diversity". 1–5 October 2007. Sapporo, Japan

Generation of Cellular Reactive Oxygen Species by Activation of the EP2 Receptor Contributes to Prostaglandin E2-Induced Cytotoxicity in Motor Neuron-Like NSC-34 Cells

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by progressive degeneration of motor neurons in the central nervous system. Prostaglandin E2 (PGE2) plays a pivotal role in the degeneration of motor neurons in human and transgenic models of ALS. We have shown previously that PGE2 directly induces neuronal death through activation of the E-prostanoid (EP) 2 receptor in differentiated NSC-34 cells, a motor neuron-like cell line. In the present study, to clarify the mechanisms underlying PGE2-induced neurotoxicity, we focused on generation of intracellular reactive oxygen species (ROS) and examined the effects of N-acetylcysteine (NAC), a cell-permeable antioxidant, on PGE2-induced cell death in differentiated NSC-34 cells. Dichlorofluorescein (DCF) fluorescence analysis of PGE2-treated cells showed that intracellular ROS levels increased markedly with time, and that this effect was antagonized by a selective EP2 antagonist (PF-04418948) but not a selective EP3 antagonist (L-798,106). Although an EP2-selective agonist, butaprost, mimicked the effect of PGE2, an EP1/EP3 agonist, sulprostone, transiently but significantly decreased the level of intracellular ROS in these cells. MTT reduction assay and lactate dehydrogenase release assay revealed that PGE2- and butaprost-induced cell death were each suppressed by pretreatment with NAC in a concentration-dependent manner. Western blot analysis revealed that the active form of caspase-3 was markedly increased in the PGE2- and butaprost-treated cells. These increases in caspase-3 protein expression were suppressed by pretreatment with NAC. Moreover, dibutyryl-cAMP treatment of differentiated NSC-34 cells caused intracellular ROS generation and cell death. Our data reveal the existence of a PGE2-EP2 signaling-dependent intracellular ROS generation pathway, with subsequent activation of the caspase-3 cascade, in differentiated NSC-34 cells, suggesting that PGE2 is likely a key molecule linking inflammation to oxidative stress in motor neuron-like NSC-34 cells

Acute and Subacute Toxicity In Vivo of Thermal-Sprayed Silver Containing Hydroxyapatite Coating in Rat Tibia

To reduce the incidence of implant-associated infection, we previously developed a novel coating technology using hydroxyapatite (HA) containing silver (Ag). This study examined in vivo acute and subacute toxicity associated with the Ag-HA coating in rat tibiae. Ten-week-old rats received implantation of HA-, 2% Ag-HA-, or 50% Ag-HA-coated titanium rods. Concentrations of silver in serum, brain, liver, kidneys, and spleen were measured in the acute phase (2–4 days after treatment) and subacute phase (4–12 weeks after treatment). Biochemical and histological examinations of those organs were also performed. Mean serum silver concentration peaked in the acute phase and then gradually decreased. Mean silver concentrations in all examined organs from the 2% Ag-HA coating groups showed no significant differences compared with the HA coating group. No significant differences in mean levels of glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, lactate dehydrogenase, creatinine, or blood urea nitrogen were seen between the three groups and controls. Histological examinations of all organs revealed no abnormal pathologic findings. No acute or subacute toxicity was seen in vivo for 2% Ag-HA coating or HA coating. Ag-HA coatings on implants may represent biologically safe antibacterial biomaterials and may be of value for reducing surgical-site infections related to implantation

The Selective SGLT2 Inhibitor Ipragliflozin Has a Therapeutic Effect on Nonalcoholic Steatohepatitis in Mice.

BACKGROUND & AIMS:In recent years, nonalcoholic steatohepatitis (NASH) has become a considerable healthcare burden worldwide. Pathogenesis of NASH is associated with type 2 diabetes mellitus (T2DM) and insulin resistance. However, a specific drug to treat NASH is lacking. We investigated the effect of the selective sodium glucose cotransporter 2 inhibitor (SGLT2I) ipragliflozin on NASH in mice. METHODS:We used the Amylin liver NASH model (AMLN), which is a diet-induced model of NASH that results in obesity and T2DM. AMLN mice were fed an AMLN diet for 20 weeks. SGLT2I mice were fed an AMLN diet for 12 weeks and an AMLN diet with 40 mg ipragliflozin/kg for 8 weeks. RESULTS:AMLN mice showed steatosis, inflammation, and fibrosis in the liver as well as obesity and insulin resistance, features that are recognized in human NASH. Ipragliflozin improved insulin resistance and liver injury. Ipragliflozin decreased serum levels of free fatty acids, hepatic lipid content, the number of apoptotic cells, and areas of fibrosis; it also increased lipid outflow from the liver. CONCLUSIONS:Ipragliflozin improved the pathogenesis of NASH by reducing insulin resistance and lipotoxicity in NASH-model mice. Our results suggest that ipragliflozin has a therapeutic effect on NASH with T2DM

Localized accumulation of tau without amyloid-beta in aged brains measured with [11C]PBB3 and [11C]PiB positron emission tomography

Objective Different regional specificity in tau accumulation is well known in Alzheimer’s disease (AD) brains. However, little is known about such distribution in aging brains and mild cognitive impairment (MCI) brains.Methods Cognitive functions and regional accumulation of tau and amyloid (A) were evaluated in 13 healthy controls (HCs), 3 patients with MCI, and 4 AD patients. Tau and A accumulation was semi-quantitatively measured with positron emission tomography (PET) using [11C]pyridinyl-butadienyl-benzothiazole 3 (PBB3) and [11C]Pittsburgh compound-B (PiB).Results Age-dependent accumulation of tau was found in all predetermined regions characteristic of AD, especially in the parahippocampal gyrus, lateral temporal cortex, frontal cortex, and posterior cingulate gyrus, where age-dependency was statistically significant. In contrast, age-dependency in accumulation of A was not observed in most regions assessed in HC. Moreover, the accumulation of tau in regions characteristic of AD in MCI patients were higher than that in HC, whereas tau accumulation was highest and statistically significant in AD patients. Unlike HC, the accumulation of tau was accompanied by that of Ain patients with MCI and AD. Conclusion Mild and age-dependent accumulation of tau without A was found in AD-related areas in aging brains. Considering age as a major risk for AD, higher accumulation of tau may trigger the neurodegenerative process of AD

Amyloid-Negative Dementia in the Elderly is Associated with High Accumulation of Tau in the Temporal Lobes

Background:We previously reported that among cases clinically diagnosed with Alzheimer’s disease, the proportion of amyloid beta (Aβ) -negative caseincreases in the elderly population. Tauopathy including Argyrophilic Grain Disease (AGD) and Neurofibrillary Tangle-Predominant Dementia(NFTPD), may be the leading causes of such dementia.Objective:To evaluate the involvement of tau, we studied tau accumulation in Amyloid-Negative Dementia Cases in the Elderly (ANDE) with PositronEmission Tomography (PET).Methods:Seven cases with slowly progressive dementia who were older than 80 years and were negative for Aβ were studied. In one case, autopsy obtained2 years after the PET examination revealed neurofibrillary tangles limited around the parahippocampal gyrus. Four cases showed strong lateralityin magnetic resonance imaging atrophy (clinical AGD), while the other three cases had no significant laterality in atrophy (clinical NFTPD). AgecorrectedPET data of healthy controls (HC; n = 12) were used as control. Tau accumulation was evaluated with [11C]PBB3-PET.Results:High accumulation was found in the lateral temporal cortex in ANDE. In autopsy case, scattered neurofibrillary tangles were found in theparahippocampal gyrus. In addition, there was a very high accumulation of PBB3 in the large area of bilateral parietal lobes, although nocorresponding tau component was found in the autopsied case.Conclusion:Relatively high burden of tau deposition was commonly observed in the lateral temporal cortex and parietal cortex of ANDE, part of which mayexplain dementia in these subjects. [11C]PBB3 may be useful in detecting tauopathy in ANDE