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The pharmacokinetic-pharmacodynamic (PK-PD) breakpoints (BPs) of garenoxacin (GRNX) and other oral quinolones were calculated using Monte Carlo simulation (MCS) based on the distribution of changes in their plasma concentrations. PK-PD BPs of 400 mg once a day (QD) of GRNX for the free area under the curve/minimum inhibitory concentration (fAUC/MIC) for 30 strains of Streptococcus pneumoniae and 100 strains of gram-negative bacteria (G [－]) were 0.5 and 0.125 μg/mL, respectively. PK-PD BPs of other quinolones for S. pneumoniae/G (－) were 1/0.25 μg/mL for levofloxacin (LVFX) 500 mg QD, 0.5/0.125 μg/mL for moxifloxacin (MFLX) 400 mg QD, 0.0625/0.0156 μg/mL for sitafloxacin (STFX) 50 mg twice a day (BID) (100 mg QD), and 0.125/0.0313 μg/mL for STFX 100 mg BID. We also investigated the hypothetical probability of target attainments (PTAs) of fAUC/MIC for community-acquired pneumonia (CAP) using MCS, in consideration of the isolation frequencies of the three main causative pathogens of CAP: S. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. For hypothetical CAP in adults, PTA of fAUC/MIC was 100% with GRNX and MFLX, 96%-97% with STFX at 100 mg BID, 45%-46% with LVFX, and 53%-58% with STFX at 100 mg QD and 50 mg BID. Based on the PK-PD BP, GRNX showed higher fAUC/MIC than the other quinolones tested against the three main pathogens of respiratory infections.

Aims Exposure to glucose and its metabolites in peritoneal dialysis fluid (PDF) results in structural alterations of the peritoneal membrane. Icodextrin-containing PDF eliminates glucose and reduces deterioration of peritoneal membrane function, but direct effects of icodextrin molecules on peritoneal mesothelial cells have yet to be elucidated. We compared the impacts of icodextrin itself with those of glucose under PDF-free conditions on wound healing processes of injured mesothelial cell monolayers, focusing on integrin-mediated cell adhesion mechanisms. Main methods Regeneration processes of the peritoneal mesothelial cell monolayer were investigated employing an in vitro wound healing assay of cultured rat peritoneal mesothelial cells treated with icodextrin powder- or glucose-dissolved culture medium without PDF, as well as icodextrin- or glucose-containing PDF. The effects of icodextrin on integrin-mediated cell adhesions were examined by immunocytochemistry and Western blotting against focal adhesion kinase (FAK). Key findings Cell migration over fibronectin was inhibited in conventional glucose-containing PDF, while icodextrin-containing PDF exerted no significant inhibitory effects. Culture medium containing 1.5% glucose without PDF also inhibited wound healing of mesothelial cells, while 7.5% icodextrin-dissolved culture medium without PDF had no inhibitory effects. Glucose suppressed cell motility by inhibiting tyrosine phosphorylation of FAK, formation of focal adhesions, and cell spreading, while icodextrin had no effects on any of these mesothelial cell functions. Significance Our results demonstrate icodextrin to have no adverse effects on wound healing processes of peritoneal mesothelial cells. Preservation of integrin-mediated cell adhesion might be one of the molecular mechanisms accounting for the superior biocompatibility of icodextrin-containing PDF.

Underwater light environment and photosynthetic accessory pigments were investigated in Ariake Bay in order to understand how change of the pigments occurs in response to the tidal-induced changes in underwater light conditions. We hypothesize that phytoplankton increases photo-protective pigments and decreases light-harvesting pigments under higher light condition in the mixed layer caused by tidal cycle. Contribution rates of non-phytoplankton particles (a nph (400‐700)) for light attenuation coefficient (K d ) was highest (32‐85%), and those of phytoplankton particles (a ph (400‐700)), dissolved organic matter (a g (400‐700)) and water were 6‐32, 6‐21 and 5‐23%, respectively. Mean K d was higher during the spring tide (0.55 ± 0.23 m ‐1 ) than the neap tide (0.44 ± 0.16 m ‐1 ), and the K d difference was caused by the substances resuspension due to the tidal current. In contrast, ratios of photo-protective pigments (diadinoxanthin and diatoxanthin) per chlorophyll a ((DD+DT)/Chl a) were higher during the neap tide (0.10 ± 0.03 mg mg-Chl a ‐1 ) than the spring tide (0.08 ± 0.03 mg mg-Chl a ‐1 ). And there was significant positive correlation between (DD+DT)/ Chl a and mean relative PAR in the mixed layer ( Imix ). Moreover, there was significant negative correlation between ratios of light-harvesting pigments (fucoxanthin) per Chl a (Fuco/Chl a) and Imix . These results suggested that phytoplankton in Ariake Bay increase photo-protective pigments and decrease light-harvesting pigments in the higher light condition of less turbid, shallower mixed layer during neap tide than spring tide.

Aims Insulin-like growth factor (IGF)-1 is a major mitogenic growth factor for mesangial cells (MCs). Statins slow the progression of chronic kidney disease by affecting inflammatory cell signaling pathways, in addition to improving lipid profile, however, no studies have investigated the effects of fluvastatin on mitogen-activated protein (MAP) kinase activity or MC proliferation in kidney cells. We investigated the effects of fluvastatin on IGF-1-induced activation of intracellular signal pathways and MC proliferation, and examined the inhibitory mechanisms of fluvastatin. Main methods Western blotting and cell proliferation assay were used. Key findings IGF-1 induced phosphorylation of extracellular-related kinase (ERK)1/2, MAP or ERK kinase (MEK)1/2, and Akt, expression of cyclin D1, and MC proliferation in cultured human MCs. Fluvastatin or PD98059, an MEK1 inhibitor, completely abolished IGF-1-induced MEK1/2 and ERK1/2 phosphorylation and MC proliferation, whereas inhibition of Akt had no effect on MC proliferation. Mevalonic acid prevented fluvastatin inhibition of IGF-1-induced MEK1/2 and ERK1/2 phosphorylation, cyclin D1 expression, and MC proliferation. Significance Fluvastatin inhibits IGF-1-induced activation of the MAP kinase pathway and MC proliferation by mevalonic acid depletion, and might have renoprotective effects by inhibiting IGF-1-mediated MC proliferation.

Activating receptor activator of NF-kappaB (RANK) and TNF receptor (TNFR) promote osteoclast differentiation. A critical ligand contact site on the TNFR is partly conserved in RANK. Surface plasmon resonance studies showed that a peptide (WP9QY) that mimics this TNFR contact site and inhibits TNF-alpha-induced activity bound to RANK ligand (RANKL). Changing a single residue predicted to play an important role in the interaction reduced the binding significantly. WP9QY, but not the altered control peptide, inhibited the RANKL-induced activation of RANK-dependent signaling in RAW 264.7 cells but had no effect on M-CSF-induced activation of some of the same signaling events. WP9QY but not the control peptide also prevented RANKL-induced bone resorption and osteoclastogenesis, even when TNFRs were absent or blocked. In vivo, where both RANKL and TNF-alpha promote osteoclastogenesis, osteoclast activity, and bone loss, WP9QY prevented the increased osteoclastogenesis and bone loss induced in mice by ovariectomy or low dietary calcium, in the latter case in both wild-type and TNFR double-knockout mice. These results suggest that a peptide that mimics a TNFR ligand contact site blocks bone resorption by interfering with recruitment and activation of osteoclasts by both RANKL and TNF.

鋼中非金属介在物の除去や形態制御による鋼の清浄化や機能化は重要な課題であり,介在物粒子の生成過程の解明と起源探索手法の確立が必要である.一方,一次ビームにGa+収束イオンビームを用いたサブミクロン二次イオン質量分析(SIMS)装置は,高い切断加工能力と0.1μm以下の高空間分解能を有し,微小領域並びに数μm程度の微粒子に対する定量分析・三次元元素分布解析に大変有効である.著者らは介在物粒子のキャラクタリゼーション手法の確立を目的として,Ti添加極低炭素鋼中の介在物粒子に対し以下の分析を行った.始めに,電子線マイクロアナリシス法により任意の粒子に対して粒別分析を行い,供試鋼中の介在物が三タイプに分類されることを明らかにした.次いで,各タイプの代表的な粒子に対してサブミクロンSIMS装置を用いて粒別定量分析を行い,粒内元素分布と任意断面の化学組成を得た.以上の分析結果から,供試鋼中に含まれる介在物粒子の生成過程に関する検討を行い重要な知見を得た.

Protein degradation in bacteria plays a dynamic and critical role in the cellular response to environmental stimuli such as heat shock and DNA damage and in removing damaged proteins or protein aggregates. Escherichia coli recN is a member of the structural maintenance of chromosomes family and is required for DNA double strand break (DSB) repair. This study shows that RecN protein has a short half-life and its degradation is dependent on the cytoplasmic protease ClpXP and a degradation signal at the C terminus of RecN. In cells with DNA DSBs, green fluorescent protein-RecN localized in discrete foci on nucleoids and formed visible aggregates in the cytoplasm, both of which disappeared rapidly in wild-type cells when DSBs were repaired. In contrast, in DeltaclpX cells, RecN aggregates persisted in the cytoplasm after release from DNA damage. Furthermore, analysis of cells experiencing chronic DNA damage revealed that proteolytic removal of RecN aggregates by ClpXP was important for cell viability. These data demonstrate that ClpXP is a critical factor in the cellular clearance of cytoplasmic RecN aggregates from the cell and therefore plays an important role in DNA damage tolerance.