Local distortion by dopants and percolation conductivity in oxides

The chemical doping is a typical method to modulate the physical and chemical properties of oxides and other ionic solids and is often applied to emerge ionic conductivity by introducing ionic defects such as oxygen vacancy with suppressed electronic defects. However, those chemical dopants, which can also be categorized as an ionic defect, attract mobile species and work as a trap center for mobile ionic and electronic defects. This study is motivated to understand the origin of such interaction by DFT calculation and Raman scattering spectroscopy. The percolation conductivity, which appears as a result of such strong interaction between dopants and mobile carriers, is further discussed with emphasis on the crucial role of local distortion and its dynamic contributions. The present study consists of two parts: The DFT simulation and Raman spectroscopy measurements on tetravalent ion-doped CeO2 to estimate the local distortion around the dopant ions. In the second part, we discuss percolation conductivities of proton and holes in proton-conducting perovskite oxides based on electrochemical measurements and the DFT simulation. Pure CeO2 with cubic fluorite structure, known as a host material for excellent oxide ion conducting electrolyte with relatively high partial electronic conductivity in reducing conditions, shows a sharp and single triply-degenerated F2g peak in Raman spectroscopy owing to the crystal symmetry. Upon chemical doping of acceptor dopants, CeO2 starts to show multiple broad peaks slightly higher wave number to the F2g main peak, usually attributed to oxygen vacancy-induced local vibrational modes. There is, however, controversy left on the assignment of these defect induced peaks because observed broad dopant induced peaks never agree with the finitely split peaks estimated by DFT calculation. In the present study, we employed CASTEP code using GGA-PBE functional for DFT simulation and made careful calculations: At first, the stable local structure of doped and undoped CeO2 was estimated by a structural relaxation concerning local distortion and energy, and Raman spectra were simulated by calculating scattering cross section. The present results on the DFT calculation suggest that the origin of dopant-induced peaks is due to a broken local symmetry by the presence of foreign atoms of dopants, but the intensity is determined by the extent of local distortion and extended relaxation length by the difference of ionic size of dopant and the matrix Ce4+ ions (1 ). Large distorted shells are isolated each other at lower concentration regime while overlapping begins at a relatively low concentration around 1-2% in case of cubic fluorite CeO2 phase owing to an extended relaxation length of local distortion. When all dopant ions are isolated, overall properties are governed by the matrix properties. In contrast, the stress shell accommodating dopant ion begin contributing to the macroscopic physical and chemical properties above a critical concentration. The overlapping shell contributes to the broadening of the Raman F2g and dopant related peaks (2). The stress shell mentioned above serves as an attracting or repulsive center for mobile ionic and electronic defects. We find good examples, such as oxide ion conductivity in acceptor-doped CeO2( ) and holes and proton conductivities in acceptor-doped perovskite oxides ( 3, 4 ). In the latter system, a transition from isolated traps to the percolation conductivity has been clearly observed, and discussion on local distortion is developed on the basis of both experimental and theoretical results ( 5 ). REFERENCES ( ) M. Hara and S. Yamaguchi; To be published. ( ) J. Koettgen, et al.; Phys. Chem. Chem. Phys. 20, 14291–14321 (2018). ( ) D.-Y. Kim, S. Miyoshi, and S. Yamaguchi; To be published. ( ) S. Miyoshi, A. Ebara, and S. Yamaguchi; To be published. ( ) H. Takahashi, et al.; Chemistry of Materials, 2017, 29 (4), pp 1518–1526

Silenced Expression of NFKBIA in Lung Adenocarcinoma Patients with a Never-smoking History

Nuclear factor of κ-light polypeptide gene enhancer in B cells inhibitor α (NFKBIA), which is a tumor suppressor gene, was found to be silenced in lung adenocarcinomas. We examined NFKBIA expression, mutations in the EGFR and K-ras genes, and EML4-ALK fusion in 101 resected lung adenocarcinoma samples from never-smokers. NFKBIA expression was evaluated using immunohistochemistry. NFKBIA expression was negative in 16 of the 101 samples (15.8%). EGFR and K-ras mutations and EML4-ALK fusion were detected in 61 (60.5%), 1 (1.0%), and 2 (2.0%) of the 101 samples, respectively, in a completely mutually exclusive manner. Negative NFKBIA expression was observed significantly more frequently among the tumors with none of the three genetic alterations compared to those with such alterations (p＝0.009). In addition, negative NFKBIA expression was significantly more frequent among the EGFR-wild type samples compared to the EGFR-mutant samples (p＝0.013). In conclusion, NFKBIA expression was silenced in adenocarcinomas without EGFR/K-ras mutations or EML4-ALK fusion, suggesting that the silencing of NFKBIA may play an important role in the carcinogenesis of adenocarcinomas independent of EGFR/K-ras mutations or EML4-ALK fusion

Presepsin and renal function

Background : Presepsin (P-SEP) is a highly specific sepsis marker, and its fluctuation with respect to advanced renal impairment or sample agitation has not been fully investigated. We evaluated several renal function-corrected P-SEP indices to establish a simple index and its reference range. Methods : Blood samples for P-SEP measurement were collected with minimal agitation. P-SEP levels were measured using the rapid automated immunoanalyzer “PATHFAST.” This study included 85 chronic kidney disease (CKD) patients, 65 healthy volunteers, and 4 sepsis patients. Results : Patients stratified by estimated glomerular filtration rate (GFR) had significantly higher P-SEP levels for CKD stage G3, especially the advanced GFR stage. We evaluated presepsin / creatinine (P-SEP / CRE) and P-SEP / eGFR ratios as possible indices for renal function. The P-SEP / CRE ratio exhibited no increase correlating with the GFR stage and was identical in the normal and CKD groups ; P-SEP / eGFR decreased if GFR stage worsened. The P-SEP / CRE ratio became significantly higher in sepsis patients and was a more useful index with a reference range of 67–263. Conclusions : P-SEP levels were inversely correlated with renal function, indicating the necessity to consider the influence of renal impairment in CKD patients. The P-SEP / CRE ratio is helpful for sepsis diagnosis, even in patients with renal impairment

Relationship Between Age and Frequency of Side Effects Associated with Postoperative Analgesia

Study Objective: Although patient-controlled analgesia (PCA) is a valid analgesic method, it is necessary to pay attention to associated side effects, especially in elderly patients. It is unclear whether the incidence of side effects increases with age. In this study, we examined the incidence of side effects by age to confirm whether the frequency of side effects varies depending on age group. Patients: Patients who underwent gastroenterological surgery at Hiroshima University Hospital between 2009 and 2013 and received postoperative analgesia using PCA [either epidural PCA (PCEA) or intravenous PCA (IVPCA) were included]. Measurements: The degree of pain using the visual analog scale, number of PCA requests, and frequency of side effects, including nausea, vomiting, pruritus, urinary disturbance, drowsiness, low blood pressure, delirium, and respiratory depression, was determined from PCA records. Main Results: A total of 2,881 patients were enrolled and categorized into PCEA (n = 1,965) or IVPCA (n = 916) group based on postoperative analgesia. The incidence of delirium significantly increased with age in both groups (P < 0.001). In the PCEA group, the incidence of nausea, vomiting, and itching decreased, whereas that of hypotension significantly increased with age. Visual analog scale scores both at rest and during activity on postoperative day 2 were not correlated with age in either group. There was a significant negative correlation with age in both groups for the number of PCA requests on postoperative day 2. Conclusions: The incidence of postoperative delirium increases with age regardless of pain relief method. Side effects related to postoperative analgesia are not necessarily more likely to occur with age

Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes

Background The number of patients with bradyarrhythmia and the number of patients with cardiac pacemakers are increasing with the aging population and the increase in the number of patients with heart diseases. Some patients in whom a cardiac pacemaker has been implanted experience problems such as pacemaker infection and inconvenience due to electromagnetic interference. We have reported that overexpression of HCN channels producing a pacemaker current in mouse embryonic stem cell-derived cardiomyocytes showed enhanced pacing function in vitro and in vivo. The aim of this study was to determine whether HCN4 overexpression in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can strengthen the pacing function of the cells. Methods Human HCN4 was transduced in the AAVS1 locus of human induced pluripotent stem cells by nucleofection and HCN4-overexpressing iPSC-CMs were generated. Gene expression profiles, frequencies of spontaneous contraction and pacing abilities of HCN4-overexpressing and non-overexpressing iPSC-CMs in vitro were compared. Results HCN4-overexpressing iPSC-CMs showed higher spontaneous contraction rates than those of non-overexpressing iPSC-CMs. They responded to an HCN channel blocker and beta adrenergic stimulation. The pacing rates against parent iPSC line-derived cardiomyocytes were also higher in HCN4-overexpressing iPSC-CMs than in non-overexpressing iPSC-CMs. Conclusions Overexpression of HCN4 showed enhancement of I-f current, spontaneous firing and pacing function in iPSC-CMs. These data suggest this transgenic cell line may be useful as a cardiac pacemaker

Clinical evaluation of presepsin considering renal function

Presepsin, a glycoprotein produced during bacterial phagocytosis, is used as a sepsis marker for bacterial infections. However, presepsin levels are affected by renal function, and the evaluation criteria according to kidney function or in chronic kidney diseases remain controversial. Furthermore, presepsin may be increased by sample stirring, but no studies have evaluated this effect.In this study, we excluded the effect of stirring by standardizing the blood collection conditions, analyzed the influence of kidney function on presepsin concentrations, and recalculated the reference range based on the findings. EDTA-whole blood from 47 healthy subjects and 85 patients with chronic kidney disease was collected to measure presepsin by PATHFAST. Presepsin was found to be significantly correlated with the levels of creatinine (r = 0.834), eGFRcreat (r = 0.837), cystatin-C (r = 0.845), and eGFRcys (r = 0.879). Furthermore, in patients with CKD, presepsin levels stratified by eGFRcys showed a significant increase in the CKD G2 patient group and with advancing glomerular filtration rate stage. The following values were obtained: Normal: 97.6 ± 27.4 pg/mL, CKD G1: 100.2 ± 27.6 pg/mL, CKD G2: 129.7 ± 40.7 pg/mL, CKD G3: 208.1 ± 70.2 pg/mL, CKD G4: 320.2 ± 170.1 pg/mL, CKD G5: 712.8 ± 336.3 pg/mL. The reference range, calculated by a nonparametric method using 67 cases of healthy volunteers and patients with chronic kidney disease G1, was found to be 59–153 pg/mL, which was notably lower than the standard reference range currently used. Presepsin concentrations were positively correlated with a few biomarkers of renal function, indicating the necessity to consider the effect of renal function in patients with renal impairment. Using the recalculated reference range considering kidney function may improve the accuracy of evaluating presepsin for diagnosis of sepsis compared to the standard reference currently in use

Pemafibrate Prevents Rupture of Angiotensin II-Induced Abdominal Aortic Aneurysms

Background: Abdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist, on AAA formation and rupture. Methods: Experimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE(-)(/)(-) mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS). Results: The size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-alpha in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPAR alpha significantly attenuated the anti-oxidative effect of pemafibrate. Conclusion: Pemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells

Effect of LCZ696, a dual angiotensin receptor neprilysin inhibitor, on isoproterenol-induced cardiac hypertrophy, fibrosis, and hemodynamic change in rats

Background: Recent clinical studies have shown that treatment with LCZ696, a complex containing the angiotensin receptor blocker valsartan and neprilysin inhibitor sacubitril, improves the prognosis of heart failure patients with a reduced ejection fraction. This study evaluated whether LCZ696 affects left ventricular hypertrophy, fibrosis, and hemodynamics in isoproterenol (ISO)-treated rats compared with valsartan alone. Methods: Male Wistar rats received subcutaneous saline (n = 10), subcutaneous ISO (2.4 mg/kg/day; n = 10), subcutaneous ISO + oral LCZ696 (60 mg/kg/day; n = 20) (ISO-LCZ), or subcutaneous ISO + oral valsartan (30 mg/kg/day; n = 20) (ISO-VAL) for 7 days. Results: LCZ696 and valsartan did not significantly reduce the increased heart weight/body weight ratio in rats treated with ISO. Echocardiography showed that the deceleration time shortened by ISO was restored by LCZ696 but not valsartan alone (p = 0.01 vs. the ISO group). Histological analysis showed that cardiac interstitial fibrosis increased by ISO was decreased significantly by LCZ696 but not valsartan alone (control: 0.10 ± 0.14%; ISO: 0.41 ± 0.32%; ISO-LCZ: 0.19 ± 0.23% [p &lt; 0.01 vs. the ISO group]; ISO-VAL: 0.34 ± 0.23% [p = 0.34 vs. the ISO group]). Quantitative polymerase chain reaction showed that mRNA expression of Tgfb1, Col1a1, Ccl2, and Anp increased by ISO was significantly attenuated by LCZ696 but not valsartan alone (p &lt; 0.05 vs. the ISO group). Conclusions: LCZ696 improves cardiac fibrosis, but not hypertrophy, caused by continuous exposure to ISO in rats

Localization of orexin B and orexin-2 receptor in the rat epididymis

The peptides orexin A (OXA) and orexin B (OXB) derived from the proteolytic cleavage of a common precursor molecule, prepro-orexin, were originally described in the rat hypothalamus. Successively, they have been found in many other brain regions as well as in peripheral organs of mammals and other less evolved animals. The widespread localization of orexins accounts for the multiple activities that they exert in the body, including the regulation of energy homeostasis, feeding, metabolism, sleep and arousal, stress, addiction, and cardiovascular and endocrine functions. Both OXA and OXB peptides bind to two G-coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R) receptor, though with different binding affinity. Altered expression/activity of orexins and their receptors has been associated with a large number of human diseases. Though at present evidence highlighted a role for orexins and cognate receptors in mammalian reproduction, their central and/or local effects on gonadal functions remain poorly known. Here, we investigated the localization of OXB and OX2R in the rat epididymis. Immunohistochemical staining of sections from caput, corpus and cauda segments of the organ showed intense signals for both OXB and OX2R in the principal cells of the lining epithelium, while no staining was detected in the other cell types. Negative results were obtained from immunohistochemical analysis of hypothalamic and testicular tissues from OX2R knock-out mice (OX2R−/−) and OX1R/OX2R double knock-out (OX1R−/−; OX2R−/−) mice, thus demonstrating the specificity of the rabbit polyclonal anti-OX2R antibody used in our study. On contrary, the same antibody clearly showed the presence of OX2R in sections from hypothalamus and testis of normal mice and rats which are well known to express the receptor. Thus, our results provide the first definite evidence for the immunohistochemical localization of OXB and OX2R in the principal cells of rat epididymis