bluuebunny/crossref_metadata_2025 huggingface dataset:
Distributed ATMD for Buffeting Control of Cable-Stayed Bridges Under Construction
Authors: Wen Yong-Kui , Sun Li-Min
Published: December 2014

This paper is concerned with mitigating multimode buffeting of cable-stayed bridges by optimizing the placements of active tuned mass dampers (ATMDs) and sensors and developing a control model and schemes. The Third Nanjing Bridge over the Yangtze River was used to formulate a mathematical control model with distributed ATMDs under wind action. Hankel norms were combined with structural mode analysis to build placement indices of the ATMDs and sensors under a defined objective while considering the influence of exterior excitation. A selection index of modes was proposed. ATMD/sensor placement on the Third Nanjing Bridge and mode selection were simulated to determine the wind response control. A control design model with accurate mode selection was developed using modal superposition and it was used to investigate control schemes of distributed ATMDs for buffeting response control of the cable-stayed bridge. The results showed that the dynamic characteristics of the developed control design model agreed well with those of the original system model. Control scheme selection depends on the tradeoff between the control objective and actuator performance. Considering realistic engineering constraints, the distributed ATMDs are shown to perform well.
Semi-Analytical Dynamic Analysis of Noncontacting Finger Seals
Authors: Du Kaibing , Li Yongjian , Suo Shuangfu , Wang Yuming
Published: December 2014

Noncontacting finger seals represent a new noncontacting and compliant seal in gas turbine sealing technology. The compliance and noncontacting nature make this kind of seals fully adaptive to rotor excursions in the radial direction without damaging the seal performance. A new semi-analytical method is developed for characterizing the linearized dynamic performance of noncontacting finger seals. The linearized dynamic characteristics of the gas film are numerically computed using the step jump method and then approximated analytically in the equations of motion using a Prony series. By combining the gas film analytical dynamic characterization with the constitutive model for the dynamic properties of noncontacting finger seals, the dynamic equation of motion for the system is derived in analytical form. The results are presented of the gas film properties, natural transient response to initial conditions, steady-state response to rotor excursion, transmissibility ratios and dynamic stability analysis using the analytical model. It is demonstrated that the steady-state responses from the closed-form solutions agree well with those by the numerical simulation, and the analytical solutions can be used as the benchmark for calibrating the results from numerical analysis.
Influence of Aspect Ratio of Vibratory Flap on Dynamic Response of Clamped Rectangular Plate
Authors: Mahadevaswamy P. , Suresh B. S.
Published: December 2014

The transverse vibration control of a clamped, rectangular, isotropic plate by a vibratory flap subjected to harmonic excitation has been investigated by Finite Element Analysis (FEA) and experimental technique. The vibratory flap is a new plate-type dynamic vibration absorber, which can vibrate on the plate when attached as a cantilever plate. The study has been focused specifically on the influence of aspect ratio of vibratory flap on the dynamic response of the plate at constant mass ratio and constant tuning frequency ratio. The study has revealed that the dynamic response of the plate varies with respect to the aspect ratio for aforementioned conditions. An optimum aspect ratio has also been obtained by minimizing the mass ratio with maximum attenuation in the first and second target frequencies. The results have shown that the optimized flap can trim down the plate vibrations by up to 90–95% in the fundamental mode. Moreover, the dynamic response of the plate can be improved to a great extent due to the adoption of an optimal aspect ratio of the flap. Finally, the experimental outcomes have shown fairly good agreement with the results obtained from the finite element analysis.
Parametric Instability of Beams with Transverse Cracks Subjected to Harmonic In-Plane Loading
Authors: Mishra Uttam Kumar , Sahu Shishir Kumar
Published: December 2014

Cracks in structural members lead to local changes in their stiffness and consequently their static, dynamic and stability behavior is altered. The influence of cracks on dynamic characteristics like free vibration, buckling and parametric resonance characteristics of a cracked beam with a transverse crack using finite element method (FEM) is investigated in the present work. Modal testing of beams with transverse open crack is conducted using FFT analyzer to verify the frequencies of vibration of beams. The crack is assumed to be open type and the analysis is linear based on small deformation theory neglecting damping. The loading on the beam is considered as axial with a simple harmonic fluctuation with respect to time. A two-noded Timoshenko beam element with provision of crack is used in this study. The equation of motion represents a system of second-order differential equations with periodic coefficients of the Mathieu–Hill type. The development of the regions of instability arises from Floquet's theory and the periodic solution is obtained by Bolotin's approach using FEM. It is observed that the frequencies of vibration and buckling load of the beam are influenced significantly by location and depth of cracks. It is observed that, for a given location of crack, the onset of instability occurs earlier with increase in depth of crack. As the location of crack moves from the fixed end to the free end the excitation frequency increases. The instability occurs later and the width of the instability regions reduces. When the damage is near to the free end, the instability region almost coincides with the instability region for the undamaged beam. This means that the damage near the fixed end is more severe on the dynamic instability behavior than that of the crack located at other positions. The vibration and instability results can be used as a technique for structural health monitoring or testing of structural integrity, performance and safety.
Benchmark of electronic structure methods for protein–ligand interactions based on high-level reference data
Authors: Yilmazer Nusret Duygu , Heitel Pascal , Schwabe Tobias , Korth Martin
Published: December 2014

The accurate prediction of the strength of protein–ligand interactions is a very difficult problem despite impressive advances in the field of biomolecular modeling. There are good reasons to believe that quantum mechanical methods can help with this task, but the application of such methods in the context of scoring is still in its infancy. Here we benchmark several wave function theory (WFT), density functional theory (DFT) and semiempirical quantum mechanical (SQM) approaches against high-level theoretical references for realistic test cases. Based on our findings for systematically generated model systems of real protein/ligand complexes from the PDB-bind database, we can recommend SCS-MP2 and B2-PLYP-D3 as reference methods, TPSS-D3+Dabc/def-TZVPP as the best DFT approach and PM6-DH+ as a fast and accurate alternative to full ab initio treatments.
Catalysis by substituted iron phthalocyanines of crystal violet leucobase oxidation with dioxygen
Authors: Fedorova Tatiana M. , Derkacheva Valentina M. , Lukyanets Eugene A. , Kaliya Oleg L.
Published: December 2014

The catalytic reaction of crystal violet leucobase oxidation by dioxygen in o-dichlorobenzene into corresponding dye was studied as a model of hydrocarbons C – H group oxidation. Substituted iron phthalocyanines in acidic form HPcFeX were used as the catalysts. It was shown that the oxidation process was accompanied in all cases by autocatalytic destruction of catalyst with induction period depending on concentrations of reactants. The kinetics of dye formation and catalyst degradation, as well as the effect of radical reaction inhibitors were studied. The nature of the process main stages was proposed.
OPENING UP AND CLOSING DOWN: THE INTERPRETATIVE REPERTOIRES OF LEADING INNOVATION
Authors: HUZZARD TONY
Published: December 2014

The article argues for greater attention to be given to discursive approaches to the leadership of innovation through proposing a variant of Potter and Wetherell's concept of interpretative repertoires. Drawing upon empirical material from a case study of managers engaged in R&D activities at a multimedia company, the study illustrates how the talk and thought of leadership reveals the contrasting discursive resources and interpretative repertoires underpinning the leadership of innovation. The article proposes, illustrates and develops six interpretative repertoires for leading the practices and processes of innovation. These are informed by six images or root metaphors: creating, challenging, focusing, selling, linking and travelling. In turn, these prompt leadership practices that either encourage variety, secure agreement or a combination of the two.
Wrinkling in Graphene Subjected to Gradient Tension
Authors: Huang Jianzhang , Han Qiang
Published: December 2014

In the present study, the initiation and evolution mechanisms of wrinkles in a square single layer graphene sheet (SLGS) under gradient tensile displacements are investigated based on molecular dynamics (MD) simulations. The mechanism of wrinkling process is elucidated by studying the atomic out-of-plane displacements development of the key atoms in SLGS. It reveals that the loading and boundary conditions play dominant roles in the wrinkling deformation of graphene. The dependences of the wrinkling amplitude, wavelength, out-of-plane displacement, direction angle and wrinkling area ratio on the applied gradient tensile displacements are obtained. The effects of temperature, size of graphene and loading grads on graphene wrinkling are investigated.
Vasoactive intestinal peptide prevents PKCε-induced intestinal epithelial barrier disruption during EPEC infection
Authors: Morampudi V. , Conlin V. S. , Dalwadi U. , Wu X. , Marshall K. C. , Nguyen C. , Vallance B. A. , Jacobson K.
Published: December 2014

We previously showed that vasoactive intestinal peptide (VIP) protects against bacterial pathogen-induced epithelial barrier disruption and colitis, although the mechanisms remain poorly defined. The aim of the current study was to identify cellular pathways of VIP-mediated protection with use of pharmacological inhibitors during enteropathogenic Escherichia coli (EPEC) infection of Caco-2 cell monolayers and during Citrobacter rodentium-induced colitis. EPEC-induced epithelial barrier disruption involved the PKC pathway but was independent of functional cAMP, Rho, and NF-κB pathways. VIP mediated its protective effects by inhibiting EPEC-induced PKC activity and increasing expression of the junctional protein claudin-4. Short-term treatment with TPA, which is known to activate PKC, was inhibited by VIP pretreatment, while PKC degradation via long-term treatment with TPA mimicked the protective actions of VIP. Immunostaining for specific PKC isotypes showed upregulated expression of PKCθ and PKCε during EPEC infection. Treatment with specific inhibitors revealed a critical role for PKCε in EPEC-induced barrier disruption. Furthermore, activation of PKCε and loss of barrier integrity correlated with claudin-4 degradation. In contrast, inhibition of PKCε by VIP pretreatment or the PKCε inhibitor maintained membrane-bound claudin-4 levels, along with barrier function. Finally, in vivo treatment with the PKCε inhibitor protected mice from C. rodentium-induced colitis. In conclusion, EPEC infection increases intracellular PKCε levels, leading to decreased claudin-4 levels and compromising epithelial barrier integrity. VIP inhibits PKCε activation, thereby attenuating EPEC-induced barrier disruption.
Cytotoxic T lymphocytes and natural killer cells display impaired cytotoxic functions and reduced activation in patients with alcoholic hepatitis
Authors: Støy Sidsel , Dige Anders , Sandahl Thomas Damgaard , Laursen Tea Lund , Buus Christian , Hokland Marianne , Vilstrup Hendrik
Published: December 2014

The dynamics and role of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and NKT cells in the life-threatening inflammatory disease alcoholic hepatitis is largely unknown. These cells directly kill infected and damaged cells through, e.g., degranulation and interferon-γ (IFNγ) production, but cause tissue damage if overactivated. They also assist tissue repair via IL-22 production. We, therefore, aimed to investigate the frequency, functionality, and activation state of such cells in alcoholic hepatitis. We analyzed blood samples from 24 severe alcoholic hepatitis patients followed for 30 days after diagnosis. Ten healthy abstinent volunteers and 10 stable abstinent alcoholic cirrhosis patients were controls. Using flow cytometry we assessed cell frequencies, NK cell degranulation capacity following K562 cell stimulation, activation by natural killer group 2 D (NKG2D) expression, and IL-22 and IFNγ production. In alcoholic hepatitis we found a decreased frequency of CTLs compared with healthy controls ( P < 0.001) and a similar trend for NK cells ( P = 0.089). The NK cell degranulation capacity was reduced by 25% compared with healthy controls ( P = 0.02) and by 50% compared with cirrhosis patients ( P = 0.04). Accordingly, the NKG2D receptor expression was markedly decreased on NK cells, CTLs, and NKT cells ( P < 0.05, all). The frequencies of IL-22-producing CTLs and NK cells were doubled compared with healthy controls ( P < 0.05, all) but not different from cirrhosis patients. This exploratory study for the first time showed impaired cellular cytotoxicity and activation in alcoholic hepatitis. This is unlikely to cause hepatocyte death but may contribute toward the severe immune incompetence. The results warrant detailed and mechanistic studies.
Endothelial Gab1 deficiency aggravates splenomegaly in portal hypertension independent of angiogenesis
Authors: Jiang Beibei , Deng Qiuping , Huo Yingqing , Li Wei , Shibuya Masabumi , Luo Jincai
Published: December 2014

Certain pathological changes, including angiogenesis, actively contribute to the pathogenesis of splenomegaly in portal hypertension (PH), although the detailed molecular and cellular mechanisms remain elusive. In this study, we demonstrated that endothelial Grb-2-associated binder 1 (Gab1) plays a negative role in PH-associated splenomegaly independent of angiogenesis. PH, which was induced by partial portal vein ligation, significantly enhanced Gab1 expression in endothelial cells in a time-dependent manner. Compared with controls, endothelium-specific Gab1 knockout (EGKO) mice exhibited a significant increase in spleen size while their PH levels remained similar. Pathological analysis indicated that EGKO mice developed more severe hyperactive white pulp and fibrosis in the enlarged spleen but less angiogenesis in both the spleen and mesenteric tissues. Mechanistic studies showed that the phosphorylation of endothelial nitric oxide synthase (eNOS) in EGKO mice was significantly lower than in controls. In addition, the dysregulation of fibrosis and inflammation-related transcription factors [e.g., Krüppel-like factor (KLF) 2 and KLF5] and the upregulation of cytokine genes (e.g., TNF-α and IL-6) were observed in EGKO mice. We thus propose that endothelial Gab1 mediates multiple pathways in inhibition of the pathogenesis of splenomegaly in PH via prevention of endothelial dysfunction and overproduction of proinflammatory/profibrotic cytokines.
Glutamatergic receptor dysfunction in spinal cord contributes to the exaggerated exercise pressor reflex in heart failure
Authors: Wang Han-Jun , Cahoon Rebecca , Cahoon Edgar B. , Zheng Hong , Patel Kaushik P. , Zucker Irving H.
Published: December 2014

Excitatory amino acids (e.g., glutamate) released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR) in physiological conditions. However, the role of glutamate and glutamate receptors in mediating the exaggerated EPR in the chronic heart failure (CHF) state remains to be determined. In the present study, we performed microinjection of glutamate receptor antagonists into ipisilateral L4/L5 dorsal horns to investigate their effects on the pressor response to static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots in decerebrate sham-operated (sham) and CHF rats. Microinjection of glutamate (10 mM, 100 nl) into the L4 or L5 dorsal horn caused a greater pressor response in CHF rats compared with sham rats. Furthermore, microinjection of either the broad-spectrum glutamate receptor antagonist kynurenate (10 mM, 100 nl) or the N-methyl-d-aspartate (NMDA) receptor antagonist dl-2-amino-5-phosphonovalerate (50 mM, 100 nl) or the non-NMDA-sensitive receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (5 mM, 100 nl) into L4/5 dorsal horns decreased the pressor response to static contraction in CHF rats to a greater extent than in sham rats. Molecular evidence showed that the protein expression of glutamate receptors (both non-NMDA and NMDA) was elevated in the dorsal horn of the lumbar spinal cord in CHF rats. In addition, data from microdialysis experiments demonstrated that although basal glutamate release at the dorsal horn at rest was similar between sham and CHF rats (225 ± 50 vs. 260 ± 63 nM in sham vs. CHF rats, n = 4, P > 0.05), CHF rats exhibit greater glutamate release into the dorsal horn during muscle contraction compared with sham rats (549 ± 60 vs. 980 ± 65 nM in sham vs. CHF rats, n = 4, P < 0.01). These data indicate that the spinal glutamate system contributes to the exaggerated EPR in the CHF state.
Peripharyngeal tissue deformation, stress distributions, and hyoid bone movement in response to mandibular advancement
Authors: Amatoury Jason , Kairaitis Kristina , Wheatley John R. , Bilston Lynne E. , Amis Terence C.
Published: December 2014

Mandibular advancement (MA) increases upper airway (UA) patency and decreases collapsibility. Furthermore, MA displaces the hyoid bone in a cranial-anterior direction, which may contribute to MA-associated UA improvements via redistribution of peripharyngeal tissue stresses (extraluminal tissue pressure, ETP). In the present study, we examined effects of MA on ETP distributions, deformation of the peripharyngeal tissue surface (UA geometry), and hyoid bone position. We studied 13 supine, anesthetized, tracheostomized, spontaneously breathing adult male New Zealand White rabbits. Graded MA was applied from 0 to ∼4.5 mm. ETP was measured at six locations distributed throughout three UA regions: tongue, hyoid, and epiglottis. Axial computed tomography images of the UA (nasal choanae to glottis) were acquired and used to measure lumen geometry (UA length; regional cross-sectional area) and hyoid displacement. MA resulted in nonuniform decreases in ETP (greatest at tongue region), ranging from −0.11 (−0.15 to −0.06) to −0.82 (−1.09 to −0.54) cmH2O/mm MA [linear mixed-effects model slope (95% confidence interval)], across all sites. UA length decreased by −0.5 (−0.8 to −0.2) %/mm accompanied by nonuniform increases in cross-sectional area (greatest at hyoid region) ranging from 7.5 (3.6–11.4) to 18.7 (14.9–22.5) %/mm. The hyoid bone was displaced in a cranial-anterior direction by 0.42 (0.36–0.44) mm/mm MA. In summary, MA results in nonuniform changes in peripharyngeal tissue pressure distributions and lumen geometry. Displacement of the hyoid bone with MA may play a pivotal role in redistributing applied MA loads, thus modifying tissue stress/deformation distributions and determining resultant UA geometry outcomes.
Muscle-specific deletion of exons 2 and 3 of theIL15RAgene in mice: effects on contractile properties of fast and slow muscles
Authors: O'Connell Grant , Guo Ge , Stricker Janelle , Quinn LeBris S. , Ma Averil , Pistilli Emidio E.
Published: December 2014

Interleukin-15 (IL-15) is a putative myokine hypothesized to induce an oxidative skeletal muscle phenotype. The specific IL-15 receptor alpha subunit (IL-15Rα) has also been implicated in specifying this contractile phenotype. The purposes of this study were to determine the muscle-specific effects of IL-15Rα functional deficiency on skeletal muscle isometric contractile properties, fatigue characteristics, spontaneous cage activity, and circulating IL-15 levels in male and female mice. Muscle creatine kinase (MCK)-driven IL-15Rα knockout mice ( mIl15rafl/fl/Cre+) were generated using the Cre-loxP system. We tested the hypothesis that IL-15Rα functional deficiency in skeletal muscle would increase resistance to contraction-induced fatigue, cage activity, and circulating IL-15 levels. There was a significant effect of genotype on the fatigue curves obtained in extensor digitorum longus (EDL) muscles from female mIl15rafl/fl/Cre+mice, such that force output was greater during the repeated contraction protocol compared with mIl15rafl/fl/Cre−control mice. Muscles from female mIl15rafl/fl/Cre+mice also had a twofold greater amount of the mitochondrial genome-specific COXII gene compared with muscles from mIl15rafl/fl/Cre−control mice, indicating a greater mitochondrial density in these skeletal muscles. There was a significant effect of genotype on the twitch:tetanus ratio in EDL and soleus muscles from mIl15rafl/fl/Cre+mice, such that the ratio was lower in these muscles compared with mIl15rafl/fl/Cre−control mice, indicating a pro-oxidative shift in muscle phenotype. However, spontaneous cage activity was not different and IL-15 protein levels were lower in male and female mIl15rafl/fl/Cre+mice compared with control. Collectively, these data support a direct effect of muscle IL-15Rα deficiency in altering contractile properties and fatigue characteristics in skeletal muscles.
Stem Cells Increase in Numbers in Perinecrotic Areas in Human Renal Cancer
Authors: Varna Mariana , Gapihan Guillaume , Feugeas Jean-Paul , Ratajczak Philippe , Tan Sophie , Ferreira Irmine , Leboeuf Christophe , Setterblad Niclas , Duval Arnaud , Verine Jérôme , Germain Stéphane , Mongiat-Artus Pierre , Janin Anne , Bousquet Guilhem
Published: December 2014

Purpose: Developing strategies to overcome resistance to sunitinib is a major challenge in human renal cell carcinoma (RCC). We hypothesized that sunitinib-induced tumor necrosis–associated hypoxia could interact with renal cancer stem cells in patients with metastatic RCC.

Experimental Design: We studied tissue samples from 7 patients with primary metastatic RCC, before and after sunitinib treatment, and from six xenograft models derived from human RCC. Two xenograft models were responders to sunitinib, the four others were nonresponders. CD133/CXCR4–coexpressing cells derived from the two responder xenograft models were used for in vitro studies.

Results: In the seven primary RCCs, we identified a significantly larger number of CD133/CXCR4–coexpressing cells in perinecrotic versus perivascular areas. Their numbers also significantly increased after treatment, in perinecrotic areas. We reproduced these clinical and pathologic results in all six RCC xenograft models with again a preferential perinecrotic distribution of CD133-expressing cells. Necrosis occurred at day 7 in the two responder models treated with sunitinib, whereas it occurred at day 21 in the untreated controls and in the four nonresponder models. Strikingly, when we studied the six RCC xenograft models at the time necrosis, whether spontaneous or sunitinib-induced, occurred, necrosis area correlated with stem-cell number in all 120 xenografted RCCs. When studied under experimental hypoxia, the number of CD133/CXCR4–coexpressing cells and their tumorigenic potency increased whereas their sensitivity to sunitinib decreased.

Conclusions: In human RCC, sunitinib was able to generate resistance to its own therapeutic effect via induced hypoxia in perinecrotic areas where cancer stem cells were found in increased numbers. Clin Cancer Res; 21(4); 916–24. ©2014 AACR.
Standardized Ki67 Diagnostics Using Automated Scoring—Clinical Validation in the GeparTrio Breast Cancer Study
Authors: Klauschen Frederick , Wienert Stephan , Schmitt Wolfgang D. , Loibl Sibylle , Gerber Bernd , Blohmer Jens-Uwe , Huober Jens , Rüdiger Thomas , Erbstößer Erhard , Mehta Keyur , Lederer Bianca , Dietel Manfred , Denkert Carsten , von Minckwitz Gunter
Published: December 2014

Purpose: Scoring proliferation through Ki67 immunohistochemistry is an important component in predicting therapy response to chemotherapy in patients with breast cancer. However, recent studies have cast doubt on the reliability of “visual” Ki67 scoring in the multicenter setting, particularly in the lower, yet clinically important, proliferation range. Therefore, an accurate and standardized Ki67 scoring is pivotal both in routine diagnostics and larger multicenter studies.

Experimental Design: We validated a novel fully automated Ki67 scoring approach that relies on only minimal a priori knowledge on cell properties and requires no training data for calibration. We applied our approach to 1,082 breast cancer samples from the neoadjuvant GeparTrio trial and compared the performance of automated and manual Ki67 scoring.

Results: The three groups of autoKi67 as defined by low (≤15%), medium (15.1%–35%), and high (>35%) automated scores showed pCR rates of 5.8%, 16.9%, and 29.5%, respectively. AutoKi67 was significantly linked to prognosis with overall and progression-free survival P values POS < 0.0001 and PPFS < 0.0002, compared with POS < 0.0005 and PPFS < 0.0001 for manual Ki67 scoring. Moreover, automated Ki67 scoring was an independent prognosticator in the multivariate analysis with POS = 0.002, PPFS = 0.009 (autoKi67) versus POS = 0.007, PPFS = 0.004 (manual Ki67).

Conclusions: The computer-assisted Ki67 scoring approach presented here offers a standardized means of tumor cell proliferation assessment in breast cancer that correlated with clinical endpoints and is deployable in routine diagnostics. It may thus help to solve recently reported reliability concerns in Ki67 diagnostics. Clin Cancer Res; 21(16); 3651–7. ©2014 AACR.
Characterising Haemodynamic Stress during Haemodialysis Using the Extrema Points Analysis Model
Authors: Eldehni Mohamed Tarek , Odudu Aghogho , McIntyre Christopher William
Published: December 2014

Background and Aims: It is becoming recognised that the process of haemodialysis (HD) itself induces circulatory stress that could be implicated in the observed higher rate of end-organ damage. We aimed to study the haemodynamic performance during HD using the extrema points (EP) analysis model, and to examine the determinants of the model and its relation to circulatory stress. Methods: 63 incident HD patients were studied. Mean arterial blood pressure (MAP) EP frequencies and baroreflex sensitivity during HD were computed for continuous non-invasive haemodynamic monitoring. Pulse-wave velocity as a measure of arterial stiffness was performed. High-sensitivity troponin-T was also measured. Results: The time of each dialysis session was divided into four quarters. Repeated measures ANOVA of the MAP EP frequencies for all subjects during HD demonstrated a gradual significant increase reaching peak levels at the third quarter of dialysis time and remaining at that peak during the fourth quarter (F(3,171228) = 392.06, p < 0.001). In multivariate regression, lower baroreflex sensitivity was the only independent predictor of higher MAP EP frequencies (β = -0.642, p = 0.001, adjusted R2 for the whole model = 0.385). In linear regression analysis, higher MAP EP frequencies were associated with higher troponin-T levels (β = 0.442, p = 0.002, R2 = 0.19, B = 103.29, 95% CI 38.88-167.70). Conclusion: The EP analysis model using MAP is a novel functional haemodynamic measure that can represent and quantify circulatory stress during HD. This measure seems to be determined by the integrity of the autonomic function in HD and could represent the link between circulatory stress and end-organ damage in HD patients.
Functional Status and Mortality in Chronic Kidney Disease: Results from a Prospective Observational Study
Authors: Ritchie James P. , Alderson Helen , Green Darren , Chiu Diana , Sinha Smeeta , Middleton Rachel , O'Donoghue Donal , Kalra Philip A.
Published: December 2014

Background/Aims: Measures of functional status are used in the general population to aid prognostication but their use has not been explored in pre-dialysis chronic kidney disease (CKD). This analysis considers the association between the Karnofsky performance score (KPS) and all-cause mortality in a CKD stage 3-5 cohort. Methods: Patients were selected from the Chronic Renal Insufficiency Standards Implementation Study (CRISIS), a prospective observational study of outcome in CKD. Risk for death was assessed using multivariate Cox regression, and differences in progression of biochemical parameters were considered in a mixed-effects model. Results: A total of 1,515 patients with a median follow-up time of 2.9 (1.5-4.8) years were considered. Baseline age was 60 ± 11 years and eGFR was 30 ± 12 ml/min/1.73 m2. Patients with a reduced KPS had an increased risk for death. The hazard ratio (HR) for death was: KPS 90 group, HR 1.2 (95% CI 0.9-1.5), p = 0.1; KPS ≤80 group, HR 1.8 (95% CI 1.4-2.4), p < 0.001. In the mixed-effects model, the average annual loss of eGFR was greater in patients with a KPS ≤80 versus patients with a KPS >80 (5 vs. 3%, p = 0.008). Conclusion: A reduced KPS is independently associated with risk for mortality in patients with CKD stages 3-5. This may relate to a more rapid loss of eGFR.
Relationship between Serum Uric Acid and Serum Oxidative Stress Markers in the Japanese General Population
Authors: Yamakado Minoru , Toda Akiko , Tani Mizuki , Ishizaka Nobukazu
Published: December 2014

Background: Increased production of reactive oxygen species is a condition that is associated with, and plays a role in the progression of, various disorders such as hypertension, atherosclerosis, and diabetes. Purpose: To assess in vivo oxidative stress levels and antioxidant potential and to analyze the relationship with serum uric acid (UA) levels. Methods and Results: Oxidative stress levels (derivatives of reactive oxygen metabolites, d-ROMs) and antioxidant potential (biological antioxidant potential, BAP) were measured in individuals who underwent a general health screening test, and data were analyzed from 8,025 individuals (2,953 women and 5,072 men) who were free from UA-lowering medication. Higher serum UA levels were associated with increased levels of d-ROMs in both genders, and this trend was more prominent in women. In addition, higher UA levels were also associated with higher BAP in both genders, although the dose dependence was not apparent in men. These associations remained statistically significant after adjusting for age, blood pressure, renal function, albuminuria, C-reactive protein, and insulin resistance index. Conclusions: In individuals who underwent general health screening, serum UA levels were positively associated with both d-ROMs and BAP levels. Whether lowering of UA by lifestyle modification or by medication alters d-ROM/BAP levels awaits further investigations.
Central Venous Oxygen Saturation: A Potential New Marker for Circulatory Stress in Haemodialysis Patients?
Authors: Harrison Laura E.A. , Selby Nicholas M. , McIntyre Christopher W.
Published: December 2014

Background/Aims: Haemodialysis causes recurrent haemodynamic stress with subsequent ischaemic end-organ dysfunction. As dialysis prescriptions/schedules can be modified to lessen this circulatory stress, an easily applicable test to allow targeted interventions in vulnerable patients is urgently required. Methods: Intra-dialytic central venous oxygen saturation (ScvO2) and clinical markers (including ultrafiltration, blood pressure) were measured in 18 prevalent haemodialysis patients. Results: Pre-dialysis ScvO2 was 63.5 ± 13% and fell significantly to 56.4 ± 8% at end dialysis (p = 0.046). Ultrafiltration volume, a key driver of dialysis-induced myocardial ischaemia, inversely correlated to ScvO2 (r = -0.680, p = 0.015). Conclusions: This initial study demonstrates ScvO2 sampling is practical, with a potential clinical utility as an indicator of circulatory stress during dialysis.
Geriatric Assessment for Therapeutic Decision-Making Regarding Renal Replacement in Elderly Patients with Advanced Chronic Kidney Disease
Authors: Rodriguez Villarreal Isabel , Ortega Olimpia , Hinostroza Julie , Cobo Gabriela , Gallar Paloma , Mon Carmen , Herrero Juan Carlos , Ortiz Milagros , Di Giogia Cristina , Oliet Aniana , Vigil Ana
Published: December 2014

In patients older than 75 years with advanced chronic kidney disease (CKD), the decision between treatment with dialysis [intention to treat with dialysis (ITD)] or conservative care (CC) is a challenge. Geriatric assessment can be helpful. The aim was to identify which factors had had an influence on decision-making. Methods: We recruited 56 patients. At baseline we analyzed age, frailty (defined following the criteria of Fried et al. [J Gerontol A Biol Sci Med Sci 2001;56:146-156]), dependence for activities of daily living (ADL), cognitive impairment, depression, comorbidity, cardiovascular disease, and diabetes. After full information about prognosis and treatment options, the preferences of the patients and families were taken into consideration as determinants in the decision-making process. During the follow-up, we evaluated clinical and laboratory parameters, hospitalization, mortality and reevaluated frailty. Results: Twenty patients opted for CC, and 36 patients opted for ITD. On univariate analysis, the predictive factors of the election of CC were age, prefrailty, cognitive impairment, and dependence for ADL. In the multivariate analysis, age and prefrailty remained as predictors for the choice of CC. Hospitalizations were more frequent in CC. Survival was similar in both groups (p = 0.098). Conclusions: Frailty assessment could be useful for decision-making about the treatment in elderly patients with CKD. CC may be a good treatment option.
Care Transitions: A Leverage Point for Safe and Effective Medication Use in Older Adults - A Mini-Review
Authors: Mixon Amanda S. , Neal Erin , Bell Susan , Powers James S. , Kripalani Sunil
Published: December 2014

Older adults often face challenges as they transition out of the acute care hospital, especially with regard to adhering to their medications. In this narrative review, we discuss medication adherence in older adults across the continuum of care, describing reasons for nonadherence, methods to assess adherence and tools to improve adherence, with particular focus on emerging techniques and technologies. Taking steps at care transitions to assess medications and foster adherence to the medication regimen can increase the safety of older adults following hospitalization.
Efficacy of Oral Hydration in the Prevention of Contrast-Induced Acute Kidney Injury in Patients Undergoing Coronary Angiography or Intervention
Authors: Akyuz Sukru , Karaca Mehmet , Kemaloglu Oz Tugba , Altay Servet , Gungor Baris , Yaylak Baris , Yazici Selcuk , Ozden Kivilcim , Karakus Gultekin , Cam Nese
Published: December 2014

Background: Efficacy of intravenous (IV) volume expansion in preventing contrast-induced acute kidney injury (CI-AKI) is well known. However, the role of oral hydration has not been well established. The aim of this work was to evaluate the efficacy of oral hydration in preventing CI-AKI. Methods: We prospectively randomized 225 patients undergoing coronary angiography and/or percutaneous coronary intervention in either oral hydration or IV hydration groups. Patients who have at least one of the high-risk factors for developing CI-AKI (advanced age, type 2 diabetes mellitus, anemia, hyperuricemia, a history of cardiac failure or systolic dysfunction) were included in the study. All patients had normal renal function or stage 1-2 chronic kidney disease. Patients in the oral hydration group were encouraged to drink unrestricted amounts of fluids freely whereas isotonic saline infusion was performed by the standard protocol in the IV hydration group. Results: CI-AKI occurred in 8/116 patients (6.9%) in the oral hydration group and 8/109 patients (7.3%) in the IV hydration group (p = 0.89). There was also no statistically significant difference between the two groups when different CI-AKI definitions were taken into account. Conclusion: Oral hydration is as effective as IV hydration in preventing CI-AKI in patients with normal kidney function or stage 1-2 chronic kidney disease, and who also have at least one of the other high-risk factors for developing CI-AKI.
Indoxyl Sulfate Induces IL-6 Expression in Vascular Endothelial and Smooth Muscle Cells through OAT3-Mediated Uptake and Activation of AhR/NF-κB Pathway
Authors: Adelibieke Yelixiati , Yisireyili Maimaiti , Ng Hwee-Yeong , Saito Shinichi , Nishijima Fuyuhiko , Niwa Toshimitsu
Published: December 2014

Background/Aims: Interleukin-6 (IL-6) is one of the inflammation biomarkers with highest predictive value for outcome in chronic kidney disease (CKD) patients. The present study aimed to determine the effects of indoxyl sulfate (IS) on IL-6 expression in vascular cells. Methods: IS was administered to normo- and hypertensive rats. Human umbilical vein endothelial cells (HUVECs) and human aortic smooth muscle cells (HASMCs) were incubated with or without IS. Results: Immunohistochemistry revealed that IS-administered rats showed increased expression of IL-6 in the aortic tissues. IS increased IL-6 expression in HUVECs and HASMCs in a time- and dose-dependent manner. Knockdown of organic anion transporter 3 (OAT3) using small interfering RNA (siRNA) inhibited IS-induced expression of IL-6 in HUVECs and HASMCs. IS induced activation of aryl hydrocarbon receptor (AhR) and nuclear factor-κB (NF-κB) subunit p65 in HUVECs and HASMCs. Both AhR siRNA and p65 siRNA inhibited IS-induced expression of IL-6. AhR siRNA inhibited IS-induced phosphorylation and nuclear translocation of p65 without change in total p65 level. However, p65 siRNA did not inhibit IS-induced nuclear translocation of AhR. Thus, AhR is responsible for IS-induced p65 signaling transduction. Conclusion: IS induces IL-6 expression in vascular endothelial and smooth muscle cells through OAT3/AhR/NF-κB pathway.
Periodontal Disease, Renal Dysfunction and Heightened Leukocytosis
Authors: Salimi Shabnam , Ng Nawi , Seliger Stephen L. , Parsa Afshin
Published: December 2014

Background: Leukocytosis is a powerful predictor of incident chronic kidney disease (CKD) and related outcomes. However, the association between periodontitis measures and increased leukocytosis in the context of CKD has not been well described. We sought to identify which individual measures of periodontal disease may best associate with reduced estimated glomerular filtration rate (eGFR) and albuminuria, and to test if these measures were associated with increased leukocytosis in subjects with established CKD. Methods: We estimated, among 13,270 participants in the National Health and Nutrition Examination Survey III study, the associations between case-based definition of periodontitis, clinical attachment loss (CAL) and pocket depth (PD) as individual measures of periodontal disease, with renal function measures and leukocytosis. Results: In adjusted multivariate analyses, case-based definition of severe periodontitis was associated with albuminuria (β = 0.003, p = 0.01) but not with eGFR. However, CAL and PD were all individually associated with both albuminuria (β = 0.08, p < 0.001 and β = 0.06, p < 0.001, respectively) and eGFR (β = -0.05, p < 0.001 and β = -0.03, p < 0.001, respectively). We found significant associations between elevated CAL and PD with leukocytosis. Lastly, we found a marked association between the joint presence of CKD and elevated CAL or PD with leukocytosis (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.4-7.5 and OR 3.2, 95% CI 1.1-9.7, respectively). Conclusion: Individual measures of periodontal disease are associated with renal function and heightened leukocytosis in CKD subjects. The significantly added inflammatory burden noted in CKD subjects with periodontal disease argue for targeting periodontitis treatment as part of our multifaceted approach to CKD patients.
JTT-751 for Treatment of Patients with Hyperphosphatemia on Peritoneal Dialysis
Authors: Yokoyama Keitaro , Akiba Takashi , Fukagawa Masafumi , Nakayama Masaaki , Hirakata Hideki
Published: December 2014

Background/Aims: JTT-751 (ferric citrate hydrate) is a novel iron-based phosphate approved in Japan for the treatment of hyperphosphatemia in dialysis and nondialysis patients with chronic kidney disease. Methods: In this phase 3, multicenter, open-label, dose-adjusted study, we investigated the efficacy and safety of JTT-751 in peritoneal dialysis patients. A total of 56 patients with serum phosphate ≥5.6 and <10.0 mg/dl were enrolled in the study. The dose of JTT-751 was adjusted to between 1.5 and 6.0 g/day, according to the target range of serum phosphate (3.5-5.5 mg/dl), for 12 weeks. The primary endpoint was change in serum phosphate from baseline to end of treatment. Secondary endpoints included the percentage of patients achieving target serum phosphate levels and changes in intact parathyroid hormone. Results: Serum phosphate was significantly reduced by 2.26 mg/dl (p < 0.001). The percentage of patients achieving target serum phosphate levels was 76.8%. Intact parathyroid hormone decreased significantly (p < 0.001). The most common adverse drug reactions were diarrhea and constipation. Most of the events were considered to be mild. Treatment with JTT-751 resulted in significant increases in serum ferritin and transferrin saturation (p < 0.001). Conclusion: In peritoneal dialysis patients with hyperphosphatemia, 12-week treatment with JTT-751 resulted in significant reductions in serum phosphate while simultaneously increasing serum iron parameters. JTT-751 was well tolerated.
Circulating Endotoxaemia and Frequent Haemodialysis Schedules
Authors: Jefferies Helen J. , Crowley Lisa E. , Harrison Laura E.A. , Szeto Cheuk-Chun , Li Philip K.T. , Schiller Brigitte , Moran John , McIntyre Christopher W.
Published: December 2014

Background/Aims: Endotoxaemia, a driver of systemic inflammation, appears to be driven by dialysis-induced circulatory stress in haemodialysis (HD) patients. More frequent HD regimens are associated with lower ultrafiltration requirements, improved haemodynamic stability and lower systemic inflammation. This study investigated the hypothesis that more frequently dialysed patients, with reduced exposure to dialysis-induced haemodynamic perturbation, would have lower circulating endotoxin (ET) levels. Methods: A cross-sectional study of 86 established HD patients compared three groups: conventional HD 3× per week (HD3, n = 56), frequent HD 5-6× per week (SDHD, n = 20), and nocturnal HD (NHD, n = 10). Data collection included ultrafiltration volume and rate, serial blood pressures and blood sampling with quantification of ET, troponin T and high-sensitivity CRP (hsCRP). Results: Pre-dialysis serum ET was highest in the conventional HD group (HD3 0.66 ± 0.29 EU/ml vs. NHD 0.08 ± 0.04 EU/ml). Across the study population, severity of endotoxaemia was associated with higher ultrafiltration rates, degree of intradialytic hypotension, troponin T and hsCRP levels. NHD patients had the lowest ultrafiltration requirements, the greatest haemodynamic stability and lower ET levels. Conclusion: More frequent HD regimens are associated with lower levels of circulating ET compared with conventional HD. Reduced ET translocation may be related to the greater haemodynamic stability of these treatments, with superior maintenance of splanchnic perfusion.
Is the Systemic Microvascular Endothelial Glycocalyx in Peritoneal Dialysis Patients Related to Peritoneal Transport?
Authors: Vlahu Carmen A. , Lopes Barreto Deirisa , Struijk Dirk G. , Vink Hans , Krediet Raymond T.
Published: December 2014

Background/Aims: The capillary wall coated by the endothelial glycocalyx is the main transport barrier during peritoneal dialysis (PD). Here, we investigated the relationships between measurements of the systemic endothelial glycocalyx and peritoneal transport in PD patients. Methods: We performed sidestream darkfield (SDF) imaging of the sublingual microvasculature in 15 patients, measured the perfused boundary region (PBR), which includes the permeable part of the glycocalyx, and calculated the estimated blood vessel density (EBVD). All patients underwent a peritoneal permeability analysis. Results: No relationships were present between the imaging and peritoneal transport parameters, neither in the group as a whole nor in fast transporters. In patients with nonfast peritoneal transport status, PBR had a negative relationship with EBVD and small solute transport, and a positive one with net ultrafiltration (NUF). The EBVD showed a positive correlation with glucose absorption and a negative one with NUF. We found no relationships with the peritoneal transport of albumin. Conclusions: No relationships are present between the systemic endothelial glycocalyx, which was assessed by SDF, and peritoneal transport. In nonfast transporters, a reduction in blood vessel density caused by endothelial glycocalyx alterations or a thicker permeable phase of the glycocalyx delaying the access of small solutes to the small pores may be important.
Treatment with Haemodiafiltration Stabilises Vascular Stiffness (Measured by Aortic Pulse Wave Velocity) Compared to Haemodialysis
Authors: Charitaki Evangelia , Belman Daniel , Davenport Andrew
Published: December 2014

Background/Aims: Cerebrovascular diseases such as stroke are increased in dialysis patients, and haemodiafiltration has been reported to reduce cerebrovascular mortality compared to haemodialysis. We wished to determine whether haemodiafiltration improves arterial stiffness. Methods: We audited aortic pulse wave velocity (PWV) measurements 6 months apart in 3 cohorts of patients: 69 treated with haemodialysis, 78 who converted from haemodialysis to haemodiafiltration and 142 treated with haemodiafiltration. Results: Cohorts were well matched for age (means ± SD: haemodialysis 64 ± 15 years vs. haemodialysis to haemodiafiltration 64 ± 17 years vs. haemodiafiltration 67 ± 16 years), sex (male 65 vs. 59 vs. 63%), diabetes (45 vs. 56.4 vs. 44%) and body mass index (26 ± 6 vs. 26 ± 5 vs. 26 ± 5), respectively. Systolic blood pressure did not differ over time (haemodialysis 143 ± 25 vs. 146 ± 27 mm Hg, haemodialysis to haemodiafiltration 153 ± 26 vs. 154 ± 25 mm Hg, haemodiafiltration 149 ± 31 vs. 148 ± 30 mm Hg) or between groups. Aortic PWV significantly increased in the haemodialysis group (9.5 ± 1.9 vs. 10.2 ± 2.2 m/s, p < 0.01) and haemodialysis to haemodiafiltration group (9.4 ± 1.9 vs. 10.1 ± 2.2 m/s, p < 0.01), but did not change with haemodiafiltration (9.9 ± 2.1 vs. 10.1 ± 2.2 m/s). Conclusions: Aortic PWV, a measure of vascular stiffness, stabilised with haemodiafiltration. Our preliminary findings require further investigation to determine how haemodiafiltration may potentially improve vascular stiffness.