bluuebunny/crossref_metadata_2025 huggingface dataset:
NODE MIXING AND GROUP STRUCTURE OF COMPLEX SOFTWARE NETWORKS
Authors: ŠUBELJ LOVRO , ŽITNIK SLAVKO , BLAGUS NELI , BAJEC MARKO
Published: December 2014

Large software projects are among most sophisticated human-made systems consisting of a network of interdependent parts. Past studies of software systems from the perspective of complex networks have already led to notable discoveries with different applications. Nevertheless, our comprehension of the structure of software networks remains to be only partial. Here we investigate correlations or mixing between linked nodes and show that software networks reveal dichotomous node degree mixing similar to that recently observed in biological networks. We further show that software networks also reveal characteristic clustering profiles and mixing. Hence, node mixing in software networks significantly differs from that in, e.g., the Internet or social networks. We explain the observed mixing through the presence of groups of nodes with common linking pattern. More precisely, besides densely linked groups known as communities, software networks also consist of disconnected groups denoted modules, core/periphery structures and other. Moreover, groups coincide with the intrinsic properties of the underlying software projects, which promotes practical applications in software engineering.
FROM MICROSCOPIC HETEROGENEITY TO MACROSCOPIC COMPLEXITY IN THE CONTRARIAN VOTER MODEL
Authors: BANISCH SVEN
Published: December 2014

An analytical treatment of a simple opinion model with contrarian behavior is presented. The focus is on the stationary dynamics of the model and in particular on the effect of inhomogeneities in the interaction topology on the stationary behavior. We start from a micro-level Markov chain description of the model. Markov chain aggregation is then used to derive a macro chain for the complete graph as well as a meso-level description for the two-community graph composed of two (weakly) coupled sub-communities. In both cases, a detailed understanding of the model behavior is possible using Markov chain tools. More importantly, however, this setting provides an analytical scenario to study the discrepancy between the homogeneous mixing case and the model on a slightly more complex topology. We show that memory effects are introduced at the macro-level when we aggregate over agent attributes without sensitivity to the microscopic details and quantify these effects using concepts from information theory. In this way, the method facilitates the analysis of the relation between microscopic processes and their aggregation to a macroscopic level of description and informs about the complexity of a system introduced by heterogeneous interaction relations.
Alternative synthetic route toward octaisopropylporphyrins and structural deformation caused by a meso-butyl group
Authors: Sugawara Shun , Kakui Takanari , Yamamoto Yohsuke
Published: December 2014

A rarely investigated octaisopropylporphyrin (OiPP) was successfully prepared by an alternative synthetic route with organic reactions. Introduction of an electron-donating butyl group at the meso-position of OiPP nickel(II) and copper(II) complexes induced structural perturbation on the porphyrin cores. Structural distortion of nickel(II) complexes decreased slightly upon introduction of a butyl group; however, structural change of the copper complexes showed opposite behavior. These results indicate that structural deformation of the OiPP metal complexes with a meso-substituent was determined by the central metal.
Characterization of Hydrogen Bonds in the End-Functionalized Single-Wall Carbon Nanotubes: A DFT Study
Authors: Ghafouri Reza , Ektefa Fatemeh , Zahedi Mansour
Published: December 2014

A systematic computational study is carried out to shed some light on the structure of semiconducting armchair single-wall carbon nanotubes (n, n) SWCNTs, n = 4, 5 and 6, functionalized at the end with carboxyl (– COOH ) and amide (– CONH 2) from the viewpoint of characterizing the intramolecular hydrogen bondings at the B3LYP/6-31++G(d, p) level. Geometry parameters display different types of intramolecular hydrogen bonding possibilities in the considered functionalized SWCNTs. All of the hydrogen bondings are confirmed by natural bonding orbitals (NBO) analysis as well as nuclear magnetic resonance (NMR) and nuclear quadrupole resonance (NQR) parameters. Based on NBO analysis, the calculated [Formula: see text] delocalization energies E(2), 1.15 kcal/mol to 7.04 kcal/mol, are in direct relation with the hydrogen bonding strengths. Differences in the chemical shielding principal components of 13 C and 17 O nuclei correlate well with the strengths of the hydrogen bondings. Participating in stronger hydrogen bondings, a larger SWCNT has a decreasing effect on 13 C (= O ) and 17 O isotropic chemical shieldings, σiso, consistent with the NBO analysis. The considerable changes of 13 C /17 O σiso can be interpreted as a result of shielding tensor component orientation. The 13 C (= O ) and 17 O quadrupole coupling constants C Q decrease under the effect of hydrogen bonding while asymmetry parameters ηQ significantly increase, indicating that 17 O ηQ is more sensitive to hydrogen bondings.
A high-fat diet modulates iron metabolism but does not promote liver fibrosis in hemochromatotic Hjv−/− mice
Authors: Padda Ranjit Singh , Gkouvatsos Konstantinos , Guido Maria , Mui Jeannie , Vali Hojatollah , Pantopoulos Kostas
Published: December 2014

Hemojuvelin (Hjv) is a membrane protein that controls body iron metabolism by enhancing signaling to hepcidin. Hjv mutations cause juvenile hemochromatosis, a disease of systemic iron overload. Excessive iron accumulation in the liver progressively leads to inflammation and disease, such as fibrosis, cirrhosis, or hepatocellular cancer. Fatty liver (steatosis) may also progress to inflammation (steatohepatitis) and liver disease, and iron is considered as pathogenic cofactor. The aim of this study was to investigate the pathological implications of parenchymal iron overload due to Hjv ablation in the fatty liver. Wild-type (WT) and Hjv−/− mice on C57BL/6 background were fed a standard chow, a high-fat diet (HFD), or a HFD supplemented with 2% carbonyl iron (HFD+Fe) for 12 wk. The animals were analyzed for iron and lipid metabolism. As expected, all Hjv−/− mice manifested higher serum and hepatic iron and diminished hepcidin levels compared with WT controls. The HFD reduced iron indexes and promoted liver steatosis in both WT and Hjv−/− mice. Notably, steatosis was attenuated in Hjv−/− mice on the HFD+Fe regimen. Hjv−/− animals gained less body weight and exhibited reduced serum glucose and cholesterol levels. Histological and ultrastructural analysis revealed absence of iron-induced inflammation or liver fibrosis despite early signs of liver injury (expression of α-smooth muscle actin). We conclude that parenchymal hepatic iron overload does not suffice to trigger progression of liver steatosis to steatohepatitis or fibrosis in C57BL/6 mice.
Effects of gap junction inhibition on contraction waves in the murine small intestine in relation to coupled oscillator theory
Authors: Parsons Sean P. , Huizinga Jan D.
Published: December 2014

Waves of contraction in the small intestine correlate with slow waves generated by the myenteric network of interstitial cells of Cajal. Coupled oscillator theory has been used to explain steplike gradients in the frequency (frequency plateaux) of contraction waves along the length of the small intestine. Inhibition of gap junction coupling between oscillators should lead to predictable effects on these plateaux and the wave dislocation (wave drop) phenomena associated with their boundaries. It is these predictions that we wished to test. We used a novel multicamera diameter-mapping system to measure contraction along 25- to 30-cm lengths of murine small intestine. There were typically two to three plateaux per length of intestine. Dislocations could be limited to the wavefronts immediately about the terminated wave, giving the appearance of a three-pronged fork, i.e., a fork dislocation; additionally, localized decreases in velocity developed across a number of wavefronts, ending with the terminated wave, which could appear as a fork, i.e., slip dislocations. The gap junction inhibitor carbenoxolone increased the number of plateaux and dislocations and decreased contraction wave velocity. In some cases, the usual frequency gradient was reversed, with a plateau at a higher frequency than its proximal neighbor; thus fork dislocations were inverted, and the direction of propagation was reversed. Heptanol had no effect on the frequency or velocity of contractions but did reduce their amplitude. To understand intestinal motor patterns, the pacemaker network of the interstitial cells of Cajal is best evaluated as a system of coupled oscillators.
Dual regulation of tumor necrosis factor-α on myosin light chain phosphorylation in vascular smooth muscle
Authors: Chen Minjie , Ma Lan , Hall John E. , Liu Xuebo , Ying Zhekang
Published: December 2014

We previously demonstrated that inhibitor κB kinase 2 (IKK2) is a myosin light chain kinase (MLCK). In the present study, we assess whether the prototypical activator of IKK2 tumor necrosis factor-α (TNF-α) regulates the MLCK activity of IKK2 and thus MLC phosphorylation in vascular smooth muscle cells (VSMCs). Kinase activity assay revealed that TNF-α downregulated the MLCK activity of IKK2 in human VSMCs (HVSMCs). However, Western blot analysis did not demonstrate a significant effect of TNF-α on MLC phosphorylation in HVSMCs, and myograph analysis did not reveal a significant effect of TNF-α on the contraction of the aorta from Sprague-Dawley rats and C57Bl/6j mice, suggesting a dual regulation of MLC phosphorylation by TNF-α. Confirming this notion, TNF-α significantly increased MLC phosphorylation in IKK2−/− but not wild-type cells. Furthermore, our results show that TNF-α increased GTP-bound RhoA and MLC phosphatase subunit MYPT1 phosphorylation and markedly reduced MLC phosphorylation in the presence of Rho-kinase inhibitor Y-27632, suggesting that downregulation of MLCK activity of IKK2 by TNF-α is antagonized by simultaneous RhoA/Rho-kinase activation. These results indicate that TNF-α dually regulates MLC phosphorylation through both IKK2 and RhoA/Rho-kinase pathways.
Aging impairs heat loss, but when does it matter?
Authors: Stapleton Jill M. , Poirier Martin P. , Flouris Andreas D. , Boulay Pierre , Sigal Ronald J. , Malcolm Janine , Kenny Glen P.
Published: December 2014

Aging is associated with an attenuated physiological ability to dissipate heat. However, it remains unclear if age-related impairments in heat dissipation only occur above a certain level of heat stress and whether this response is altered by aerobic fitness. Therefore, we examined changes in whole body evaporative heat loss (HE) as determined using whole body direct calorimetry in young ( n = 10; 21 ± 1 yr), untrained middle-aged ( n = 10; 48 ± 5 yr), and older ( n = 10; 65 ± 3 yr) males matched for body surface area. We also studied a group of trained middle-aged males ( n = 10; 49 ± 5 yr) matched for body surface area with all groups and for aerobic fitness with the young group. Participants performed intermittent aerobic exercise (30-min exercise bouts separated by 15-min rest) in the heat (40°C and 15% relative humidity) at progressively greater fixed rates of heat production equal to 300 (Ex1), 400 (Ex2), and 500 (Ex3) W. Results showed that HE was significantly lower in middle-aged untrained (Ex2: 426 ± 34; and Ex3: 497 ± 17 W) and older (Ex2: 424 ± 38; and Ex3: 485 ± 44 W) compared with young (Ex2: 472 ± 42; and Ex3: 558 ± 51 W) and middle-aged trained (474 ± 21; Ex3: 552 ± 23 W) males at the end of Ex2 and Ex3 ( P < 0.05). No differences among groups were observed during recovery. We conclude that impairments in HE in older and middle-aged untrained males occur at exercise-induced heat loads of ≥400 W when performed in a hot environment. These impairments in untrained middle-aged males can be minimized through regular aerobic exercise training.
Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells
Authors: Wu Lixian , Yu Jing , Chen Ruijia , Liu Yang , Lou Liguang , Wu Ying , Huang Lisen , Fan Yingjuan , Gao Pinzhang , Huang Meijuan , Wu Yong , Chen Yuanzhong , Xu Jianhua
Published: December 2014

Purpose: Although tyrosine kinase inhibitors (TKI) such as imatinib provide an effective treatment against Bcr-Abl kinase activity in the mature cells of patients with chronic myelogenous leukemia (CML), TKIs probably cannot eradicate the leukemia stem cell (LSC) population. Therefore, alternative therapies are required to target both mature CML cells with wild-type (WT) or mutant Bcr-Abl and LSCs. To investigate the effect of C086, a derivative of curcumin, on imatinib-resistant cells, we explored its underlying mechanisms of Bcr-Abl kinase and heat shock protein 90 (Hsp90) function inhibition.

Experimental Design: Biochemical assays were used to test ABL kinase activity; fluorescence measurements using recombinant NHsp90, Hsp90 ATPase assay, immunoprecipitation, and immunoblotting were applied to examine Hsp90 function. Colony-forming unit, long-term culture-initiating cells (LTC-IC), and flow cytometry were used to test CML progenitor and stem cells.

Results: Biochemical assays with purified recombinant Abl kinase confirmed that C086 can directly inhibit the kinase activity of Abl, including WT and the Q252H, Y253F, and T315I mutations. Furthermore, we identified C086 as a novel Hsp90 inhibitor with the capacity to disrupt the Hsp90 chaperone function in CML cells. Consequently, it inhibited the growth of both imatinib-sensitive and -resistant CML cells. Interestingly, C086 has the capacity to inhibit LTC-ICs and to induce apoptosis in both CD34+CD38+ and CD34+CD38− cells in vitro. Moreover, C086 could decrease the number of CD45+, CD45+CD34+CD38+, and CD45+CD34+CD38− cells in CML NOD-SCID mice.

Conclusions: Dual suppression of Abl kinase activity and Hsp90 chaperone function by C086 provides a new therapeutic strategy for treating Bcr-Abl–induced leukemia resistant to TKIs. Clin Cancer Res; 21(4); 833–43. ©2014 AACR.
Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer
Authors: Fernandez-Cuesta Lynnette , Thomas Roman K.
Published: December 2014

The four members of the ERBB (HER) family of transmembrane receptor tyrosine kinases are frequently activated in cancer by several mechanisms, such as mutation, amplification, or autocrine ligand–receptor stimulation. We recently identified gene fusions involving the ERBB ligand gene, NRG1, which represent a novel mechanism for ERBB pathway deregulation. These fusions lead to expression and presentation of the EGF-like domain of NRG1 on the cell surface, which binds to ERBB3 in an autocrine and juxtacrine manner, thus inducing the formation of ERBB2–ERBB3 heterodimers, and subsequent activation of the PI3K–AKT and MAPK signaling pathways. These fusion genes were exclusively detected in lung adenocarcinomas of never smokers of the invasive mucinous subtype, which usually presents as a multifocal and unresectable disease, for which no effective treatment exists. Considering the large amount of drugs that target ERBB2 (HER2) and ERBB3 (HER3), and which are currently in different stages of clinical development, detecting and targeting NRG1 fusions in invasive mucinous lung adenocarcinomas may represent a therapeutic opportunity for this aggressive disease. Clin Cancer Res; 21(9); 1989–94. ©2014 AACR.
Molecular Pathways: Aspirin and Wnt Signaling—A Molecularly Targeted Approach to Cancer Prevention and Treatment
Authors: Gala Manish K. , Chan Andrew T.
Published: December 2014

The anti-inflammatory properties of aspirin have resulted in its widespread use as an analgesic, antipyretic, and cardioprotective agent. Beyond these applications, multiple observational studies and randomized controlled trials have demonstrated a chemopreventative role for aspirin, particularly in the development of colorectal neoplasia. Given the critical importance of Wnt dysregulation in colorectal carcinogenesis, the interplay between aspirin and canonical Wnt signaling has become a focus of investigation. These studies have illuminated our understanding of the anticancer mechanisms of aspirin, yielding the identification of potential biomarkers for which aspirin's chemopreventative efficacy can be safely optimized into routine clinical practice and providing leads into the discovery of novel preventive and therapeutic targets. In this review, we summarize key experimental and clinical studies of this interaction, as well as highlighting future strategies to advance their clinical translation. Clin Cancer Res; 21(7); 1543–8. ©2014 AACR.
CDK 4/6 Inhibitor Palbociclib (PD0332991) in Rb+ Advanced Breast Cancer: Phase II Activity, Safety, and Predictive Biomarker Assessment
Authors: DeMichele Angela , Clark Amy S. , Tan Kay See , Heitjan Daniel F. , Gramlich Kristi , Gallagher Maryann , Lal Priti , Feldman Michael , Zhang Paul , Colameco Christopher , Lewis David , Langer Melissa , Goodman Noah , Domchek Susan , Gogineni Keerthi , Rosen Mark , Fox Kevin , O'Dwyer Peter
Published: December 2014

Purpose: The G1–S checkpoint of the cell cycle is frequently dysregulated in breast cancer. Palbociclib (PD0332991) is an oral inhibitor of CDK4/6. Based upon preclinical/phase I activity, we performed a phase II, single-arm trial of palbociclib in advanced breast cancer.

Experimental Design: Eligible patients had histologically confirmed, metastatic breast cancer positive for retinoblastoma (Rb) protein and measureable disease. Palbociclib was given at 125 mg orally on days 1 to 21 of a 28-day cycle. Primary objectives were tumor response and tolerability. Secondary objectives included progression-free survival (PFS) and assessment of Rb expression/localization, KI-67, p16 loss, and CCND1 amplification.

Results: Thirty-seven patients were enrolled; 84% hormone-receptor (HR)+/Her2−, 5% HR+/Her2+, and 11% HR−/Her2−, with a median of 2 prior cytotoxic regimens. Two patients had partial response (PR) and 5 had stable disease ≥ 6 months for a clinical benefit rate (CBR = PR + 6moSD) of 19% overall, 21% in HR+, and 29% in HR+/Her2− who had progressed through ≥2 prior lines of hormonal therapy. Median PFS overall was 3.7 months [95% confidence interval (CI), 1.9–5.1], but significantly longer for those with HR+ versus HR− disease (P = 0.03) and those who had previously progressed through endocrine therapy for advanced disease (P = 0.02). Grade 3/4 toxicities included neutropenia (51%), anemia (5%), and thrombocytopenia (22%). Twenty-four percent had treatment interruption and 51% had dose reduction, all for cytopenias. No biomarker identified a sensitive tumor population.

Conclusions: Single-agent palbociclib is well tolerated and active in patients with endocrine-resistant, HR+, Rb-positive breast cancer. Cytopenias were uncomplicated and easily managed with dose reduction. Clin Cancer Res; 21(5); 995–1001. ©2014 AACR.
Pre-Procedure Desmopressin Acetate to Reduce Bleeding in Renal Failure: Does It Really Work?
Authors: Radhakrishnan Seetha , Chanchlani Rahul , Connolly Bairbre , Langlois Valerie
Published: December 2014

Background: Desmopressin (DDAVP) is often used prior to procedures to minimize bleeding in patients with renal failure; however, there is little evidence to support this practice. The objectives of this study were to evaluate the practice of administration of DDAVP prior to procedures within our division and to determine the number of bleeding episodes for patients who received DDAVP compared to those who did not. Methods: Hospital records of patients who underwent renal biopsy or central line placement between April 2006 and March 2008 were reviewed. Patients with glomerular filtration rate (GFR) <60 ml/min/1.73 m2 were identified and subcategorized into three groups: group A GFR <15 ml/min/1.73 m2, group B GFR 15-29 ml/min/1.73 m2, and group C GFR 30-60 ml/min/1.73 m2. The number of bleeding events was noted in each group. Results: No significant difference was found in the number of bleeding events between those who received and did not receive DDAVP overall and in each GFR group. A possible trend towards the benefit with treatment in group A was observed. Conclusion: There was no significant reduction in bleeding for those who received DDAVP which questions the validity of this practice. Patients with GFR <15 ml/min/1.73 m2 may possibly derive benefit.
Exercise Counselling Practices for Patients with Chronic Kidney Disease in the UK: A Renal Multidisciplinary Team Perspective
Authors: Greenwood Sharlene A. , Koufaki Pelagia , Rush Robert , Macdougall Iain C. , Mercer Thomas H. ,   On behalf of the British Renal Society Rehabilitation Network
Published: December 2014

Background: Patients with chronic kidney disease (CKD) have elevated cardiovascular disease (CVD) risk. Physical activity (PA) is a strong and independent CVD risk factor, and despite the fact that current clinical practice guidelines recommend simultaneous treatment of multiple risk factors for optimum management of CKD, PA is rarely addressed by renal care teams. The aim of this observational cross-sectional survey was to document current exercise/PA practices across renal units in the UK, and capture views and experiences regarding the provision of PA/exercise options for patients with CKD. Methods: An 18-item online survey questionnaire regarding exercise counselling practice patterns was administered to 565 multidisciplinary renal care professionals. Results: 142 individuals (25% response rate) completed the questionnaire. Overall, 42% of respondents discussed and encouraged PA, but only 18 and 11% facilitated implementation of PA for their patients. Nephrologists (p < 0.003) were more likely to prescribe or recommend PA compared to professionals with a nursing background and believed that specific renal rehabilitation services, including an active PA/exercise component, should be available to all patients (p < 0.01). The most commonly reported barriers for the development and implementation of PA/exercise options included lack of funding, time, and knowledgeable personnel, such as physiotherapists or other exercise professionals. Conclusion: Beliefs and attitudes towards PA amongst members of the renal multidisciplinary team are encouraging. However there is a big gap between believing in the benefits of PA and promoting/implementing PA for patient benefit. This gap needs to be minimised by at least trying to address some of the reported barriers.
Association of Serum Bicarbonate with Bone Fractures in Hemodialysis Patients: The Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D)
Authors: Kato Akihiko , Kido Ryo , Onishi Yoshihiro , Kurita Noriaki , Fukagawa Masafumi , Akizawa Tadao , Fukuhara Shunichi
Published: December 2014

Background/Aims: Bone fracture is often complicated in hemodialysis (HD) patients. Metabolic acidosis is related to bone disease and muscle wasting, but it is not known whether acid-base disturbance is associated with the risk of bone fractures. The aim of this study was to clarify the association of serum bicarbonate level with bone fracture in HD patients. Methods: Using a subcohort of the Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D), 890 prevalent HD patients (age: 62 years old, male: 62.8%, duration of dialysis: 8.3 years) with secondary hyperparathyroidism were studied. After measuring predialysis serum bicarbonate at a 2-day interdialytic interval, we prospectively followed them every 3 months, and examined the occurrence of any type of bone fracture or hospitalization due to fracture over a 3-year observation period. Results: Seventy-four bone fractures and 47 hospitalizations due to fracture were observed during the follow-up period. HD patients with serum bicarbonate <20 mmol/l had a 1.93 (95% CI 1.01-3.71)-fold higher risk for all-cause fractures than those with serum bicarbonate of 20.0-21.9 mmol/l. A higher bicarbonate level (≥22 mmol/l) was also related to an increased risk of bone fracture. A restricted cubic regression spline disclosed that the higher or the lower than 21.0 mmol/l of serum bicarbonate, the greater the risk for bone fracture. Conclusion: Both a lower level and a higher level of predialysis bicarbonate concentration were associated with risk of bone fracture in HD patients with secondary hyperparathyroidism.
Fibroblast Growth Factor 23/Klotho Axis in Chronic Kidney Disease
Authors: Nitta Kosaku , Nagano Nobuo , Tsuchiya Ken
Published: December 2014

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that regulates phosphate and 1,25-hydroxyvitamin D [1,25(OH)2D] metabolism. FGF23 binds to FGF receptor 1 with its coreceptor Klotho and maintains serum phosphate levels within the normal range by increasing renal phosphate excretion. In addition, FGF23 reduces the synthesis and accelerates the degradation of 1,25(OH)2D to reduce intestinal phosphate absorption. Moreover, FGF23 acts at the parathyroid gland to decrease parathyroid hormone synthesis and secretion. In chronic kidney disease (CKD), serum FGF23 levels rise exponentially as renal function declines long before a significant increase in serum phosphate concentration occurs. Although there is room for argument, FGF23 and Klotho are recently reported contributors to vascular calcification. Finally, prospective observational studies have shown that serum FGF23 concentrations predict mortality not only among dialysis patients but among predialysis CKD patients. In addition to being a coreceptor for FGF23, Klotho circulates as an endocrine substance and exerts a multitude of effects. This review describes recent advances in research on the FGF23-Klotho axis in CKD.
Protective Effects of Relaxin against Cisplatin-Induced Nephrotoxicity in Rats
Authors: Yoshida Takuya , Kumagai Hiromichi , Kohsaka Tetsuya , Ikegaya Naoki
Published: December 2014

Background: Cisplatin (CDDP)-induced acute kidney injury (AKI) involves pro-inflammatory responses, apoptosis of renal tubular epithelial cells and vascular damage. AKI increases the risk of chronic kidney disease. Relaxin (RLX) has anti-apoptotic and anti-fibrosis properties. The aim of this study was to investigate the effects of RLX on CDDP-induced nephrotoxicity. Methods: We investigated the mitigating effects of RLX based on the etiopathology of AKI induced by CDDP, and also the anti-fibrotic effect of RLX on renal fibrosis after AKI. In the short-term experiments, rats were divided into the control group, CDDP group, and CDDP+RLX group. In the latter group, RLX was infused for 5 or 14 days using an implanted osmotic minipump. CDDP was injected intraperitoneally (6 mg/kg) after RLX or saline infusion. At 5 and 14 days post-CDDP, the kidneys were removed for analysis. The effect of RLX on renal fibrosis after AKI was evaluated at 6 weeks post-CDDP. Results: In short-term experiments, CDDP transiently increased plasma creatinine and blood urea nitrogen with peaks at day 5, and RLX prevented such rises. Semiquantitative analysis of the histological lesions indicated marked structural damage and apoptotic cells in the CDDP group, with the lesions being reduced by RLX treatment. Overexpression of Bax, interleukin-6 and tumor necrosis factor-α observed in the kidneys of the CDDP group was reduced in the CDDP+RLX group. In the long-term experiments, RLX significantly reduced renal fibrosis compared with the CDDP group. Conclusions: The results suggested that RLX provided protection against CDDP-induced AKI and subsequent fibrosis by reducing apoptosis and inflammation.
IL-10 Deficiency Increases Renal Ischemia-Reperfusion Injury
Authors: Wan Xin , Huang Wen Juan , Chen Wen , Xie Hong-Guang , Wei Pan , Chen Xin , Cao Chang-Chun
Published: December 2014

Background: Renal ischemia-reperfusion (IR) injury is a frequent cause of acute kidney injury, which results in high morbidity and mortality. Inflammation is an important factor that is involved in kidney repair after renal IR injury. IL-10 is a potent anti-inflammatory cytokine that inhibits inflammatory pathways, but the role of IL-10 in repairing renal IR injury is not known. Here, we investigated the role of IL-10 in kidney repair after renal IR injury. Methods: We used an IL-10-/- mouse model and examined the serologic and histomorphology of kidney after IR injury. We also measured ki67, TNF-α, IL-6, and macrophages with immunohistochemistry or Western blotting. Results: There was a greater increase in serum creatinine in IL-10-/- mice than in wild-type (WT) mice. And compared with WT mice, IL-10-/- mice had increased histologic renal injury and decreased proliferation. Moreover, the expression of TNF-α, IL-6 and macrophages was clearly increased in IL-10-/- mice compared with the WT mice. Conclusion: These data reveal an important role for IL-10 in the improvement of renal IR injury, acting through suppression of inflammatory mediators, and that IL-10 would be a crucial target for the treatment of IR injury.
Agreement of Single- and Multi-Frequency Bioimpedance Measurements in Hemodialysis Patients: An Ancillary Study of the Frequent Hemodialysis Network Daily Trial
Authors: Raimann Jochen G. , Abbas Samer R. , Liu Li , Zhu Fansan , Larive Brett , Kotanko Peter , Levin Nathan W. , Kaysen George A. ,   for the FHN Trial
Published: December 2014

Background: Bioimpedance analysis (BIA) is well established to assess body composition. Agreements between single- and multi-frequency bioimpedance (SF-BIA, MF-BIS) measurements in subjects undergoing 6 or 3 times/week hemodialysis (HD) were analyzed. Methods: Total body water (TBW) and intra- and extracellular fluid (ICF, ECF) of subjects enrolled in the Frequent Hemodialysis Network (FHN) Daily Trial (www.clinicaltrials.gov No. NCT00264758) were measured with a Hydra 4200 at baseline (BL) and at 5 months (M5). Volumes were computed using SF (at 50 kHz) and MF approaches. Agreement was assessed by means of linear regression and Bland-Altman analysis and treatment effects by t test. Results: 35 subjects (17 on the more frequent regimen, 26 males, 20 African-American, 48 ± 9 years, pre-HD weight 84 ± 19 kg) were studied. Assessments with SF-BIA and MF-BIS correlated significantly at BL and M5 in both arms. No proportional errors, but systematic biases over the entire range of values were found at BL and M5. Agreement did not differ between subjects randomized to either HD treatment arm at both time points. MF-BIS appears to have better precision than SF-BIA allowing the observation of a significant treatment effect by the intervention [-1.5 (95% CI -2.5 to -0.5) l] on ECF, not found for ECF SF-BIA. Precision also affected the statistical power of the SF-BIA data in the current analysis. Conclusion: Both methods showed agreement without significant proportional errors regardless of HD frequency and can be used for longitudinal analyses. SF-BIA has lower precision which needs thorough consideration in the design of future trials with similar outcomes.
Clinical and Biological Determinants of Sclerostin Plasma Concentration in Hemodialysis Patients
Authors: Delanaye Pierre , Krzesinski Jean-Marie , Warling Xavier , Moonen Martial , Smelten Nicole , Médart Laurent , Bruyère Olivier , Reginster Jean-Yves , Pottel Hans , Cavalier Etienne
Published: December 2014

Background: Sclerostin is a potent inhibitor of bone formation, but the meaning of its serum levels remains undetermined. We evaluated the association between sclerostin levels and clinical or biological data in hemodialyzed patients (HD), notably parathormone (PTH), biomarkers of bone turnover, vascular calcifications and mortality after 2 years. Methods: 164 HD patients were included in this observational study. The calcification score was assessed with the Kauppila method. Patients were followed for 2 years. Results: Median sclerostin levels were significantly (p < 0.0001) higher in HD versus healthy subjects (n = 94) (1,375 vs. 565 pg/ml, respectively). In univariate analysis a significant association (p < 0.05) was found between sclerostin and age, height, dialysis vintage, albumin, troponin, homocysteine, PTH, C-terminal telopeptide of collagen type I, bone-specific alkaline phosphatase and osteoprotegerin, but not with the calcification score. In a multivariate model, the association remained with age, height, dialysis vintage, troponin, homocysteine, phosphate, PTH, but also with vascular calcifications. Association was positive for all variables, except PTH and vascular calcifications. The baseline sclerostin concentration was not different in survivors and non-survivors. Conclusions: We confirm a higher concentration of sclerostin in HD patients, a positive association with age and a negative association with PTH. A positive association with phosphate, homocysteine and troponin calls for additional research. The clinical interest of sclerostin to assess vascular calcifications in HD is limited and no association was found between sclerostin and mortality.
Multiple Mechanisms in Renal Artery Stenosis-Induced Renal Interstitial Fibrosis
Authors: Cui Rui , Chen Xiao , Peng Lei , Ma Jing , Zhu Dan , Li Tong , Wei Qiuju , Li Bing
Published: December 2014

Background/Aims: Renal artery stenosis (RAS), which may lead to renal fibrosis, is a common cause of end-stage renal disease in elderly patients. However, the potential mechanisms leading to the development of renal fibrosis and atrophy have not been clarified. Methods: A two-kidney, one-clip Goldblatt mouse model was established in the present study. Blood pressure, morphological and pathological alterations were examined on days 7, 14, and 28 after surgery. Peritubular capillary loss and pericyte changes after injury were evaluated. Inflammatory macrophage infiltration and Wnt/β-catenin signaling were also investigated. Results: A significant increase in blood pressure and obvious renal atrophy were observed on days 7, 14, and 28 after surgery. Following surgery, the clipped kidneys developed aggravated interstitial fibrosis and tubular epithelial injury over time. Moreover, RAS induced obvious peritubular capillary loss and inflammatory macrophage infiltration. Increased pericyte number was found in the clipped kidneys, but these cells detached from the endothelial cells and migrated to the interstitium. Wnt/β-catenin signaling was also significantly upregulated in the clipped kidneys after surgery. Conclusion: Our study provides a novel insight into the mechanisms linking peritubular capillary loss and pericyte changes in RAS-induced renal fibrosis. Our findings also suggest that inflammatory macrophages and Wnt/β-catenin signaling participate in these pathological processes. Therefore, multi-target therapeutic strategies may significantly contribute to the prevention of renal interstitial fibrosis and the preservation of renal function in patients with RAS.
Comparison of Different Methods of Erythrocyte Dysmorphism Analysis to Determine the Origin of Hematuria
Authors: Martinez Marila Gaste , dos S. Silva Vanessa , do Valle Adriana P. , Amaro Carmen R.P.R. , Corrente José E. , Martin Luis Cuadrado
Published: December 2014

Background/Aims: There is disagreement regarding the performance of conventional optical microscopy to assess the origin of hematuria. The aim of this study was to determine the optimal cutoff point for dysmorphic cells in order to detect glomerular hematuria by optical and phase-contrast microscopy. Methods: In total, 131 urine samples (66 from patients with glomerulopathies and 65 from nephrolithiasis patients) were evaluated in a blinded fashion. The percentages of doughnut cells and acanthocytes were verified by optical and phase-contrast microscopy. A total of 131 patients were randomly allocated to the derivation (n = 73) and validation (n = 58) groups. Receiver-operating characteristic (ROC) curves were plotted to check the discriminatory power of each group and the best cutoff points were determined by the Youden index in the derivation group and subsequently tested in the validation group. Results: All areas under the ROC curve (AUCs) were statistically significant using both methods (conventional optical and phase-contrast microscopy) and both groups (derivation and validation). AUCs did not differ between different glomerulopathies. The best cutoff point to determine the glomerular origin of hematuria by total dysmorphic cells was 22% using an optical conventional microscope and 40% by phase-contrast microscopy. Conclusion: We determined the best cutoff points to interpret erythrocyte dysmorphism and demonstrated that it is possible to discriminate the origin of hematuria by evaluating erythrocyte dysmorphism in urinalysis using either an optical or a phase-contrast microscope.
Longitudinal Assessments of Erythropoietin-Stimulating Agent Responsiveness and the Association with Specific Clinical Outcomes in Dialysis Patients
Authors: Schneider Andreas , Gutjahr-Lengsfeld Lena , Ritz Eberhard , Scharnagl Hubert , Gelbrich Götz , Pilz Stefan , Macdougall Iain C. , Wanner Christoph , Drechsler Christiane
Published: December 2014

Background: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. Methods: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. Results: Patients had a mean age of 66 ± 8.2 years; 53% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25% (HR = 1.25, 95% CI = 1.18-1.32) and infectious death increased by 27% (HR = 1.27, 95% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). Conclusions: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness.
Benidipine Suppresses in situ Proliferation of Leukocytes and Slows the Progression of Renal Fibrosis in Rat Kidneys with Advanced Chronic Renal Failure
Authors: Kazama Itsuro , Baba Asuka , Matsubara Mitsunobu , Endo Yasuhiro , Toyama Hiroaki , Ejima Yutaka
Published: December 2014

Background/Aims: Leukocytes, such as lymphocytes and macrophages, predominantly express delayed rectifier K+ channels (Kv1.3) in their plasma membranes. In our previous study, the overexpression of these channels in leukocytes was strongly associated with their proliferation in kidneys and the progression of renal fibrosis in advanced-stage chronic renal failure (CRF). Since benidipine, a long-acting 1,4-dihydropyridine Ca2+ channel blocker, is also highly potent as a Kv1.3 channel inhibitor, it could exert therapeutic efficacy in advanced CRF. Methods: Male Sprague-Dawley rats that underwent 5/6 nephrectomy followed by a 14-week recovery period were used as the model of advanced CRF. Benidipine hydrochloride (5 mg/kg) was started at 8 weeks after nephrectomy and orally administered daily for 6 weeks. The histopathological features of the kidneys were examined in vehicle-treated and benidipine-treated CRF rat kidneys. Cellular proliferation of leukocytes and the cortical expression of proinflammatory cytokines were also examined. Results: In CRF rat kidneys, Kv1.3 channels began to be overexpressed in leukocytes as early as 8 weeks after nephrectomy. In the cortical interstitium of benidipine-treated CRF rat kidneys, both immunohistochemistry and real-time PCR demonstrated decreased expression of fibrotic markers. Benidipine treatment significantly reduced the number of proliferating leukocytes within the cortical interstitium and decreased the expression of cell cycle markers and proinflammatory cytokines. Conclusion: This study demonstrated for the first time that benidipine slowed the progression of renal fibrosis in rat kidneys with advanced CRF. Kv1.3 channels overexpressed in leukocytes were thought to be the most likely therapeutic targets of benidipine in decreasing the number of proliferating leukocytes and repressing the production of inflammatory cytokines.
The Effects of Acute Kidney Injury on Long-Term Renal Function and Proteinuria in a General Hospitalised Population
Authors: Horne Kerry L. , Packington Rebecca , Monaghan John , Reilly Timothy , McIntyre Christopher W. , Selby Nicholas M.
Published: December 2014

Background: Acute kidney injury (AKI) is common in hospitalised patients and is associated with adverse long-term consequences. There is an urgent need to understand these sequelae in general hospitalised patients utilising a prospective cohort-based approach. We aimed to test the feasibility of study methodology prior to commencing a large-scale study and investigate the effects of AKI on chronic kidney disease (CKD) progression and proteinuria. Methods: Pilot study testing novel methodology for remote patient recruitment within a prospective case-control design. 300 cases (hospitalised patients with AKI) and controls (hospitalised patients without AKI) were matched 1:1 for age and baseline estimated glomerular filtration rate (eGFR). 70% of cases had AKI stage 1, 16% AKI stage 2 and 14% AKI stage 3. Renal function and proteinuria were measured 3 and 12 months after hospital admission. Results: The study met pre-defined recruitment, withdrawal and matching criteria. Renal function was worse in the AKI group at 3 (eGFR 61 ± 20 vs. 74 ± 23 ml/min/1.73 m2, p < 0.001) and 12 months (eGFR 64 ± 23 vs. 75 ± 25 ml/min/1.73 m2, p < 0.001). More cases than controls had CKD progression at 3 months (14 vs. 0.7%, p < 0.001). This difference persisted to 12 months, but there was no significant change between 3 and 12 months. Proteinuria and albuminuria were more prevalent in the AKI group and associated with CKD progression. Conclusions: We describe a method of remote patient recruitment which could be employed more widely for prospective observational studies. Even mild AKI is associated with long-term renal dysfunction. Further investigation using this methodology is now underway.
From Breathing to Respiration
Authors: Fitting Jean-William
Published: December 2014

The purpose of breathing remained an enigma for a long time. The Hippocratic school described breathing patterns but did not associate breathing with the lungs. Empedocles and Plato postulated that breathing was linked to the passage of air through pores of the skin. This was refuted by Aristotle who believed that the role of breathing was to cool the heart. In Alexandria, breakthroughs were accomplished in the anatomy and physiology of the respiratory system. Later, Galen proposed an accurate description of the respiratory muscles and the mechanics of breathing. However, his heart-lung model was hampered by the traditional view of two non-communicating vascular systems - veins and arteries. After a period of stagnation in the Middle Ages, knowledge progressed with the discovery of pulmonary circulation. The comprehension of the purpose of breathing progressed by steps thanks to Boyle and Mayow among others, and culminated with the contribution of Priestley and the discovery of oxygen by Lavoisier. Only then was breathing recognized as fulfilling the purpose of respiration, or gas exchange. A century later, a controversy emerged concerning the active or passive transfer of oxygen from alveoli to the blood. August and Marie Krogh settled the dispute, showing that passive diffusion was sufficient to meet the oxygen needs.
Mouse ERG K
+
Channel Clones Reveal Differences in Protein Trafficking and Function
Authors: Lin Eric C. , Moungey Brooke M. , Lim Evi , Concannon Sarah P. , Anderson Corey L. , Kyle John W. , Makielski Jonathan C. , Balijepalli Sadguna Y. , January Craig T.
Published: December 2014

Background

The mouse ether‐a‐go‐go‐related gene 1a (

mERG
1a,
mKCNH
2

) encodes
mERG
K
+
channels in mouse cardiomyocytes. The
mERG
channels and their human analogue,
hERG
channels, conduct I
Kr
. Mutations in
hERG
channels reduce I
Kr
to cause congenital long‐QT syndrome type 2, mostly by decreasing surface membrane expression of trafficking‐deficient channels. Three
cDNA
sequences were originally reported for
mERG
channels that differ by 1 to 4 amino acid residues (
mERG
‐London,
mERG
‐Waterston, and
mERG
‐Nie). We characterized these
mERG
channels to test the postulation that they would differ in their protein trafficking and biophysical function, based on previous findings in long‐QT syndrome type 2.

Methods and Results

The 3
mERG
and
hERG
channels were expressed in HEK293 cells and neonatal mouse cardiomyocytes and were studied using Western blot and whole‐cell patch clamp. We then compared our findings with the recent sequencing results in the Welcome Trust Sanger Institute Mouse Genomes Project (WTSIMGP).

Conclusions

First, the
mERG
‐London channel with amino acid substitutions in regions of highly ordered structure is trafficking deficient and undergoes temperature‐dependent and pharmacological correction of its trafficking deficiency. Second, the voltage dependence of channel gating would be different for the 3
mERG
channels. Third, compared with the WTSIMGP data set, the
mERG
‐Nie clone is likely to represent the wild‐type mouse sequence and physiology. Fourth, the WTSIMGP analysis suggests that substrain‐specific sequence differences in
mERG
are a common finding in mice. These findings with
mERG
channels support previous findings with
hERG
channel structure–function analyses in long‐QT syndrome type 2, in which sequence changes in regions of highly ordered structure are likely to result in abnormal protein trafficking.
Two new species of Oxytrechus Jeannel, 1927 from Ecuador (Coleoptera, Carabidae)
Authors: GIACHINO PIER MAURO , ALLEGRO GIANNI , BAVIERA COSIMO
Published: December 2014

Two new species of Oxytrechus Jeannel 1927 are described from the páramos of the Ecuadorian Andes in Pichincha province (Ecuador: Northern Sierra): O. osellai n. sp. from Cangahua at 3375 m a.s.l. and O. belloi n. sp. from Paso de la Virgen at 3515 m a.s.l.
A new species of the Gekko japonicus group (Squamata: Gekkonidae) from central Laos
Authors: LUU VINH QUANG , CALAME THOMAS , Nguyen Truong QUang , LE MINH DUC , BONKOWSKI MICHAEL , ZIEGLER THOMAS
Published: December 2014

A new species of the Gekko japonicus group is described from Khammouane Province, central Laos, based on distinct morphological and molecular features. Gekko thakhekensis sp. nov. is distinguished from the remaining congeners by a combination of the following characters: size moderate (SVL 67.6–79.2 mm); nares in contact with rostral; internasals absent; postmentals enlarged; interorbital scales between anterior corners of the eyes 22–26; dorsal tubercles absent; ventral scales between mental and cloacal slit 165–174; midbody scale rows 110–116; ventral scale rows 32–40; subdigital lamellae on first toe 11–13, on fourth toe 14–15; finger and toe webbing present at base, about one fifth of length of digits; tubercles on upper surface of fore and hind limbs absent; precloacal pores 1–5 in males; postcloacal tubercles two; tubercles absent on dorsal surface of tail base; subcaudals enlarged; dorsal surface of body with greyish brown blotches. In molecular analyses, the new species is recovered as a sister taxon to G. scientiadventura, but the two species are separated by approximately 12% divergence as shown by the partial mitochondrial ND2 gene.