bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonverbal Generics: Human Infants Interpret Objects as Symbols of Object Kinds
Authors: Csibra Gergely , Shamsudheen Rubeena
Published: September 2014

Human infants are involved in communicative interactions with others well before they start to speak or understand language. It is generally thought that this communication is useful for establishing interpersonal relations and supporting joint activities, but, in the absence of symbolic functions that language provides, these early communicative contexts do not allow infants to learn about the world. However, recent studies suggest that when someone demonstrates something using an object as the medium of instruction, infants can conceive the object as an exemplar of the whole class of objects of the same kind. Thus, an object, just like a word, can play the role of a symbol that stands for something else than itself, and infants can learn general knowledge about a kind of object from nonverbal communication about a single item of that kind. This rudimentary symbolic capacity may be one of the roots of the development of symbolic understanding in children.
Maternal insulin resistance and transient hyperglycemia impact the metabolic and endocrine phenotypes of offspring
Authors: Kahraman Sevim , Dirice Ercument , De Jesus Dario F. , Hu Jiang , Kulkarni Rohit N.
Published: September 2014

Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced β-cell area in control offspring of LIRKO mothers shortly after birth. β-Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller β-cell mass/area and β-cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development.
Regulation of skeletal muscle energy/nutrient-sensing pathways during metabolic adaptation to fasting in healthy humans
Authors: Wijngaarden Marjolein A. , Bakker Leontine E. H. , van der Zon Gerard C. , 't Hoen Peter A. C. , van Dijk Ko Willems , Jazet Ingrid M. , Pijl Hanno , Guigas Bruno
Published: September 2014

During fasting, rapid metabolic adaptations are required to maintain energy homeostasis. This occurs by a coordinated regulation of energy/nutrient-sensing pathways leading to transcriptional activation and repression of specific sets of genes. The aim of the study was to investigate how short-term fasting affects whole body energy homeostasis and skeletal muscle energy/nutrient-sensing pathways and transcriptome in humans. For this purpose, 12 young healthy men were studied during a 24-h fast. Whole body glucose/lipid oxidation rates were determined by indirect calorimetry, and blood and skeletal muscle biopsies were collected and analyzed at baseline and after 10 and 24 h of fasting. As expected, fasting induced a time-dependent decrease in plasma insulin and leptin levels, whereas levels of ketone bodies and free fatty acids increased. This was associated with a metabolic shift from glucose toward lipid oxidation. At the molecular level, activation of the protein kinase B (PKB/Akt) and mammalian target of rapamycin pathways was time-dependently reduced in skeletal muscle during fasting, whereas the AMP-activated protein kinase activity remained unaffected. Furthermore, we report some changes in the phosphorylation and/or content of forkhead protein 1, sirtuin 1, and class IIa histone deacetylase 4, suggesting that these pathways might be involved in the transcriptional adaptation to fasting. Finally, transcriptome profiling identified genes that were significantly regulated by fasting in skeletal muscle at both early and late time points. Collectively, our study provides a comprehensive map of the main energy/nutrient-sensing pathways and transcriptomic changes during short-term adaptation to fasting in human skeletal muscle.
SPECT Findings in Alzheimer’s Disease and Parkinson’s Disease with Dementia
Authors: Starkstein S. E. , Vázquez S. , Petracca G. , Sabe L. , Merello M. , Leiguarda R.
Published: September 2014

We examined, with single photon emission tomography (SPECT) and (99mTc)-HMPAO, 18 patients with idiopathic Parkinson's disease and no dementia (PD), 12 patients with PD and dementia, 24 patients with probable Alzheimer's disease (AD), and 14 controls. While the three patient groups showed significantly lower perfusion in frontal inferior and temporal inferior areas as compared to controls, both demented groups showed significantly more severe bilateral hypoperfusion in superior frontal, superior temporal and parietal areas as compared to non-demented PD patients and controls. On the other hand, no significant differences in cerebral perfusion were found between patients with AD and patients with PD and dementia. In conclusion, our findings demonstrated specific but similar cerebral perfusion deficits in demented patients with either AD or PD.
Convergence Theorems for Fixed Points of Multivalued Mappings in Hilbert Spaces
Authors: Djitte N. , Sene M.
Published: September 2014

Let H be a real Hilbert space and K a nonempty closed convex subset of H. Suppose T:K→CB(K) is a multivalued Lipschitz pseudocontractive mapping such that F(T)≠∅. An Ishikawa-type iterative algorithm is constructed and it is shown that, for the corresponding sequence {xn}, under appropriate conditions on the iteration parameters, lim infn→∞⁡ d (xn,Txn)=0 holds. Finally, convergence theorems are proved under approximate additional conditions. Our theorems are significant improvement on important recent results of Panyanak (2007) and Sastry and Babu (2005).
Influence of the Parameterization in the Interval Solution of Elastic Beams
Authors: Gabriele Stefano , Varano Valerio
Published: September 2014

We are going to analyze the interval solution of an elastic beam under uncertain boundary conditions. Boundary conditions are defined as rotational springs presenting interval stiffness. Developments occur according to the interval analysis theory, which is affected, at the same time, by the overestimation of interval limits (also known as overbounding, because of the propagation of the uncertainty in the model). We suggest a method which aims to reduce such an overestimation in the uncertain solution. This method consists in a reparameterization of the closed form Euler-Bernoulli solution and set intersection.
Associations between Aspects of Friendship Networks, Physical Activity, and Sedentary Behaviour among Adolescents
Authors: Sawka Keri Jo , McCormack Gavin R. , Nettel-Aguirre Alberto , Blackstaffe Anita , Perry Rosemary , Hawe Penelope
Published: September 2014

Background.Adolescent friendships have been linked to physical activity levels; however, network characteristics have not been broadly examined.Method.In a cross-sectional analysis of 1061 adolescents (11–15 years), achieving 60 minutes/day of moderate-to-vigorous physical activity (MVPA) and participating in over 2 hours/day of sedentary behaviour were determined based on friendship network characteristics (density; proportion of active/sedentary friends; betweenness centrality; popularity; clique membership) and perceived social support.Results.Adolescents with no friendship nominations participated in less MVPA. For boys and girls, a ten percent point increase in active friends was positively associated with achievement of 60 minutes/day of MVPA (OR 1.11; 95% CI 1.02–1.21, OR 1.14; 95% CI 1.02–1.27, resp.). For boys, higher social support from friends was negatively associated with achieving 60 minutes/day of MVPA (OR 0.63; 95% CI 0.42–0.96). Compared with low density networks, boys in higher density networks were more likely to participate in over 2 hours/day of sedentary behaviour (OR 2.93; 95% CI 1.32–6.49). Social support from friends also modified associations between network characteristics and MVPA and sedentary behaviour.Conclusion.Different network characteristics appeared to have different consequences. The proportion of active close friends was associated with MVPA, while network density was associated with sedentary behaviour. This poses challenges for intervention design.
The Inhibition Effect of Potassium Iodide on the Corrosion of Pure Iron in Sulphuric Acid
Authors: Attar Tarik , Larabi Lahcène , Harek Yahia
Published: September 2014

The use of inorganic inhibitors as an alternative to organic compounds is based on the possibility of degradation of organic compounds with time and temperature. The inhibition effect of potassium iodide on the corrosion of pure iron in 0.5 M H2SO4has been studied by weight loss. It has been observed from the results that the inhibition efficiency (IE%) of KI increases from 82.17% to 97.51% with the increase in inhibitor concentration from 1·10−4to 2·10−3 M. The apparent activation energy (Ea) and the equilibrium constant of adsorption (Kads) were calculated. The adsorption of the inhibitor on the pure iron surface is in agreement with Langmuir adsorption isotherm.
Patient Satisfaction with Postaural Incision Site
Authors: Barrett George , Koecher Susanne , Ronan Natalie , Whinney David
Published: September 2014

Introduction. Controversy exists over the optimum incision placement when performing ear surgery via the postauricular approach. Little is known about the impact of incision placement on future comfort in wearing audio or visual aids or the effect on the minor auricular muscles cut in the approach.Objective. (1) To establish patient satisfaction with their postauricular surgical incision, and to establish the impact on comfort wearing hearing or visual aids. (2) To establish whether patients’ voluntary ear movements were affected by surgery.Materials and Methods. In January 2014, questionnaires were sent to 81 patients who underwent mastoid surgery requiring a postauricular incision between January 2004 and December 2012. The incision placement was broadly the same for all patients as they were operated on by the same surgeon (or under his supervision). The incision is sited far posteriorly at the hairline.Results. 42 (52%) of the patients contacted responded. 80% of patients wearing glasses reported no discomfort or problems associated with their incision. 82% of patients who wear hearing aids were comfortable. Only 1 of the 5 patients who could move their ears preoperatively noticed a change afterwards.Conclusion. A hairline incision is well tolerated by most of the patients.
Breast Cancer Prognostic Biomarker Using Attractor Metagenes and the FGD3–SUSD3 Metagene
Authors: Ou Yang Tai-Hsien , Cheng Wei-Yi , Zheng Tian , Maurer Matthew A. , Anastassiou Dimitris
Published: September 2014

Background: The winning model of the Sage Bionetworks/DREAM Breast Cancer Prognosis Challenge made use of several molecular features, called attractor metagenes, as well as another metagene defined by the average expression level of the two genes FGD3 and SUSD3. This is a follow-up study toward developing a breast cancer prognostic test derived from and improving upon that model.

Methods: We designed a feature selector facility calculating the prognostic scores of combinations of features, including those that we had used earlier, as well as those used in existing breast cancer biomarker assays, identifying the optimal selection of features for the test.

Results: The resulting test, called BCAM (Breast Cancer Attractor Metagenes), is universally applicable to all clinical subtypes and stages of breast cancer and does not make any use of breast cancer molecular subtype or hormonal status information, none of which provided additional prognostic value. BCAM is composed of several molecular features: the breast cancer–specific FGD3–SUSD3 metagene, four attractor metagenes present in multiple cancer types (CIN, MES, LYM, and END), three additional individual genes (CD68, DNAJB9, and CXCL12), tumor size, and the number of positive lymph nodes.

Conclusions: Our analysis leads to the unexpected and remarkable suggestion that ER, PR, and HER2 status, or molecular subtype classification, do not provide additional prognostic value when the values of the FGD3–SUSD3 and attractor metagenes are taken into consideration.

Impact: Our results suggest that BCAM's prognostic predictions show potential to outperform those resulting from existing breast cancer biomarker assays. Cancer Epidemiol Biomarkers Prev; 23(12); 2850–6. ©2014 AACR.
Phase I Trial of Bortezomib (PS-341; NSC 681239) and “Nonhybrid” (Bolus) Infusion Schedule of Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms
Authors: Holkova Beata , Kmieciak Maciej , Perkins E. Brent , Bose Prithviraj , Baz Rachid C. , Roodman G. David , Stuart Robert K. , Ramakrishnan Viswanathan , Wan Wen , Peer Cody J. , Dawson Jana , Kang Loveleen , Honeycutt Connie , Tombes Mary Beth , Shrader Ellen , Weir-Wiggins Caryn , Wellons Martha , Sankala Heidi , Hogan Kevin T. , Colevas A. Dimitrios , Doyle L. Austin , Figg William D. , Coppola Domenico , Roberts John D. , Sullivan Daniel , Grant Steven
Published: September 2014

Purpose: This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma).

Experimental Design: Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted.

Results: A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m2 for bortezomib and 40 mg/m2 for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses.

Conclusions: The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies. Clin Cancer Res; 20(22); 5652–62. ©2014 AACR.
Pseudogene PTENP1 Functions as a Competing Endogenous RNA to Suppress Clear-Cell Renal Cell Carcinoma Progression
Authors: Yu Gan , Yao Weimin , Gumireddy Kiranmai , Li Anping , Wang Ji , Xiao Wei , Chen Ke , Xiao Haibing , Li Heng , Tang Kun , Ye Zhangqun , Huang Qihong , Xu Hua
Published: September 2014

PTENP1 is a pseudogene of the PTEN tumor suppression gene (TSG). The functions of PTENP1 in clear-cell renal cell carcinoma (ccRCC) have not yet been studied. We found that PTENP1 is downregulated in ccRCC tissues and cells due to methylation. PTENP1 and PTEN are direct targets of miRNA miR21 and their expression is suppressed by miR21 in ccRCC cell lines. miR21 expression promotes ccRCC cell proliferation, migration, invasion in vitro, and tumor growth and metastasis in vivo. Overexpression of PTENP1 in cells expressing miR21 reduces cell proliferation, invasion, tumor growth, and metastasis, recapitulating the phenotypes induced by PTEN expression. Overexpression of PTENP1 in ccRCC cells sensitizes these cells to cisplatin and gemcitabine treatments in vitro and in vivo. In clinical samples, the expression of PTENP1 and PTEN is correlated, and both expressions are inversely correlated with miR21 expression. Patients with ccRCC with no PTENP1 expression have a lower survival rate. These results suggest that PTENP1 functions as a competing endogenous RNA (ceRNA) in ccRCC to suppress cancer progression. Mol Cancer Ther; 13(12); 3086–97. ©2014 AACR.
Splenectomy Promotes Indirect Elimination of Intraocular Tumors by CD8+ T Cells That Is Associated with IFNγ- and Fas/FasL-Dependent Activation of Intratumoral Macrophages
Authors: Miller Maxine R. , Mandell Jonathan B. , Beatty Kelly M. , Harvey Stephen A.K. , Rizzo Michael J. , Previte Dana M. , Thorne Stephen H. , McKenna Kyle C.
Published: September 2014

Ocular immune privilege (IP) limits the immune surveillance of intraocular tumors as certain immunogenic tumor cell lines (P815, E.G7-OVA) that are rejected when transplanted in the skin grow progressively when placed in the anterior chamber of the eye. As splenectomy (SPLNX) is known to terminate ocular IP, we characterized the immune mechanisms responsible for rejection of intraocular tumors in SPLNX mice as a first step toward identifying how to restore tumoricidal activity within the eye. CD8+ T cells, IFNγ, and FasL, but not perforin, or TNFα were required for the elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthisis). IFNγ and FasL did not target tumor cells directly as the majority of SPLNX IFNγR1−/− mice and Fas-defective lpr mice failed to eliminate intraocular E.G7-OVA tumors that expressed Fas and IFNγR1. Bone marrow chimeras revealed that IFNγR1 and Fas expression on immune cells was most critical for rejection, and SPLNX increased the frequency of activated macrophages (Mφ) within intraocular tumors in an IFNγ- and Fas/FasL-dependent manner, suggesting an immune cell target of IFNγ and Fas. As depletion of Mφs limited CD8 T cell–mediated rejection of intraocular tumors in SPLNX mice, our data support a model in which IFNγ- and Fas/FasL-dependent activation of intratumoral Mφs by CD8+ T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis, and suggests that immunosuppressive mechanisms that maintain ocular IP interfere with the interaction between CD8+ T cells and Mφs to limit the immunosurveillance of intraocular tumors. Cancer Immunol Res; 2(12); 1175–85. ©2014 AACR.
The J-Curve in Arterial Hypertension: Fact or Fallacy?
Authors: Tsika Evangelia P. , Poulimenos Leonidas E. , Boudoulas Konstantinos Dean , Manolis Athanasios J.
Published: September 2014

It is known that a large proportion of patients with arterial hypertension are undertreated. This may result in an increase of the incidence of cardiovascular events. On the other hand, aggressive reduction of blood pressure may increase cardiovascular events (J-curve phenomenon) in certain populations. This phenomenon may be seen in patients with coronary artery disease and left ventricular hypertrophy when the diastolic blood pressure decreases below 70-80 mm Hg, and the systolic blood pressure decreases below 130 mm Hg. This phenomenon is not seen in patients with stroke or renal disease. Thus, a safer and more conservative strategy should be applied in patients with coronary artery disease, left ventricular hypertrophy, elderly, and in patients with isolated systolic hypertension. This is depicted in the recently published European Society of Hypertension/European Society of Cardiology guidelines in which higher targets of blood pressure are suggested in certain cardiovascular diseases and in the elderly.
Electropermeabilization of Adherent Cells with Cochlear Implant Electrical Stimulation in vitro
Authors: Newbold Carrie , Farrington Andrew , Peters Lawson , Cowan Robert , Needham Karina
Published: September 2014

Cochlear implant stimulation creates a reduction in electrode impedance that returns to pre-stimulation levels following cessation of stimulation and is presumed to be associated with the fibrous tissue covering over the electrode array. This study assessed the possibility that transitory impedance reduction originates from a change in the membrane permeability of cells on the electrode (electropermeabilization). These changes can be recorded using the dye propidium iodide, which fluoresces upon entry into the leaky cell. The in vitro model used showed impedance reduction and dye uptake into adherent cells overlying planar gold electrodes stimulated with as little as 5 min of clinically relevant cochlear implant stimulation. The delayed additions of propidium iodide showed a similar dye uptake to those groups with concurrent dye addition, suggesting the electropermeabilization was not reversible. Further understanding of the mechanisms behind these impedance and cell permeability changes with cochlear implant electrical stimulation may provide opportunities for creating long-lasting reductions in electrode impedance.
The Evolution of Pediatric Continuous Renal Replacement Therapy
Authors: Garzotto Francesco , Zanella Monica , Ronco Claudio
Published: September 2014

The provision of continuous renal replacement therapies (CRRT) to small children has generally required the adaptation of adult machines and modified operational characteristics. CRRT prescription for younger and smaller children versus adults differs significantly due to problems concerning the extracorporeal blood volume, the need for circuit blood priming, and the adaptation of machines designed for adult-sized patients. Moreover, the provision of renal replacement therapy to infants and neonates presents a unique problem: no more than 10-15% of their blood volume should be removed by the extracorporeal circuit to prevent hypotension and anemia. In 2012, a dedicated machine, i.e. the Cardio-Renal, Pediatric Dialysis Emergency Machine (CARPEDIEM), was developed and launched the ‘fitted era' for pediatric CRRT. In this review, we analyze how CRRT techniques have evolved for pediatric application and describe the first in vivo application of the CARPEDIEM for the safe and efficacious provision of CRRT to infants.
Repair or Progression after AKI: A Role for Biomarkers?
Authors: Srisawat Nattachai , Murugan Raghavan , Kellum John A.
Published: September 2014

Recent progress in biomarkers represents a paradigm shift in acute kidney injury (AKI) research. Most studies have evaluated the use of these biomarkers for early diagnosis of AKI. However, the role of novel biomarkers in predicting renal recovery, though less understood, holds great clinical promise. Accurate prediction would help physicians distinguish patients with poor renal prognosis in whom further therapy is unlikely to be useful from those who are likely to have good renal prognosis. Unfortunately, current general clinical severity scores (APACHE, SOFA, etc.) and AKI-specific severity scores are not good predictors of renal recovery. The biology of renal recovery requires the repopulation by surviving renal tubular epithelial cells with the assistance of certain renal epithelial cell and specific growth factors such as neutrophil gelatinase-associated lipocalin (NGAL), hepatocyte growth factor (HGF), epidermal growth factor, and insulin-like growth factor-1 (IGF-1), etc. These markers play a major role in the recovery process. This review will describe the mechanisms of the renal recovery, epidemiology, the role of conventional clinical predictors and finally the role of novel biomarkers (NGAL, HGF, IL-8, IL-18, TNFR-1, IGF-binding protein-7 and tissue inhibitor of metalloproteinase-2) in predicting renal recovery.
The Spleen: The Forgotten Organ in Acute Kidney Injury of Critical Illness
Authors: Gigliotti Joseph C. , Okusa Mark D.
Published: September 2014

Acute kidney injury (AKI) is an increasing medical burden and is independently associated with mortality. AKI is a common comorbidity in the intensive care unit (ICU), with sepsis-associated AKI seen in almost a quarter of all ICU patients. Due to the high mortality seen in these patients, improved therapeutic options are needed. Data from experimental studies in animals support observations in humans that the host immune response to sepsis and trauma contributes to multiorgan failure and the high morbidity and mortality seen in critically ill patients. The spleen, a major component of the reticuloendothelial system, appears to be a key player in the ‘cytokine storm' that develops after infection and trauma, and the resultant systemic inflammation is regulated by the autonomic nervous system. Over the past decade, evidence has suggested that controlling the splenic cytokine response improves tissue function and mortality in sepsis and other inflammatory-mediated diseases. One pathway that controls the response of the spleen to sepsis and trauma is the cholinergic anti-inflammatory pathway, and it may provide a key target for therapeutic intervention. Here, we review this concept and highlight the potential use of ultrasound to stimulate the cholinergic anti-inflammatory pathway and reduce systemic inflammation and disease severity.
Do Tubular Changes in the Diabetic Kidney Affect the Susceptibility to Acute Kidney Injury?
Authors: Vallon Volker
Published: September 2014

Diabetes is the single largest contributor to the growing prevalence of chronic kidney disease (CKD), and episodes of acute kidney injury (AKI) increase the risk of advanced CKD in diabetic patients. Here we discuss whether the pathophysiological changes that occur in the tubular system of the diabetic kidney affect the intrinsic susceptibility to AKI. There is abundant data showing that drug-induced nephrotoxicity is attenuated in rodents with experimental diabetes mellitus, and some mechanistic explanations have been provided, in particular in response to aminoglycosides. Besides downregulation in proximal tubular megalin, which mediates the aminoglycoside uptake in proximal tubules, a role for hyperglycemia-induced activation of regenerative mechanisms has been proposed. The available clinical data, however, indicates that diabetes is a risk factor for AKI, including aminoglycoside nephrotoxicity. While much needs to be learned about this disconnect, the isolated induction of diabetes in otherwise healthy young adult rodents may simply not fully mimic the influence that diabetes exerts in the setting of a critically ill and often elderly patient. We speculate that diabetic tubular growth and the associated molecular signature (including upregulation of TGF-β, senescence, and inflammation) set up the development of diabetic nephropathy and renal failure in part by increasing the susceptibility to AKI, which further promotes hypoxia and apoptosis. Considering the strong association between AKI episodes and the cumulative risk of developing advanced CKD in diabetes, strategies that reduce AKI in these patients are expected to help reduce the growing burden of end-stage renal disease.
Role of Hypoxia-Inducible Factors in Acute Kidney Injury
Authors: Andringa Kelly K. , Agarwal Anupam
Published: September 2014

Oxygen is vital to mammalian survival. Oxygen deprivation, defined as hypoxia, elicits adaptive responses in cells and tissues, a process regulated by proteins known as hypoxia-inducible factors (HIF). Animal studies have provided compelling data to demonstrate a pivotal role for the HIF pathway in the pathogenesis of acute kidney injury (AKI) that have led to initial human clinical trials examining this pathway in ischemia-reperfusion injury in various organ systems, including the kidney. HIF are master regulators and mediate adaptive responses to low oxygen in tissues and cells. This review will summarize recent key advances in the field highlighting preclinical and clinical studies relevant to the HIF pathway in the pathophysiology of AKI.
Effects of Renal Replacement Therapy on Renal Recovery after Acute Kidney Injury
Authors: Schneider Antoine G. , Bagshaw Sean M.
Published: September 2014

Recovery of kidney function following an episode of acute kidney injury (AKI) is now acknowledged as a vital patient-centered outcome with clear health economic implications. In approximately 5-8% of critically ill patients with more severe forms of AKI, support with renal replacement therapy (RRT) is provided. Recent data have suggested that rates of RRT utilization in AKI are increasing. Despite advances in our understanding of how best to prescribe acute RRT in critically ill patients with AKI, additional aspects remain uncertain, predisposing to suboptimal delivery and variation in practice. Importantly, if, when, how, and by what principles we apply acute RRT for AKI are all treatment decision-related factors that are modifiable and may interact with recovery of kidney function. Limited data, mostly from observational studies and secondary analyses, have explored the specific association between acute RRT and recovery. Available data are not able to clarify whether providing any RRT in otherwise eligible patients with AKI impacts recovery. They are also unable to inform whether the timing or circumstance under which RRT is started impacts recovery. No studies have evaluated whether there is an optimal time to start RRT to maximize the probability of recovery. Accumulated evidence, mostly derived from observational studies, suggests initial therapy in critically ill patients with AKI with continuous RRT, compared with intermittent modalities, improves the probability of recovery to dialysis independence. Evidence from high-quality randomized trials failed to show any association between delivered dose intensity of RRT and recovery. The use of biocompatible membranes for acute RRT may improve recovery in AKI; however, data are inconsistent. Limited data have evaluated the impact of membrane flux properties on recovery. Preliminary data have suggested that circuit anticoagulation with citrate, which results in a reduction in membrane-induced oxidative stress and leukocyte activation, may be associated with improved recovery; however, further corroborative data are needed. Additional evidence, ideally from randomized trials, is clearly needed to inform best practice in the delivery of acute RRT to optimize probability of recovery of kidney function for survivors of AKI.
Maladaptive Proximal Tubule Repair: Cell Cycle Arrest
Authors: Bonventre Joseph V.
Published: September 2014

Acute kidney injury (AKI) leads to worsening of chronic kidney disease (CKD), and CKD predisposes to the clinical entity of AKI. The tubules of the kidney play a central role in the fibrotic response, which ultimately leads to progressive kidney disease. The cellular mechanisms responsible for the epidemiological association between AKI and CKD are complex. In order to unravel characteristics of this direct involvement of the tubules, in particular the proximal tubules, we established a model to specifically target injury to the proximal tubule using a genetic approach to express the simian diphtheria toxin (DT) receptor in the proximal tubule. A single administration of DT to the proximal tubule resulted in inflammation, reversible injury, and adaptive repair. By contrast, thrice repeated injury led to maladaptive repair with sustained tubule injury, vascular rarefaction, proliferation of interstitial myofibroblasts, interstitial fibrosis, and glomerular sclerosis. An important feature of the maladaptive repair process after severe injury is the development of cell cycle arrest in G2/M. There is a subsequent activation of the DNA repair response with activation of a secretory phenotype whereby profibrotic factors are released. This insight introduces a number of potential new targets for therapeutic intervention to prevent and/or arrest CKD progression.
How Can We Define Recovery after Acute Kidney Injury? Considerations from Epidemiology and Clinical Trial Design
Authors: Kellum John A.
Published: September 2014

The recent recognition that acute kidney injury (AKI) may lead to the development of chronic kidney disease and end-stage renal disease, with the attendant increase in mortality, has led to interest in the clinical epidemiology and the mechanistic understanding of renal recovery after an episode of AKI. At present, no uniform definition for recovery after AKI exists and various considerations should be taken into account in the development of a definition. Renal recovery after an AKI episode may affect clinical decision making around the initiation of renal replacement therapy, and has significant implication for biomarker assessment and identification of mechanistic targets to guide potential future clinical trials.
Clinical Determinants of Renal Recovery
Authors: Godin Mélanie , Macedo Etienne , Mehta Ravindra L.
Published: September 2014

Acute kidney injury (AKI) is associated with increased mortality, prolonged hospitalization, and renal replacement therapy. Until recently, it was believed that the vast majority of patients recover from AKI without subsequent consequences. It is now recognized that patients with AKI may have very different renal outcomes, including complete recovery, incipient and progressive chronic kidney disease, and end-stage renal disease. Factors that influence these different outcomes have not been thoroughly evaluated and so are not currently understood. The patient's baseline demographic characteristics, subsequent clinical evolution, and factors associated with the treatment of these patients may all influence global and renal outcomes. Recovery from AKI is a potentially modifiable event and should be targeted for therapy. Useful tools are needed to monitor renal recovery and identify the patients at high risk for adverse outcomes.
Biology of Renal Recovery: Molecules, Mechanisms, and Pathways
Authors: Vincent Isaah S. , Okusa Mark D.
Published: September 2014

Acute kidney injury (AKI) contributes to progressive kidney disease. Although significant advances have been made in the understanding of mechanisms of AKI, less is known about the biological basis that links the initial injury to progressive interstitial fibrosis, tubular dysfunction, and capillary rarefaction. The round table discussion focused on mechanisms of renal recovery and fibrosis following AKI. The knowledge gained by understanding these pathways will serve to identify novel therapeutic targets in the future.
Apoptosis, Fibrosis and Senescence
Authors: Portilla Didier
Published: September 2014

Fibrosis is a major hallmark of progressive kidney disease. The cellular mechanisms that lead to kidney tissue fibrosis are complex and include, for example, increased inflammation, increased oxidative stress, and proximal tubule cell death in the form of apoptosis or senescence. Recent studies have identified TWEAK, a tumor necrosis factor-like weak inducer of apoptosis, as a novel cytokine that mediates kidney inflammation in models of renal fibrosis. Inhibition of apoptosis via TWEAK inhibition has been shown to reduce kidney fibrosis. Recent studies using lineage tracing suggest that interstitial pericytes/perivascular fibroblasts differentiate into myofibroblasts and undergo proliferative expansion during fibrosis. Furthermore, increased expression of nuclear peroxisome proliferator-activated receptor-α in proximal tubules can directly reduce increased expression of transforming growth factor-β1 and interstitial inflammation in models of renal fibrosis, which suggests preservation of proximal tubule cell metabolism and integrity represents an important new therapeutic target. In this review, the current evidence and potential molecular mechanisms involved in the development of kidney fibrosis are discussed.
The Immunomodulatory Role of Bile Acids
Authors: Sipka Sándor , Bruckner Geza
Published: September 2014

Enzymatic oxidation of cholesterol generates numerous distinct bile acids which function both as detergents that facilitate the digestion and absorption of dietary lipids and as hormones that activate five distinct receptors. Activation of these receptors alters gene expression in multiple tissues, leading to changes not only in bile acid metabolism but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility, bacterial growth, inflammation, and in the liver-gut axis. This review focuses on the present knowledge regarding the physiologic and pathologic role of bile acids and their immunomodulatory role, with particular attention to bacterial lipopolysaccharides (endotoxins) and bile acid and immunological disorders. The specific role that bile acids play in the regulation of innate immunity, various systemic inflammations, inflammatory bowel diseases, allergy, psoriasis, cholestasis, obesity, metabolic syndrome, alcoholic liver disease, and colon cancer will be reviewed.
A Comparative Study of the Beneficial Effects of Ipratropium and Beclomethasone against Insulin-Induced Tracheal Tissue Contraction in a Guinea Pig Model
Authors: Sharif Mahjabeen , Khan Bushra Tayyaba , Aleem Shoaib Bin , Anwar Mohammad Asim
Published: September 2014

Objective: To evaluate the acute effects of insulin on airway reactivity and the protective effects of beclomethasone and ipratropium against insulin-induced airway hyperresponsiveness on isolated tracheal smooth muscle in a guinea pig model. Materials and Methods: The trachea of each guinea pig was excised; one end of the tracheal strip was attached to the hook of the oxygen tube of a tissue bath and the other end was connected to a research-grade isometric force displacement transducer. The effects of varying concentrations of insulin (10-7 to 10-3M) and insulin pretreated with a fixed concentration of beclomethasone (10-6M) and ipratropium (10-6M) on the isolated tracheal tissue were studied by constructing cumulative concentration-response curves. Changes in tracheal smooth muscle contractions were recorded on a 4-channel oscillograph. Results: The means ± standard error of the mean of the maximum amplitude of contraction with increasing concentrations of insulin and of insulin pretreated with fixed concentrations of beclomethasone and ipratropium were 35 ± 1.13, 22 ± 1.15 and 27.8 ± 1.27 mm, respectively. Conclusion: The data showed that beclomethasone inhibited the contractile response of insulin to a greater extent than ipratropium. Thus we suggest that inhalational insulin pretreated with beclomethasone may be more efficacious than with ipratropium for the amelioration of potential respiratory adverse effects such as bronchoconstriction.
Pi3kcb
Links Hippo-YAP and PI3K-AKT Signaling Pathways to Promote Cardiomyocyte Proliferation and Survival
Authors: Lin Zhiqiang , Zhou Pingzhu , von Gise Alexander , Gu Fei , Ma Qing , Chen Jinghai , Guo Haidong , van Gorp Pim R.R. , Wang Da-Zhi , Pu William T.
Published: September 2014

Rationale:

Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence–specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined.

Objective:

To identify direct YAP targets that mediate its mitogenic and antiapoptotic effects in the heart.

Methods and Results:

We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP-bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified
Pik3cb
, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase, as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEA-domain occupied a conserved enhancer within the first intron of
Pik3cb
, and this enhancer drove YAP-dependent reporter gene expression.
Yap
gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the phosphoinositol-3-kinase-Akt pathway. Like
Yap
,
Pik3cb
gain-of-function stimulated cardiomyocyte proliferation, and
Pik3cb
knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in
Yap
loss-of-function was significantly rescued by adeno-associated virus–mediated
Pik3cb
expression.

Conclusions:

Pik3cb
is a crucial direct target of YAP, through which the YAP activates phosphoinositol-3-kinase-AKT pathway and regulates cardiomyocyte proliferation and survival.
Why Did the “Leper” Get Under Jesus’ Skin? Emotion Theory and Angry Reaction in Mark 1:40-45
Authors: Spencer F. Scott
Published: September 2014

Accepting the more difficult reading in Mark 1:41 that Jesus was “moved with anger” (ὀργισθείς) in response to a leper’s request for healing, this article investigates the motives behind this vehement response, which persists after Jesus cures the man (1:43). A close analysis of Mark 1:40-45, in conjunction with key Markan co-texts (6:14-29; 10:35-52; 14:32-36; 15:6-15) and ancient and modern theories of emotion, demonstrates that the leper chiefly provokes Jesus’ ire by belittling his deep desire or will to heal (ἐὰν θέλῃς). Discussions of anger (ὀργή/ira) by Aristotle and Seneca serve as primary resources from Greco-Roman antiquity. In contemporary thought, the study of emotion has recently surged in various disciplines, not least in philosophy, psychology, and literary criticism. Biblical scholarship has just begun to engage with this material in examining characters’ emotions. This article sets forth an example and framework for further exploration of the passionate Markan Jesus.
Does the Gospel of John Have a High Christology?
Authors: Gaston Thomas E.
Published: September 2014

John’s gospel is often presented as having a “high” Christology but are alternative readings possible or even more credible? In this essay I re-evaluate the foundations of the purported high Christology of John’s gospel in light of recent Johannine scholarship. I will argue that some conventional readings of John are precarious and common proof texts, when read properly, are more indicative of a low Christology. I will also acknowledge that some passages might indicate a high Christology and warrant further study. If the Gospel of John has, in fact, a low Christology then this has implications for both the dating of the gospel and its relevance for the quest for the historical Jesus.
Kazakhstan and the Global Nuclear Order
Authors: Kassenova Togzhan
Published: September 2014

Kazakhstan’s advanced nuclear industry and active foreign nuclear policy make it a significant player on the global nuclear scene. This article sets the stage by addressing Kazakhstan’s nuclear inheritance from the Soviet period. It then provides an overview of the country’s nuclear sector with an emphasis on the nuclear fuel cycle and on prospects for introducing nuclear energy into Kazakhstan’s energy mix. The article’s final section analyzes Astana’s nuclear diplomacy on the international global nuclear scene.
Proliferation Challenges in Central Asia and the Need for International Cooperation
Authors: Aben Dauren
Published: September 2014

International cooperation on wmd nonproliferation in Central Asia must continue. In addition to unsolved problems related from the Soviet era, the region faces new challenges and threats, such as illicit trafficking in wmd materials, technologies, equipment, and delivery systems, as well as the threat of wmd terrorism. In addition, some Central Asian countries plan to develop their national nuclear industries. Future cooperation on wmd nonproliferation in Central Asia should focus on improving nuclear security and safety systems at nuclear facilities, continued engagement on the Semipalatinsk test site, countering radiological security and safety threats, enhancing export controls and border security, encouraging regional cooperation, strengthening cybersecurity, and promoting nuclear science cooperation and wmd nonproliferation education.
Species of Blepharicera Macquart from China with descriptions of two new species (Diptera: Blephariceridae)
Authors: KANG ZEHUI , YANG DING
Published: September 2014

Blepharicera asiatica (Brodsky, 1930) is newly recorded from China. Two species, Blepharicera hainana sp. nov. and B. hebeiensis sp. nov., are described as new to science. A key to the known species of the genus Blepharicera from China is presented.
Congestive Heart Failure With Apparently Preserved Left Ventricular Systolic Function
Authors: El-Menyar Ayman , Shabana Adel , Arabi Abdulrahman , Al-Thani Hassan , Asaad Nidal , AlBinALi Hajar , Singh Rajvir , Gomaa Mohammed , Gehani A.
Published: September 2014

We analyzed the clinical presentation and outcomes (from 2003 to 2013) of heart failure (HF) with apparently normal systolic function (HFPEF). Based on the echocardiographic left ventricular ejection fraction (LVEF), patients were divided into 2 groups, group 1 (<50%) and group 2 (≥50%). Of 2212 patients with HF, 20% were in group 2. Patients in group 2 were more likely to be older, females, Arabs, hypertensive, and obese ( P = .001). Patients in group 1 were mostly Asians and had more troponin-T positivity ( P = .001). Inhospital cardiac arrest, shock, and deaths were significantly greater in group 1. On multivariate analysis, age, ST-segment elevation myocardial infarction, lack of on-admission β-blockers, and angiotensin-converting enzyme inhibitors use were independent predictors of mortality. HFPEF is associated with less mortality compared to those who presented with reduced LVEF. On admission, use of evidence-based medications could in part predict this difference in the hospital outcome.