bluuebunny/crossref_metadata_2025 huggingface dataset:
Dielectric Loss at MM Range and Deep Level Transient Spectroscopy of the Diamond Grown by DC Arc Plasma Jet Technique
Authors: Garin B.M. , Parshin V.V. , Polyakov V. I. , Rukovishnikov A.I. , Serov E.A. , Jia Ch.Ch. , Tang W.Z. , Lu F.X. , Meriakri V. V. , Parkhomenko M. P. , Kalenov D. S.
Published: April 2012

The results of complex investigation of dielectric parameters at millimeter wavelengths range and defects are presented for the diamond prepared by the DC arc plasma jet (APJ) technique. Also a comparison with conventional CVD diamonds grown by microwave plasma chemical vapor deposition (MPCVD) technique was made. It was found that the dielectric loss in the APJ diamond increases with frequency while it decreases in MPCVD diamonds. It corresponds to the mechanism of the lattice loss induced by lattice disorder in the APJ diamond. The activation energies of the conductivity and energy spectrum of the defect levels were studied. As follows from the data obtained by the charge-based deep level transient spectroscopy (Q-DLTS), all diamonds have significant defect concentrations with continuous energy spectrum. However the concentration of shallow levels is significantly more in APJ diamond. A correlation between the observed defect parameters and values of dielectric parameters was found.
Computational Studies of Trends in Electrocatalysis
Authors: Greeley Jeffrey
Published: April 2012

A brief overview of concepts relevant to the use of first principles Density Functional Theory calculations for screening of novel electrocatalysts is presented. The development of volcano plots for common electrocatalytic reactions, including the Hydrogen Evolution Reaction and the Oxygen Reduction Reaction, is described, and the use of these plots to identify improved catalysts for these reactions is discussed. Selected future directions for this field are briefly summarized at the conclusion.
Investigation of Electrocatalytic Activity of Titania Nanotube Supported Nanostructured Pt-Ni Catalyst towards Methanol Oxidation
Authors: Tamašauskaitė-Tamašiu¯naitė Loreta , Balčiu¯naitė Aldona , Vaiciukevičienė Aušrinė , Selskis Algirdas
Published: April 2012

Here we report the study and use of Pt-Ni catalysts deposited on the titania nanotubed surface as electrocatalysts for methanol oxidation. The nanostructured Pt(Ni)/TiO2-NTs electrocatalysts with different Pt loadings were fabricated by electroless deposition of Ni onto the TiO2-NTs surface and its subsequent partial displacement by Pt upon immersion into the H2PtCl6 solution. The surface morphology and composition of the catalysts were examined using scanning electron microscopy and energy dispersive X-ray spectroscopy. The electrocatalytic activity of these catalysts was evaluated towards the oxidation of methanol by means of cyclic voltammetry, chronoamperometry. The fabricated nanostructured Pt(Ni)/TiO2-NTs catalysts exhibit an enhanced electrochemical activity towards electrochemical oxidation of methanol as compared to that of pure Pt electrode.
Automated region of interest analysis of dynamic Ca2+ signals in image sequences
Authors: Francis Michael , Qian Xun , Charbel Chimène , Ledoux Jonathan , Parker J. C. , Taylor Mark S.
Published: April 2012

Ca2+ signals are commonly measured using fluorescent Ca2+ indicators and microscopy techniques, but manual analysis of Ca2+ measurements is time consuming and subject to bias. Automated region of interest (ROI) detection algorithms have been employed for identification of Ca2+ signals in one-dimensional line scan images, but currently there is no process to integrate acquisition and analysis of ROIs within two-dimensional time lapse image sequences. Therefore we devised a novel algorithm for rapid ROI identification and measurement based on the analysis of best-fit ellipses assigned to signals within noise-filtered image sequences. This algorithm was implemented as a plugin for ImageJ software (National Institutes of Health, Bethesda, MD). We evaluated the ability of our algorithm to detect synthetic Gaussian signal pulses embedded in background noise. The algorithm placed ROIs very near to the center of a range of signal pulses, resulting in mean signal amplitude measurements of 99.06 ± 4.11% of true amplitude values. As a practical application, we evaluated both agonist-induced Ca2+ responses in cultured endothelial cell monolayers, and subtle basal endothelial Ca2+ dynamics in opened artery preparations. Our algorithm enabled comprehensive measurement of individual and localized cellular responses within cultured cell monolayers. It also accurately identified characteristic Ca2+ transients, or Ca2+ pulsars, within the endothelium of intact mouse mesenteric arteries and revealed the distribution of this basal Ca2+ signal modality to be non-Gaussian with respect to amplitude, duration, and spatial spread. We propose that large-scale statistical evaluations made possible by our algorithm will lead to a more efficient and complete characterization of physiologic Ca2+-dependent signaling.
Effect of vertical sleeve gastrectomy in melanocortin receptor 4-deficient rats
Authors: Mul Joram D. , Begg Denovan P. , Alsters Suzanne I. M. , Haaften Gijs van , Duran Karen J. , D'Alessio David A. , le Roux Carel W. , Woods Stephen C. , Sandoval Darleen A. , Blakemore Alexandra I. F. , Cuppen Edwin , van Haelst Mieke M. , Seeley Randy J.
Published: April 2012

Bariatric surgery is currently the most effective treatment for obesity. Vertical sleeve gastrectomy (VSG), a commonly applied bariatric procedure, involves surgically incising most of the volume of the stomach. In humans, partial loss of melanocortin receptor-4 ( MC4R) activity is the most common monogenic correlate of obesity regardless of lifestyle. At present it is unclear whether genetic alteration of MC4R signaling modulates the beneficial effects of VSG. Following VSG, we analyzed body weight, food intake, glucose sensitivity, and macronutrient preference of wild-type and MC4R-deficient ( Mc4r+/− and Mc4r−/−) rats compared with sham-operated controls. VSG reduced body weight and fat mass and improved glucose metabolism and also shifted preference toward carbohydrates and away from fat. All of this occurred independently of MC4R activity. In addition, MC4R was resequenced in 46 human subjects who underwent VSG. We observed common genetic variations in the coding sequence of MC4R in five subjects. However, none of those variations appeared to affect the outcome of VSG. Taken together, these data suggest that the beneficial effect of VSG on body weight and glucose metabolism is not mediated by alterations in MC4R activity.
Arachidonic acid stimulates TNFα production in Kupffer cells via a reactive oxygen species-pERK1/2-Egr1-dependent mechanism
Authors: Cubero Francisco Javier , Nieto Natalia
Published: April 2012

Kupffer cells are a key source of mediators of alcohol-induced liver damage such as reactive oxygen species, chemokines, growth factors, and eicosanoids. Since diets rich in polyunsaturated fatty acids are a requirement for the development of alcoholic liver disease, we hypothesized that polyunsaturated fatty acids could synergize with ethanol to promote Kupffer cell activation and TNFα production, hence, contributing to liver injury. Primary Kupffer cells from control and from ethanol-fed rats incubated with arachidonic acid showed similar proliferation rates than nontreated cells; however, arachidonic acid induced phenotypic changes, lipid peroxidation, hydroperoxides, and superoxide radical generation. Similar effects occurred in human Kupffer cells. These events were greater in Kupffer cells from ethanol-fed rats, and antioxidants and inhibitors of arachidonic acid metabolism prevented them. Arachidonic acid treatment increased NADPH oxidase activity. Inhibitors of NADPH oxidase and of arachidonic acid metabolism partially prevented the increase in oxidant stress. Upon arachidonic acid stimulation, there was a rapid and sustained increase in TNFα, which was greater in Kupffer cells from ethanol-fed rats than in Kupffer cells from control rats. Arachidonic acid induced ERK1/2 phosphorylation and nuclear translocation of early growth response-1 (Egr1), and ethanol synergized with arachidonic acid to promote this effect. PD98059, a mitogen extracellular kinase 1/2 inhibitor, and curcumin, an Egr1 inhibitor, blocked the arachidonic acid-mediated upregulation of TNFα in Kupffer cells. This study unveils the mechanism whereby arachidonic acid and ethanol increase TNFα production in Kupffer cells, thus contributing to alcoholic liver disease.
Myocardial ischemia, reperfusion, and infarction in chronically instrumented, intact, conscious, and unrestrained mice
Authors: Lujan Heidi L. , Janbaih Hussein , Feng Han-Zhong , Jin Jian-Ping , DiCarlo Stephen E.
Published: April 2012

In the United States alone, the National Heart, Lung, and Blood Institute (NHLBI) has invested several hundred million dollars in pursuit of myocardial infarct-sparing therapies. However, due largely to methodological limitations, this investment has not produced any notable clinical application or cardioprotective therapy. Among the major methodological limitations is the reliance on animal models that do not mimic the clinical situation. In this context, the limited use of conscious animal models is of major concern. In fact, whenever possible, studies of cardiovascular physiology and pathophysiology should be conducted in conscious, complex models to avoid the complications associated with the use of anesthesia and surgical trauma. The mouse has significant advantages over other experimental models for the investigation of infarct-sparing therapies. The mouse is inexpensive, has a high throughput, and presents the ability of one to create genetically modified models. However, successful infarct-sparing therapies in anesthetized mice or isolated mouse hearts may not be successful in more complex models, including conscious mice. Accordingly, a conscious mouse model of myocardial ischemia and reperfusion has the potential to be of major importance for advancing the concepts and methods that drive the development of infarct-sparing therapies. Therefore, we describe, for the first time, the use of an intact, conscious, and unrestrained mouse model of myocardial ischemia-reperfusion and infarction. The conscious mouse model permits occlusion and reperfusion of the left anterior descending coronary artery in an intact, complex model free of the confounding influences of anesthetics and surgical trauma. This methodology may be adopted for advancing the concepts and ideas that drive cardiovascular research.
Mechanical loading and TGF-β change the expression of multiple miRNAs in tendon fibroblasts
Authors: Mendias Christopher L. , Gumucio Jonathan P. , Lynch Evan B.
Published: April 2012

Tendons link skeletal muscles to bones and are important components of the musculoskeletal system. There has been much interest in the role of microRNA (miRNA) in the regulation of musculoskeletal tissues to mechanical loading, inactivity, and disease, but it was unknown whether miRNA is involved in the adaptation of tendons to mechanical loading. We hypothesized that mechanical loading and transforming growth factor-β (TGF-β) treatment would regulate the expression of several miRNA molecules with known roles in cell proliferation and extracellular matrix synthesis. To test our hypothesis, we subjected untrained adult rats to a single session of mechanical loading and measured the expression of several miRNA transcripts in Achilles tendons. Additionally, as TGF-β is known to be an important regulator of tendon growth and adaptation, we treated primary tendon fibroblasts with TGF-β and measured miRNA expression. Both mechanical loading and TGF-β treatment modulated the expression of several miRNAs that regulate cell proliferation and extracellular matrix synthesis. We also identified mechanosensitive miRNAs that may bind to the 3′-untranslated region of the basic helix-loop-helix transcription factor scleraxis, which is a master regulator of limb tendon development. The results from this study provide novel insight into the mechanobiology of tendons and indicate that miRNA could play an important role in the adaptation of tendons to growth stimuli.
Pitfalls in the dipolar model for the neocortical EEG sources
Authors: Riera Jorge J. , Ogawa Takeshi , Goto Takakuni , Sumiyoshi Akira , Nonaka Hiroi , Evans Alan , Miyakawa Hiroyoshi , Kawashima Ryuta
Published: April 2012

For about six decades, primary current sources of the electroencephalogram (EEG) have been assumed dipolar in nature. In this study, we used electrophysiological recordings from anesthetized Wistar rats undergoing repeated whisker deflections to revise the biophysical foundations of the EEG dipolar model. In a first experiment, we performed three-dimensional recordings of extracellular potentials from a large portion of the barrel field to estimate intracortical multipolar moments generated either by single spiking neurons (i.e., pyramidal cells, PC; spiny stellate cells, SS) or by populations of them while experiencing synchronized postsynaptic potentials. As expected, backpropagating spikes along PC dendrites caused dipolar field components larger in the direction perpendicular to the cortical surface (49.7 ± 22.0 nA·mm). In agreement with the fact that SS cells have “close-field” configurations, their dipolar moment at any direction was negligible. Surprisingly, monopolar field components were detectable both at the level of single units (i.e., −11.7 ± 3.4 nA for PC) and at the mesoscopic level of mixed neuronal populations receiving extended synaptic inputs within either a cortical column (−0.44 ± 0.20 μA) or a 2.5-m3-voxel volume (−3.32 ± 1.20 μA). To evaluate the relationship between the macroscopically defined EEG equivalent dipole and the mesoscopic intracortical multipolar moments, we performed concurrent recordings of high-resolution skull EEG and laminar local field potentials. From this second experiment, we estimated the time-varying EEG equivalent dipole for the entire barrel field using either a multiple dipole fitting or a distributed type of EEG inverse solution. We demonstrated that mesoscopic multipolar components are altogether absorbed by any equivalent dipole in both types of inverse solutions. We conclude that the primary current sources of the EEG in the neocortex of rodents are not precisely represented by a single equivalent dipole and that the existence of monopolar components must be also considered at the mesoscopic level.
Penetration mechanism of dimethyl sulfoxide in human and pig ear skin: An ATR–FTIR and near-FT Raman spectroscopicin vivoandin vitrostudy
Authors: Greve Tanja M. , Andersen Kristine B. , Nielsen Ole F.
Published: April 2012

The penetration mechanism of dimethyl sulfoxide (DMSO) in human skinin vivoandin vitroand pig ear skin in vitro was studied using attenuated total reflectance (ATR) Fourier transform (FT) infrared (IR) and near-FT-Raman spectroscopy. The results showed changes in the conformation of the skin keratins from an α-helical to a β-sheet conformation. These changes were proved to depend on the concentration of free water in the sample as DMSO tended to bind to free water before the protein-bound water was replaced and the protein conformational changes were induced. The induced conformational changes were shown to be completely reversible as the proteins are returned to their original state within 20 h after the treatment with DMSO. The penetration depth of DMSO was shown to depend on the time of exposure – however, after only 15 min DMSO has penetrated thestratum corneum, which is the skin barrier.
The Bad, the Good, and the Ugly about Oxidative Stress
Authors: Jimenez-Del-Rio Marlene , Velez-Pardo Carlos
Published: April 2012

Alzheimer’s disease (AD), Parkinson’s disease (PD), and cancer (e.g., leukemia) are the most devastating disorders affecting millions of people worldwide. Except for some kind of cancers, no effective and/or definitive therapeutic treatment aimed to reduce or to retard the clinic and pathologic symptoms induced by AD and PD is presently available. Therefore, it is urgently needed to understand the molecular basis of these disorders. Since oxidative stress (OS) is an important etiologic factor of the pathologic process of AD, PD, and cancer, understanding how intracellular signaling pathways respond to OS will have a significant implication in the therapy of these diseases. Here, we propose a model of minimal completeness of cell death signaling induced by OS as a mechanistic explanation of neuronal and cancer cell demise. This mechanism might provide the basis for therapeutic design strategies. Finally, we will attempt to associate PD, cancer, and OS. This paper critically analyzes the evidence that support the “oxidative stress model” in neurodegeneration and cancer.
A Two‐Phase Support Method for Solving Linear Programs: Numerical Experiments
Authors: Bentobache Mohand , Bibi Mohand Ouamer
Published: April 2012

We develop a single artificial variable technique to initialize the primal support method for solving linear programs with bounded variables. We first recall the full artificial basis technique, then we will present the proposed algorithm. In order to study the performances of the suggested algorithm, an implementation under the MATLAB programming language has been developed. Finally, we carry out an experimental study about CPU time and iterations number on a large set of the NETLIB test problems. These test problems are practical linear programs modelling various real‐life problems arising from several fields such as oil refinery, audit staff scheduling, airline scheduling, industrial production and allocation, image restoration, multisector economic planning, and data fitting. It has been shown that our approach is competitive with our implementation of the primal simplex method and the primal simplex algorithm implemented in the known open‐source LP solver LP_SOLVE.
Glucocorticosteroids Rescue Basophils from Dasatinib-Augmented Immunoglobulin E-Mediated Histamine Release
Authors: Herrmann Harald , Blatt Katharina , Ghanim Viviane , Kneidinger Michael , Marth Katharina , Valenta Rudolf , Valent Peter
Published: April 2012

Background: Dasatinib is a multikinase inhibitor active against several tyrosine kinases including ABL, KIT, Lyn and Btk. Apart from its known antileukemic activity, the drug produces several side effects including edemas and pleural effusions, which are supposedly triggered by activated immune cells. Effusion formation can be treated effectively by glucocorticosteroids. We have recently shown that low concentrations of dasatinib (<0.1 µM) promote IgE-dependent secretion of histamine in basophils, especially in allergic individuals. In the current study, we asked whether glucocorticosteroids inhibit dasatinib-induced activation of basophils. Methods: Basophils were preincubated with dexamethasone, prednisolone and hydrocortisone for 24 h, and were then exposed to an anti-IgE antibody (normal basophils) or the allergens Bet v 1 and Phl p 5 (allergic patients) with or without low concentrations of dasatinib (0.025 µM). After incubation, basophils were examined for histamine release and expression of CD63 and CD203c. Results: All three glucocorticosteroids were found to counteract IgE-dependent and dasatinib-enhanced histamine release in basophils in nonallergic and allergic individuals. In addition, glucocorticosteroids were found to inhibit anti-IgE-induced upregulation of CD63 and CD203c in the presence or absence of dasatinib. The inhibitory effects of glucocorticosteroids were dose-dependent (effective range: 1–10 µM) and seen in all donors examined. Conclusions: Glucocorticosteroids rescue IgE receptor cross-linked basophils from additional costimulatory effects of low-dose dasatinib which may have clinical implications in dasatinib-treated patients.
Clinical Benefit of High-Sensitivity KRAS Mutation Testing in Metastatic Colorectal Cancer Treated with Anti-EGFR Antibody Therapy
Authors: Kimura Tetsuo , Okamoto Koichi , Miyamoto Hiroshi , Kimura Masako , Kitamura Shinji , Takenaka Hidetaka , Muguruma Naoki , Okahisa Toshiya , Aoyagi Eriko , Kajimoto Mayumi , Tsuji Yasushi , Kogawa Takahiro , Tsuji Akihito , Takayama Tetsuji
Published: April 2012

Objective: We compared high-sensitivity KRAS mutation testing with direct sequencing for predicting the efficacy of antiepidermal growth factor receptor antibodies in patients with metastatic colorectal cancer (mCRC). Methods: We analyzed the KRAS status in 61 tumors from cetuximab-treated mCRC patients by both direct sequencing and a high-sensitivity method: 2-step PCR restriction fragmentation length polymorphism (RFLP). Therapeutic effects in each mutational status were evaluated. Results: The incidences of KRAS mutations determined by direct sequencing and 2-step PCR RFLP were 34.4 and 52.5%, respectively (p = 0.02). Patients were categorized into 3 groups [W/W, wild-type by both methods (n = 29); W/M, wild-type by direct sequencing, detected mutation by 2-step PCR RFLP (n = 11); M/M, mutant-type by both methods (n = 21)]. The response rate for cetuximab in the W/M group (0%) was the same as that in the M/M group, and was significantly lower than in the W/W group (41.4%) (p < 0.001). Progression-free survival in the W/M group (11.0 weeks) was similar to that in the M/M group (8.0 weeks), and was significantly shorter than in the W/W group (18.0 weeks) (p < 0.002). Conclusion: High-sensitivity KRAS mutation testing is useful for selecting true responders to cetuximab.
Hypopituitarism due to Hydrocephalus: Case Report and Review of the Literature
Authors: Pinto Fernando Campos Gomes , da Cunha Neto Malebranche Berardo Carneiro , Rocha Manuela Giuliani Marcondes , do Lago Daniel Vicaria , Bronstein Marcello Delano , Teixeira Manoel Jacobsen
Published: April 2012

Introduction: Although rare, chronic hydrocephalus may cause amenorrhea and delayed puberty associated with obesity as the main endocrine manifestations. Since the first operation carried out in 1950 on a patient with amenorrhea and hydrocephalus, fewer than 30 patients with these features have been reported. Case Report: Our patient represents a teenage case of primary amenorrhea, partial adrenal insufficiency and adult growth hormone deficiency caused by hydrocephalus due to aqueductal stenosis. Our English-language literature search for similar well-documented cases yielded less than 30 cases. Our management consisted of endoscopic third ventriculostomy, which resulted in regular menstrual cycles and normalization of somato- and adrenocorticotropic axes. Discussion: This is a rare case of a 20-year-old woman with primary amenorrhea caused by hydrocephalus due to aqueductal stenosis. Neurosurgical treatment produced relief in hypothalamic hydrodynamics tension, allowing recovery of hormonal function and restoring normal menstrual cycles.
Tongue Movements and Their Acoustic Consequences in Amyotrophic Lateral Sclerosis
Authors: Yunusova Yana , Green Jordan R. , Greenwood Lauren , Wang Jun , Pattee Gary L. , Zinman Lorne
Published: April 2012

Objective: The relations between acoustic measures and their articulatory bases have rarely been tested in dysarthria but are important for diagnostic and treatment purposes. We tested the association between acoustic measures of F2 range and F2 slope with kinematic measures of tongue movement displacement and speed in individuals with amyotrophic lateral sclerosis (ALS) and healthy controls speaking at normal and slow rates. Relations between acoustic and kinematic measures and speech intelligibility were examined. Results: As healthy controls reduced their speaking rate, their F2 slopes and movement speeds decreased. In talkers with ALS, acoustic and kinematic variables were associated with changes in speaking rate, characteristic of disease progression. Participants with slow rate had shallower F2 slopes and slower movement speeds than those with normal rate. Relations between F2 range and tongue displacement were weaker. F2 slope, displacement, and duration were correlated with speech intelligibility most consistently. Conclusion: Findings suggested that F2 slope is a useful marker for tracking disease progression in ALS. F2 slope reflects changes in tongue function with disease progression and is linked to speech intelligibility. Changes in movement speed, however, might be the earliest sign of disease in the tongue.
A Phase II Study of Clinical Outcomes of 3-Week Cycles of Irinotecan and S-1 in Patients with Previously Untreated Metastatic Colorectal Cancer: Influence of the UGT1A1 and CYP2A6 Polymorphisms on Clinical Activity
Authors: Choi Yoon Hee , Kim Tae Won , Kim Kyu-Pyo , Lee Sung Sook , Hong Yong Sang , Ryu Min-Hee , Lee Jae-Lyun , Chang Heung Moon , Ryoo Baek-Yeol , Kim Ho-Sook , Shin Jae-Gook , Kang Yoon-Koo
Published: April 2012

Objectives: We investigated the efficacy and safety of the combination of irinotecan (CPT-11) and S-1 (IRIS regimen) as a first-line treatment in patients with metastatic colorectal cancer. We also evaluated the association between UGT1A1 and CYP2A6 polymorphisms and clinical phenotypes. Methods: The patients received CPT-11 (225 mg/m2) on day 1 and S-1 (80 mg/m2) on days 1–14 every 3 weeks. The association of the UGT1A1 (*6 and *28) and CYP2A6(*4, *7, *9, and *10) polymorphisms with toxicities and efficacy were analyzed. Results: Thirty patients were treated. The overall response rate was 66.7% (95% CI 48.7–84.6). The median time to progression was 7.6 months (95% CI 5.8–9.5). The most common grade 3/4 hematologic and non-hematologic toxicity were neutropenia (53.4%) and diarrhea (16.7%), respectively. The allele frequencies of UGT1A1*6 and *28 were 15.5 and 10.3%, respectively. The frequencies of CYP2A6*4, *7, *9, and *10 were 15.5, 8.6, 29.3, and 3.5%, respectively. Stratification of patients according to the number of UGT1A1*28 and *6 alleles showed a significant correlation between the number of defective alleles and the incidence of grade 3/4 neutropenia. Conclusions: Our results indicate that IRIS is a promising first-line regimen in patients with metastatic colorectal cancer. Severe neutropenia may be associated with interindividual variations in UGT1A1 polymorphisms.
Renalase, a Novel Enzyme Involved in Blood Pressure Regulation, Is Related to Kidney Function but Not to Blood Pressure in Hemodialysis Patients
Authors: Zbroch Edyta , Malyszko Jolanta , Malyszko Jacek S. , Koc-Zorawska Ewa , Mysliwiec Michal
Published: April 2012

Renalase, secreted by the kidney, degrades catecholamines and may play a role in the regulation of sympathetic tone and blood pressure. The aim of this study was to assess serum renalase levels in hemodialysis patients and their relationship to blood pressure control, type of antihypertensive therapy and the presence of residual renal function. Results: The mean serum renalase in the study cohort was significantly higher than in the control group (27.53 ± 7.18 vs. 3.86 ± 0.73 µg/ml, p < 0.001). The serum renalase concentration was significantly lower in patients with residual renal function when compared to the anuric patients. The type of hypotensive treatment (β-blockers, ACE inhibitors or AT1 receptor blockers) did not affect renalase levels. There was a significant inverse correlation between the serum renalase and age (r = –0.28, p = 0.023) and residual renal function (r = –0.327, p = 0.001). Renalase was not related to blood pressure, heart rate or hemodialysis vintage. Conclusion: Elevated renalase levels in HD patients may be due to impaired kidney function. Further studies are needed to prove or disprove the possible role of renalase in the pathogenesis of hypertension in patients with kidney diseases.
Staphylococcal Extracellular Adherence Protein Induces Platelet Activation by Stimulation of Thiol Isomerases
Authors: Bertling Anne , Niemann Silke , Hussain Muzaffar , Holbrook Lisa , Stanley Ronald G. , Brodde Martin F. , Pohl Silke , Schifferdecker Tina , Roth Joachim , Jurk Kerstin , Müller Anja , Lahav Judith , Peters Georg , Heilmann Christine , Gibbins Jonathan M. , Kehrel Beate E.
Published: April 2012

Objective—

Staphylococcus aureus
can induce platelet aggregation. The rapidity and degree of this correlates with the severity of disseminated intravascular coagulation, and depends on platelet peptidoglycans. Surface-located thiol isomerases play an important role in platelet activation. The staphylococcal extracellular adherence protein (Eap) functions as an adhesin for host plasma proteins. Therefore we tested the effect of Eap on platelets.

Methods and Results—

We found a strong stimulation of the platelet-surface thiol isomerases protein disulfide isomerase and endoplasmic reticulum stress
proteins
57 and 72 by Eap. Eap induced thiol isomerase-dependent glycoprotein IIb/IIIa activation, granule secretion, and platelet aggregation. Treatment of platelets with thiol blockers, bacitracin, and anti–protein disulfide isomerase antibody inhibited Eap-induced platelet activation. The effect of Eap on platelets and protein disulfide isomerase activity was completely blocked by glycosaminoglycans. Inhibition by the hydrophobic probe bis(1-anilinonaphthalene 8-sulfonate) suggested the involvement of hydrophobic sites in protein disulfide isomerase and platelet activation by Eap.

Conclusion—

In the present study, we found an additional and yet unknown mechanism of platelet activation by a bacterial adhesin, involving stimulation of thiol isomerases. The thiol isomerase stimulatory and prothrombotic features of a microbial secreted protein are probably not restricted to
S aureus
and Eap. Because many microorganisms are coated with amyloidogenic proteins, it is likely that the observed mechanism is a more general one.
Pro- and Antiatherogenic Effects of a Dominant-Negative P465L Mutation of Peroxisome Proliferator–Activated Receptor-γ in Apolipoprotein E–Null Mic
Authors: Pendse Avani A. , Johnson Lance A. , Kim Hyung-Suk , McNair Marcus , Nipp C. Taylor , Wilhelm Carolyn , Maeda Nobuyo
Published: April 2012

Objective—

The dominant-negative mutation,
P467L
, in peroxisome proliferator–activated receptor-γ (PPARγ) affects adipose tissue distribution, insulin sensitivity, and blood pressure in heterozygous humans. We hypothesized that the equivalent mutation, PPARγ-
P465L
, in mice will worsen atherosclerosis.

Methods and Results—

Apolipoprotein E–null mice with and without PPARγ-
P465L
mutation were bred in 129S6 inbred genetic background. Mild hypertension and lipodystrophy of PPARγ-
P465L
persisted in the apolipoprotein E–null background. Glucose homeostasis was normal, but plasma adiponectin was significantly lower and resistin was higher in PPARγ-
P465L
mice. Plasma cholesterol and lipoprotein distribution were not different, but plasma triglycerides tended to be reduced. Surprisingly, there were no overall changes in the atherosclerotic plaque size or composition. PPARγ-
P465L
macrophages had a small decrease in CD36 mRNA and a small yet significant reduction in very-low-density lipoprotein uptake in culture. In unloaded apolipoprotein E–null macrophages with PPARγ-
P465L
, cholesterol uptake was reduced whereas apolipoprotein AI–mediated efflux was increased. However, when cells were cholesterol loaded in the presence of acetylated low-density lipoprotein, no genotype difference in uptake or efflux was apparent. A reduction of vascular cell adhesion molecule-1 expression in aorta suggests a relatively antiatherogenic vascular environment in mice with PPARγ-
P465L
.

Conclusion—

Small, competing pro- and antiatherogenic effects of PPARγ-
P465L
mutation result in unchanged plaque development in apolipoprotein E–deficient mice.
Vectorcardiography as a Tool for Easy Optimization of Cardiac Resynchronization Therapy in Canine Left Bundle Branch Block Hearts
Authors: van Deursen Caroline J.M. , Strik Marc , Rademakers Leonard M. , van Hunnik Arne , Kuiper Marion , Wecke Liliane , Crijns Harry J.G.M , Vernooy Kevin , Prinzen Frits W.
Published: April 2012

Background—

In cardiac resynchronization therapy (CRT), optimization of left ventricular (LV) stimulation timing is often time consuming. We hypothesized that the QRS vector in the vectorcardiogram (VCG) reflects electric interventricular dyssynchrony, and that the QRS vector amplitude (VA
QRS
), halfway between that during left bundle branch block (LBBB) and LV pacing, reflects optimal resynchronization, and can be used for easy optimization of CRT.

Methods and Results—

In 24 canine hearts with LBBB (12 acute, 6 with heart failure, and 6 with myocardial infarction), the LV was paced over a wide range of atrioventricular (AV) delays. Surface ECGs were recorded from the limb leads, and VA
QRS
was calculated in the frontal plane. Mechanical interventricular dyssynchrony (MIVD) was determined as the time delay between upslopes of LV and right ventricular pressure curves, and systolic function was assessed as LV dP/dt
max
. VA
QRS
and MIVD were highly correlated (
r
=0.94). The VA
QRS
halfway between that during LV pacing with short AV delay and intrinsic LBBB activation accurately predicted the optimal AV delay for LV pacing (1 ms; 95% CI, –5 to 8ms). Increase in LV dP/dt
max
at the VCG predicted AV delay was only slightly lower than the highest observed ∆LV dP/dt
max
(–2.7%; 95% CI, –3.6 to –1.8%). Inability to reach the halfway value of VA
QRS
during simultaneous biventricular pacing (53% of cases) was associated with suboptimal hemodynamic response, which could be corrected by sequential pacing.

Conclusions—

The VA
QRS
reflects electric interventricular dyssynchrony and accurately predicts optimal timing of LV stimulation in canine LBBB hearts. Therefore, VCG may be useful as a reliable and easy tool for individual optimization of CRT.
Transient Exposure of Neonatal Female Mice to Testosterone Abrogates the Sexual Dimorphism of Abdominal Aortic Aneurysms
Authors: Zhang Xuan , Thatcher Sean E. , Rateri Debra L. , Bruemmer Dennis , Charnigo Richard , Daugherty Alan , Cassis Lisa A.
Published: April 2012

Rationale:

Abdominal aortic aneurysms (AAAs) exhibit marked sexual dimorphism with higher prevalence in men. Similarly, AAAs induced by angiotensin II (AngII) infusion into mice exhibit a higher prevalence in males. Testosterone promotes AAA pathology in adult male mice through regulation of angiotensin type 1A receptors (AT1aR) in abdominal aortas. However, mechanisms for sexual dimorphism of regional aortic angiotensin receptor expression and AAA formation are unknown.

Objective:

To define the role of developmental testosterone exposures in sexual dimorphism of AAAs, we determined if exposure of neonatal female mice to testosterone confers adult susceptibility to AngII-induced AAAs.

Methods and Results:

One-day–old female hypercholesterolemic mice were administered a single dose of either vehicle or testosterone. Neonatal testosterone administration increased abdominal aortic AT1aR mRNA abundance and promoted a striking increase in AngII-induced AAAs in adult females exhibiting low serum testosterone concentrations. AngII-induced atherosclerosis and ascending aortic aneurysms were also increased by testosterone administration to neonatal females. In contrast, neonatal testosterone administration in males had no effect on AngII-induced vascular pathologies. Deficiency of AT1aR in smooth muscle cells reduced effects of neonatal testosterone to promote AAAs in adult females but did not alter atherosclerosis or ascending aortic aneurysms. Testosterone increased AT1aR mRNA abundance and hydrogen peroxide generation in cultured abdominal aortic SMCs. Increased AT1aR mRNA abundance was maintained during progressive passaging of female smooth muscle cells.

Conclusions:

These data reveal an unrecognized role of transient sex hormone exposures during neonatal development as long-lasting mediators of regional aortic AT1aR expression and sexual dimorphism of AAAs.
MicroRNA-Mediated In Vitro and In Vivo Direct Reprogramming of Cardiac Fibroblasts to Cardiomyocytes
Authors: Jayawardena Tilanthi M. , Egemnazarov Bakytbek , Finch Elizabeth A. , Zhang Lunan , Payne J. Alan , Pandya Kumar , Zhang Zhiping , Rosenberg Paul , Mirotsou Maria , Dzau Victor J.
Published: April 2012

Rationale:

Repopulation of the injured heart with new, functional cardiomyocytes remains a daunting challenge for cardiac regenerative medicine. An ideal therapeutic approach would involve an effective method at achieving direct conversion of injured areas to functional tissue in situ.

Objective:

The aim of this study was to develop a strategy that identified and evaluated the potential of specific micro (mi)RNAs capable of inducing reprogramming of cardiac fibroblasts directly to cardiomyocytes in vitro and in vivo.

Methods and Results:

Using a combinatorial strategy, we identified a combination of miRNAs 1, 133, 208, and 499 capable of inducing direct cellular reprogramming of fibroblasts to cardiomyocyte-like cells in vitro. Detailed studies of the reprogrammed cells demonstrated that a single transient transfection of the miRNAs can direct a switch in cell fate as documented by expression of mature cardiomyocyte markers, sarcomeric organization, and exhibition of spontaneous calcium flux characteristic of a cardiomyocyte-like phenotype. Interestingly, we also found that miRNA-mediated reprogramming was enhanced 10-fold on JAK inhibitor I treatment. Importantly, administration of miRNAs into ischemic mouse myocardium resulted in evidence of direct conversion of cardiac fibroblasts to cardiomyocytes in situ. Genetic tracing analysis using Fsp1Cre-traced fibroblasts from both cardiac and noncardiac cell sources strongly suggests that induced cells are most likely of fibroblastic origin.

Conclusions:

The findings from this study provide proof-of-concept that miRNAs have the capability of directly converting fibroblasts to a cardiomyocyte-like phenotype in vitro. Also of significance is that this is the first report of direct cardiac reprogramming in vivo. Our approach may have broad and important implications for therapeutic tissue regeneration in general.
Overcoming the Ethical Dilemmas of Skilled Migration? An Analysis of International Narratives on the “Brain Drain”
Authors: Levatino Antonina , Pécoud Antoine
Published: April 2012

Migration-related issues have, since approximately 2000, been the object of increased attention at the international level. This has led, among other things, to the production of international narratives, which aim both at understanding migration and at proposing policy recommendations on how to address it, with the objective of improving the governance of migration at the global level. But this implies overcoming dilemmas stemming from the diverging interests of states and other actors (such as NGOs and the private sector). This article examines the way in which international migration narratives address skilled migration, which is characterized by some of the clearest political trade-offs between stakeholders. It argues that these narratives attempt to speak to all parties and conciliate contradictory arguments about what should be done to discursively overcome policy dilemmas and create a consensus. Although this is line with the mandate of international organizations, it depoliticizes migration issues.
Privilege and Belonging
Authors: Mollen Debra , Smith Nathan Grant , Levy Jacob J. , Magyar-Moe Jeana L.
Published: April 2012

In this rejoinder, we advance the dialogue stimulated by our major contribution (Smith et al., 2012) in which we present the findings from a survey of early career professionals (ECPs) in Division 17, the Society of Counseling Psychology. We respond to the reactants’ concerns and observations using the lenses of privilege and belonging to guide our response. Building from the premise that the Society needs to continue to create and sustain efforts to attract and retain burgeoning counseling psychologists—including faculty members, practitioners, and those whose careers have combined or unique foci—we offer additional suggestions toward meeting the goal of expanding the richness of membership to include a wide array of those who identify with the premises of the Society and the specialty of counseling psychology. The importance of mentoring for advanced students and ECPs with an array of career trajectories is particularly emphasized.
Variations in professions’ adaption of quality reforms: The cases of doctors and auditors in Sweden
Authors: Jonnergård Karin , Erlingsdóttir Gudbjörg
Published: April 2012

This article investigates variations in two professions’ adaption of quality reforms. The adaption of reforms is viewed as a part of the professions’ legitimacy and identity processes. Literature in the area suggests that the adaption of reforms is influenced by the profession’s knowledge base, professional norms, organizational belonging and organizational field. The two cases here on how doctors and auditors adapt to quality reforms show that the influences of these factors are, however, moulded by the professions’ strategies and the salience of the different aforementioned factors. A general conclusion is that compatibility between the bases of knowledge and the professional norms are vital for the adaption of reforms and that organizational fields are important for setting the agenda. Organizational belongings, on the other hand, seem of less importance for adaption of quality reforms.
Individual Differences and Their Impact on the Safety and the Efficiency of Human-Wheelchair Systems
Authors: Jipp Meike
Published: April 2012

Objective:

The extent to which individual differences in fine motor abilities affect indoor safety and efficiency of human-wheelchair systems was examined.

Background:

To reduce the currently large number of indoor wheelchair accidents, assistance systems with a high level of automation were developed. It was proposed to adapt the wheelchair’s level of automation to the user’s ability to steer the device to avoid drawbacks of highly automated wheelchairs. The state of the art, however, lacks an empirical identification of those abilities.

Method:

A study with 23 participants is described. The participants drove through various sections of a course with a powered wheelchair. Repeatedly measured criteria were safety (numbers of collisions) and efficiency (times required for reaching goals). As covariates, the participants’ fine motor abilities were assessed.

Results:

A random coefficient modeling approach was conducted to analyze the data, which were available on two levels as course sections were nested within participants. The participants’ aiming, precision, and arm–hand speed contributed significantly to both criteria: Participants with lower fine motor abilities had more collisions and required more time for reaching goals.

Conclusion:

Adapting the wheelchair’s level of automation to these fine motor abilities can improve indoor safety and efficiency. In addition, the results highlight the need to further examine the impact of individual differences on the design of automation features for powered wheelchairs as well as other applications of automation.

Application:

The results facilitate the improvement of current wheelchair technology.
Formation of Engineered Bone with Adipose Stromal Cells from Buccal Fat Pad
Authors: Shiraishi T. , Sumita Y. , Wakamastu Y. , Nagai K. , Asahina I.
Published: April 2012

A robust method for inducing bone formation from adipose-derived stromal cells (ADSCs) has not been established. Moreover, the efficacy of strong osteogenic inducers including BMP-2 for ADSC-mediated bone engineering remains controversial. Meanwhile, the buccal fat pad (BFP), which is found in the oral cavity as an adipose-encapsulated mass, has been shown to have potential as a new accessible source of ADSCs for oral surgeons. However, to date, there have been no reports that define the practical usefulness of ADSCs from BFP (B-ADSCs) for bone engineering. Here, we report an efficient method of generating bone from B-ADSCs using rhBMP-2. The analyses show that B-ADSCs can differentiate in vitro toward the osteoblastic lineage by the addition of rhBMP-2 to culture medium, regardless of the presence of osteoinductive reagents (OSR), as demonstrated by measurements of ALP activity, in vitro calcification, and osteogenic gene expression. Interestingly, adipogenic genes were clearly detectable only in cultures with rhBMP-2 and OSR. However, in vivo bone formation was most substantial when B-ADSCs cultured in this condition were transplanted. Thus, B-ADSCs reliably formed engineered bone when pre-treated with rhBMP-2 for inducing mature osteoblastic differentiation. This study supports the potential translation for B-ADSC use in the clinical treatment of bone defects.
Association among Vitamin D, Oral Candidiasis, and Calprotectinemia in HIV
Authors: Sroussi H.Y. , Burke-Miller J. , French A.L. , Adeyemi O.M. , Weber K.M. , Lu Y. , Cohen M.
Published: April 2012

Vitamin D deficiency is associated with negative health outcomes, including infections. Vitamin D modulates inflammation and down-regulates the expression of calprotectin, a molecule which influences neutrophil functions and which has been linked to oral candidiasis (OC), the most prevalent oral lesion in human immunodeficiency virus (HIV). We hypothesized a positive association between vitamin D deficiency and OC, and that this effect was partially modulated by calprotectinemia. Plasma calprotectin and serum 25 (OH) vitamin D levels were measured in stored samples from 84 HIV-seropositive Chicago women enrolled in the Oral Substudy of the Women’s Interagency HIV Study (WIHS). OC and vitamin D deficiency were diagnosed in, respectively, 14 (16.7%) and 46 (54.8%) of those studied. Vitamin D deficiency was positively associated with OC (p = 0.011) and with higher calprotectinemia (p = 0.019) in univariate analysis. After adjustment for CD4, HIV viral load, HIV treatment, and tobacco and heroin/methadone use, vitamin D deficiency remained a significant predictor of OC (OR 5.66; 95% confidence interval 1.01-31.71). This association weakened after adjustment for calprotectinemia, supporting a role for calprotectinemia as a moderator of this effect. These findings support studies to examine the effect of vitamin D status on calprotectinemia, neutrophil functions, and opportunistic mucosal infections in HIV.
Amphotericin B Up-regulates Lipid A-induced IL-6 Production via Caspase-8
Authors: Tamai R. , Sugamata M. , Kiyoura Y.
Published: April 2012

Amphotericin B, an antifungal drug used to treat candidiasis, has been reported to induce pro-inflammatory cytokine production in cultured cells. This study investigated the effects of amphotericin B on pro-inflammatory cytokine production in response to lipid A, the bioactive component of lipopolysaccharide (LPS) in the cell walls of Gram-negative bacteria. Amphotericin B alone elicited a slight increase in interleukin (IL)-6 and IL-8 production by human gingival fibroblasts. However, amphotericin B synergistically up-regulated lipid A-induced production of IL-6 and IL-8. While amphotericin B minimally activated nuclear factor (NF)-κB, it synergistically increased lipid A–induced NF-κB activation. Pre-treatment with methyl-β-cyclodextrin (MβCD), a cholesterol-binding agent, reduced IL-6 and IL-8 production in human gingival fibroblasts. Cholesterol-saturated MβCD also reversed cytokine production, suggesting that the synergistic production of cytokines by amphotericin B and lipid A is dependent on cholesterol-rich microdomains. Amphotericin B activated caspase-8. In addition, a caspase-8 inhibitor inhibited IL-6 production by amphotericin B and lipid A. This suggests that caspase-8 is required for the synergistic production of IL-6 by amphotericin B and lipid A. Collectively, our results suggest that periodontal treatment carried out before amphotericin B treatment may protect against lipid A-induced pro-inflammatory cytokine production.
Bernhard Guggenheim – Critical Mind at the Forefront of Oral Microbiology
Authors: Gmür R.
Published: April 2012

Bernhard Guggenheim is a distinguished leader in oral microbiology and immunology and a recipient of many honors. This article outlines his background and scientific career and illuminates some of his important contributions to dental research. At the age of 75, he continues to scrutinize established paradigms and unremittingly fosters demanding biofilm research.