bluuebunny/crossref_metadata_2025 huggingface dataset:
IGF-I increases the expression of fibronectin by Nox4-dependent Akt phosphorylation in renal tubular epithelial cells
Authors: New David D. , Block Karen , Bhandhari Basant , Gorin Yves , Abboud Hanna E.
Published: September 2011

Extracellular matrix accumulation contributes to the progression of chronic kidney disease. Many growth factors including insulin-like growth factor-I (IGF-I) enhance matrix protein accumulation. Proximal tubular epithelial cells (PTCs) synthesize matrix proteins. NADPH oxidases are major sources of reactive oxygen species (ROS), important signaling molecules that mediate biological responses in a variety of cells and tissue. We investigated the mechanism by which IGF-I regulates fibronectin accumulation in PTCs and the role of a potential redox-dependent signaling pathway. IGF-I induces an increase in NADPH-dependent superoxide generation, enhances the release of hydrogen peroxide, and increases the expression of NADPH oxidase 4 (Nox4) in PTCs. IGF-I also stimulates phosphorylation of Akt, and inhibition of Akt or its upstream activator phosphatidylinositol 3-kinase attenuates IGF-I-induced fibronectin accumulation. Expression of dominant negative Akt also inhibits IGF-I-induced expression of fibronectin, indicating a role for this kinase in fibronectin accumulation. Expression of dominant negative adenovirus Nox4 inhibits IGF-I-induced NADPH oxidase activity, Akt phosphorylation, and fibronectin protein expression. Moreover, transfection of small interfering RNA targeting Nox4 decreases Nox4 protein expression and blocks IGF-I-induced Akt phosphorylation and the increase in fibronectin, placing Nox4 and ROS upstream of Akt signaling pathway. To confirm the role of Nox4, PTCs were infected with adenovirus construct expressing wild-type Nox4. Ad-Nox4, but not control Ad-green fluorescent protein, upregulated Nox4 expression and increased NADPH oxidase activity as well as fibronectin expression. Taken together, these results provide the first evidence for a role of Nox4 in IGF-I-induced Akt phosphorylation and fibronectin expression in tubular epithelial cells.
Doxorubicin acts via mitochondrial ROS to stimulate catabolism in C2C12 myotubes
Authors: Gilliam Laura A. A. , Moylan Jennifer S. , Patterson Elaine W. , Smith Jeffrey D. , Wilson Anne S. , Rabbani Zaheen , Reid Michael B.
Published: September 2011

Doxorubicin, a commonly prescribed chemotherapeutic agent, causes skeletal muscle wasting in cancer patients undergoing treatment and increases mitochondrial reactive oxygen species (ROS) production. ROS stimulate protein degradation in muscle by activating proteolytic systems that include caspase-3 and the ubiquitin-proteasome pathway. We hypothesized that doxorubicin causes skeletal muscle catabolism through ROS, causing upregulation of E3 ubiquitin ligases and caspase-3. We tested this hypothesis by exposing differentiated C2C12 myotubes to doxorubicin (0.2 μM). Doxorubicin decreased myotube width 48 h following exposure, along with a 40–50% reduction in myosin and sarcomeric actin. Cytosolic oxidant activity was elevated in myotubes 2 h following doxorubicin exposure. This increase in oxidants was followed by an increase in the E3 ubiquitin ligase atrogin-1/muscle atrophy F-box (MAFbx) and caspase-3. Treating myotubes with SS31 (opposes mitochondrial ROS) inhibited expression of ROS-sensitive atrogin-1/MAFbx and protected against doxorubicin-stimulated catabolism. These findings suggest doxorubicin acts via mitochondrial ROS to stimulate myotube atrophy.
Divergent CFTR orthologs respond differently to the channel inhibitors CFTRinh-172, glibenclamide, and GlyH-101
Authors: Stahl Maximilian , Stahl Klaus , Brubacher Marie B. , Forrest John N.
Published: September 2011

Comparison of diverse orthologs is a powerful tool to study the structure and function of channel proteins. We investigated the response of human, killifish, pig, and shark cystic fibrosis transmembrane conductance regulator (CFTR) to specific inhibitors of the channel: CFTRinh-172, glibenclamide, and GlyH-101. In three systems, including organ perfusion of the shark rectal gland, primary cultures of shark rectal gland tubules, and expression studies of each ortholog in cRNA microinjected Xenopus laevis oocytes, we observed fundamental differences in the sensitivity to inhibition by these channel blockers. In organ perfusion studies, shark CFTR was insensitive to inhibition by CFTRinh-172. This insensitivity was also seen in short-circuit current experiments with cultured rectal gland tubular epithelial cells (maximum inhibition 4 ± 1.3%). In oocyte expression studies, shark CFTR was again insensitive to CFTRinh-172 (maximum inhibition 10.3 ± 2.5% at 25 μM), pig CFTR was insensitive to glibenclamide (maximum inhibition 18.4 ± 4.4% at 250 μM), and all orthologs were sensitive to GlyH-101. The amino acid residues considered responsible by previous site-directed mutagenesis for binding of the three inhibitors are conserved in the four CFTR isoforms studied. These experiments demonstrate a profound difference in the sensitivity of different orthologs of CFTR proteins to inhibition by CFTR blockers that cannot be explained by mutagenesis of single amino acids. We believe that the potency of the inhibitors CFTRinh-172, glibenclamide, and GlyH-101 on the CFTR chloride channel protein is likely dictated by the local environment and the three-dimensional structure of additional residues that form the vestibules, the chloride pore, and regulatory regions of the channel.
Enhanced store-operated Ca2+ entry and TRPC channel expression in pulmonary arteries of monocrotaline-induced pulmonary hypertensive rats
Authors: Liu Xiao-Ru , Zhang Ming-Fang , Yang Na , Liu Qing , Wang Rui-Xing , Cao Yuan-Ning , Yang Xiao-Ru , Sham James S. K. , Lin Mo-Jun
Published: September 2011

Pulmonary hypertension (PH) is associated with profound vascular remodeling and alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Previous studies show that canonical transient receptor potential (TRPC) genes are upregulated and store-operated Ca2+ entry (SOCE) is augmented in PASMCs of chronic hypoxic rats and patients of pulmonary arterial hypertension (PAH). Here we further examine the involvement of TRPC and SOCE in PH with a widely used rat model of monocrotaline (MCT)-induced PAH. Rats developed severe PAH, right ventricular hypertrophy, and significant increase in store-operated TRPC1 and TRPC4 mRNA and protein in endothelium-denuded pulmonary arteries (PAs) 3 wk after MCT injection. Contraction of PA and Ca2+ influx in PASMC evoked by store depletion using cyclopiazonic acid (CPA) were enhanced dramatically, consistent with augmented SOCE in the MCT-treated group. The time course of increase in CPA-induced contraction corresponded to that of TRPC1 expression. Endothelin-1 (ET-1)-induced vasoconstriction was also potentiated in PAs of MCT-treated rats. The response was partially inhibited by SOCE blockers, including Gd3+, La3+, and SKF-96365, as well as the general TRPC inhibitor BTP-2, suggesting that TRPC-dependent SOCE was involved. Moreover, the ET-1-induced contraction and Ca2+ response in the MCT group were more susceptible to the inhibition caused by the various SOCE blockers. Hence, our study shows that MCT-induced PAH is associated with increased TRPC expression and SOCE, which are involved in the enhanced vascular reactivity to ET-1, and support the hypothesis that TRPC-dependent SOCE is an important pathway for the development of PH.
Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines
Authors: Zampell Jamie C. , Avraham Tomer , Yoder Nicole , Fort Nicholas , Yan Alan , Weitman Evan S. , Mehrara Babak J.
Published: September 2011

Lymphangiogenic cytokines such as vascular endothelial growth factor-C (VEGF-C) are critically required for lymphatic regeneration; however, in some circumstances, lymphatic function is impaired despite normal or elevated levels of these cytokines. The recent identification of anti-lymphangiogenic molecules such as interferon-γ (IFN-γ), transforming growth factor-β1, and endostatin has led us to hypothesize that impaired lymphatic function may represent a dysregulated balance in the expression of pro/anti-lymphangiogenic stimuli. We observed that nude mice have significantly improved lymphatic function compared with wild-type mice in a tail model of lymphedema. We show that gradients of lymphatic fluid stasis regulate the expression of lymphangiogenic cytokines (VEGF-A, VEGF-C, and hepatocyte growth factor) and that paradoxically the expression of these molecules is increased in wild-type mice. More importantly, we show that as a consequence of T-cell-mediated inflammation, these same gradients also regulate expression patterns of anti-lymphangiogenic molecules corresponding temporally and spatially with impaired lymphatic function in wild-type mice. We show that neutralization of IFN-γ significantly increases inflammatory lymph node lymphangiogenesis independently of changes in VEGF-A or VEGF-C expression, suggesting that alterations in the balance of pro- and anti-lymphangiogenic cytokine expression can regulate lymphatic vessel formation. In conclusion, we show that gradients of lymphatic fluid stasis regulate not only the expression of pro-lymphangiogenic cytokines but also potent suppressors of lymphangiogenesis as a consequence of T-cell inflammation and that modulation of the balance between these stimuli can regulate lymphatic function.
Structural selectivity of human SGLT inhibitors
Authors: Hummel Charles S. , Lu Chuan , Liu Jie , Ghezzi Chiari , Hirayama Bruce A. , Loo Donald D. F. , Kepe Vladimir , Barrio Jorge R. , Wright Ernest M.
Published: September 2011

Human Na+-d-glucose cotransporter (hSGLT) inhibitors constitute the newest class of diabetes drugs, blocking up to 50% of renal glucose reabsorption in vivo. These drugs have potential for widespread use in the diabetes epidemic, but how they work at a molecular level is poorly understood. Here, we use electrophysiological methods to assess how they block Na+-d-glucose cotransporter SGLT1 and SGLT2 expressed in human embryonic kidney 293T (HEK-293T) cells and compared them to the classic SGLT inhibitor phlorizin. Dapagliflozin [(1 S)-1,5,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-d-glucitol], two structural analogs, and the aglycones of phlorizin and dapagliflozin were investigated in detail. Dapagliflozin and fluoro-dapagliflozin [(1 S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-4-F-4-deoxy-d-glucitol] blocked glucose transport and glucose-coupled currents with ≈100-fold specificity for hSGLT2 ( Ki = 6 nM) over hSGLT1 ( Ki = 400 nM). As galactose is a poor substrate for SGLT2, it was surprising that galacto-dapagliflozin [(1 S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-d-galactitol] was a selective inhibitor of hSGLT2, but was less potent than dapagliflozin for both transporters (hSGLT2 Ki = 25 nM, hSGLT1 Ki = 25,000 nM). Phlorizin and galacto-dapagliflozin rapidly dissociated from SGLT2 [half-time off rate ( t1/2,Off) ≈ 20–30 s], while dapagliflozin and fluoro-dapagliflozin dissociated from hSGLT2 at a rate 10-fold slower ( t1/2,Off ≥ 180 s). Phlorizin was unable to exchange with dapagliflozin bound to hSGLT2. In contrast, dapagliflozin, fluoro-dapagliflozin, and galacto-dapagliflozin dissociated quickly from hSGLT1 ( t1/2,Off = 1–2 s), and phlorizin readily exchanged with dapagliflozin bound to hSGLT1. The aglycones of phlorizin and dapagliflozin were poor inhibitors of both hSGLT2 and hSGLT1 with Ki values > 100 μM. These results show that inhibitor binding to SGLTs is composed of two synergistic forces: sugar binding to the glucose site, which is not rigid, and so different sugars will change the orientation of the aglycone in the access vestibule; and the binding of the aglycone affects the binding affinity of the entire inhibitor. Therefore, the pharmacophore must include variations in both the structure of the sugar and the aglycone.
Hydrogen sulfide regulates cAMP homeostasis and renin degranulation in As4.1 and rat renin-rich kidney cells
Authors: Lu Ming , Liu Yi-Hong , Ho Chui Ying , Tiong Chi Xin , Bian Jin-Song
Published: September 2011

The present study aims to investigate the regulatory effect of hydrogen sulfide (H2S) on cAMP homeostasis and renin degranulation in As4.1 and rat renin-rich kidney cells. It was found in the present study that NaHS at 0.1–10 μM significantly decreased cAMP production in As4.1 cells treated with isoproterenol (a β-adrenoceptor agonist), forskolin (an adenylyl cyclase activator), or 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor). NaHS at 10 μM suppressed adenylate cyclase activity but stimulated phosphodiesterase activity. We continued to study whether H2S may mediate cAMP-dependent renin degranulaion in As4.1 cells. It was found that NaHS at 0.1–10 μM significantly increased intracellular renin protein level. Moreover, NaHS reversed the declined renin content within As4.1 cells and normalized the upregulated renin activity in the culture medium of As4.1 cells treated with the above three stimuli. RT-PCR showed that cystathionine-γ-lyase is the main enzyme to produce endogenous H2S in As4.1 cells. Overexpression of cystathionine-γ-lyase increased endogenous H2S production and suppressed isoproterenol-induced renin release, suggesting that endogenous H2S may also inhibit renin release from As4.1 cells. We also tested whether H2S has a similar effect in renin-rich kidney cells. It was found that isoproterenol elevated intracellular cAMP level and extracellular renin activity but decreased renin protein level in the renin-rich kidney cells. Pretreatment with NaHS abolished these effects. In conclusion, H2S regulates cAMP homeostasis via inhibition of adenylate cyclase and stimulation of phosphodiesterase. Our findings suggest that H2S plays a critical role in regulation of renin degranulation in As4.1 and rat renin-rich kidney cells.
Ano1 as a regulator of proliferation
Authors: Stanich Jennifer E. , Gibbons Simon J. , Eisenman Seth T. , Bardsley Michael R. , Rock Jason R. , Harfe Brian D. , Ordog Tamas , Farrugia Gianrico
Published: September 2011

Ano1 is a recently discovered Ca2+-activated Cl− channel expressed on interstitial cells of Cajal (ICC) that has been implicated in slow-wave activity in the gut. However, Ano1 is expressed on all classes of ICC, even those that do not contribute to generation of the slow wave, suggesting that Ano1 may have an alternate function in these cells. Ano1 is also highly expressed in gastrointestinal stromal tumors. Mice lacking Ano1 had fewer proliferating ICC in whole mount preparations and in culture, raising the possibility that Ano1 is involved in proliferation. Cl− channel blockers decreased proliferation in cells expressing Ano1, including primary cultures of ICC and in the pancreatic cancer-derived cell line, CFPAC-1. Cl− channel blockers had a reduced effect on Ano1(−/−) cultures, confirming that the blockers are acting on Ano1. Ki67 immunoreactivity, 5-ethynyl-2′-deoxyuridine incorporation, and cell-cycle analysis of cells grown in low-Cl− media showed fewer proliferating cells than in cultures grown in regular medium. We confirmed that mice lacking Ano1 had less phosphorylated retinoblastoma protein compared with controls. These data led us to conclude that Ano1 regulates proliferation at the G1/S transition of the cell cycle and may play a role in tumorigenesis.
Immunomodulatory action of dietary fish oil and targeted deletion of intestinal epithelial cell PPARδ in inflammation-induced colon carcinogenesis
Authors: Monk Jennifer M. , Kim Wooki , Callaway Evelyn , Turk Harmony F. , Foreman Jennifer E. , Peters Jeffrey M. , He Weimin , Weeks Brad , Alaniz Robert C. , McMurray David N. , Chapkin Robert S.
Published: September 2011

The ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR)-δ is highly expressed in colonic epithelial cells; however, the role of PPARδ ligands, such as fatty acids, in mucosal inflammation and malignant transformation has not been clarified. Recent evidence suggests that the anti-inflammatory/chemoprotective properties of fish oil (FO)-derived n-3 polyunsaturated fatty acids (PUFAs) may be partly mediated by PPARδ. Therefore, we assessed the role of PPARδ in modulating the effects of dietary n-3 PUFAs by targeted deletion of intestinal epithelial cell PPARδ (PPARδΔIEpC). Subsequently, we documented changes in colon tumorigenesis and the inflammatory microenvironment, i.e., local [mesenteric lymph node (MLN)] and systemic (spleen) T cell activation. Animals were fed chemopromotive [corn oil (CO)] or chemoprotective (FO) diets during the induction of chronic inflammation/carcinogenesis. Tumor incidence was similar in control and PPARδΔIEpCmice. FO reduced mucosal injury, tumor incidence, colonic STAT3 activation, and inflammatory cytokine gene expression, independent of PPARδ genotype. CD8+T cell recruitment into MLNs was suppressed in PPARδΔIEpCmice. Similarly, FO reduced CD8+T cell numbers in the MLN. Dietary FO independently modulated MLN CD4+T cell activation status by decreasing CD44 expression. CD11a expression by MLN CD4+T cells was downregulated in PPARδΔIEpCmice. Lastly, splenic CD62L expression was downregulated in PPARδΔIEpCCD4+and CD8+T cells. These data demonstrate that expression of intestinal epithelial cell PPARδ does not influence azoxymethane/dextran sodium sulfate-induced colon tumor incidence. Moreover, we provide new evidence that dietary n-3 PUFAs attenuate intestinal inflammation in an intestinal epithelial cell PPARδ-independent manner.
Functional contribution of P2Y1receptors to the control of coronary blood flow
Authors: Bender Shawn B. , Berwick Zachary C. , Laughlin M. Harold , Tune Johnathan D.
Published: September 2011

Activation of ADP-sensitive P2Y1receptors has been proposed as an integral step in the putative “nucleotide axis” regulating coronary blood flow. However, the specific mechanism(s) and overall contribution of P2Y1receptors to the control of coronary blood flow have not been clearly defined. Using vertically integrative studies in isolated coronary arterioles and open-chest anesthetized dogs, we examined the hypothesis that P2Y1receptors induce coronary vasodilation via an endothelium-dependent mechanism and contribute to coronary pressure-flow autoregulation and/or ischemic coronary vasodilation. Immunohistochemistry revealed P2Y1receptor expression in coronary arteriolar endothelial and vascular smooth muscle cells. The ADP analog 2-methylthio-ADP induced arteriolar dilation in vitro and in vivo that was abolished by the selective P2Y1antagonist MRS-2179 and the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. MRS-2179 did not alter baseline coronary flow in vivo but significantly attenuated coronary vasodilation to ATP in vitro and in vivo and the nonhydrolyzable ATP analog ATPγS in vitro. Coronary blood flow responses to alterations in coronary perfusion pressure (40–100 mmHg) or to a brief 15-s coronary artery occlusion were unaffected by MRS-2179. Our data reveal that P2Y1receptors are functionally expressed in the coronary circulation and that activation produces coronary vasodilation via an endothelium/nitric oxide-dependent mechanism. Although these receptors represent a critical component of purinergic coronary vasodilation, our findings indicate that P2Y1receptor activation is not required for coronary pressure-flow autoregulation or reactive hyperemia.
Functional effect of longitudinal heterogeneity in constricted airways before and after lung expansion
Authors: Wongviriyawong C. , Harris R. S. , Zheng H. , Kone M. , Winkler T. , Venegas J. G.
Published: September 2011

Heterogeneity in narrowing among individual airways is an important contributor to airway hyperresponsiveness. This paper investigates the contribution of longitudinal heterogeneity (the variability along the airway in cross-sectional area and shape) to airway resistance ( Raw). We analyzed chest high-resolution computed tomography scans of 8 asthmatic (AS) and 9 nonasthmatic (NA) subjects before and after methacholine (MCh) challenge, and after lung expansion to total lung capacity. In each subject, Raw was calculated for 35 defined central airways with >2 mm diameter. Ignoring the area variability and noncircular shape results in an underestimation of Raw (%Utotal) that was substantial in some airways (∼50%) but generally small (median <6%). The average contribution of the underestimation of Raw caused by longitudinal heterogeneity in the area (%Uarea) to %Utotal was 36%, while the rest was due to the noncircularity of the shape (%Ushape). After MCh challenge, %Uarea increased in AS and NA ( P < 0.05). A lung volume increase to TLC reduced %Utotal and %Uarea in both AS and NA ( P < 0.0001, except for %Utotal in AS with P < 0.01). Only in NA, %Ushape had a significant reduction after increasing lung volume to TLC ( P < 0.005). %Uarea was highly correlated, but not identical to the mean-normalized longitudinal heterogeneity in the cross-sectional area [CV2( A)] and %Ushape to the average eccentricity of the elliptical shape. This study demonstrates that Raw calculated assuming a cylindrical shape and derived from an average area along its length may, in some airways, substantially underestimate Raw. The observed changes in underestimations of Raw with the increase in lung volume to total lung capacity may be consistent with, and contribute in part to, the differences in effects of deep inhalations in airway function between AS and NA subjects.
A Comprehensive View of Nuclear Receptor Cancer Cistromes
Authors: Tang Qianzi , Chen Yiwen , Meyer Clifford , Geistlinger Tim , Lupien Mathieu , Wang Qian , Liu Tao , Zhang Yong , Brown Myles , Liu Xiaole Shirley
Published: September 2011

Nuclear receptors comprise a superfamily of ligand-activated transcription factors that play important roles in both physiology and diseases including cancer. The technologies of chromatin immunoprecipitation followed by array hybridization (ChIP-chip) or massively parallel sequencing (ChIP-seq) has been used to map, at an unprecedented rate, the in vivo genome-wide binding (cistrome) of nuclear receptors in both normal and cancer cells. We developed a curated database of 88 nuclear receptor cistrome data sets and other associated high-throughput data sets including 121 collaborating factor cistromes, 94 epigenomes, and 319 transcriptomes. Through integrative analysis of the curated nuclear receptor ChIP-chip/seq data sets, we discovered novel factor-specific noncanonical motifs that may have important regulatory roles. We also revealed a common feature of nuclear receptor pioneering factors to recognize relatively short and AT-rich motifs. Most nuclear receptors bind predominantly to introns and distal intergenetic regions, and binding sites closer to transcription start sites were found to be neither stronger nor more evolutionarily conserved. Interestingly, while most nuclear receptors appear to be predominantly transcriptional activators, our analysis suggests that the binding of ESR1, RARA, and RARG has both activating and repressive effects. Through meta-analysis of different omic data of the same cancer cell line model from multiple studies, we generated consensus cistrome and expression profiles. We further made probabilistic predictions of the nuclear receptor target genes by integrating cistrome and transcriptome data and validated the predictions using expression data from tumor samples. The final database, with comprehensive cistrome, epigenome, and transcriptome data sets and downstream analysis results, constitutes a valuable resource for the nuclear receptor and cancer community. Cancer Res; 71(22); 6940–7. ©2011 AACR.
DNA Cytometry Testing for Cervical Cancer Screening: Approaches and Reporting Standards for New Technologies
Authors: Colditz Graham A. , Crowley John
Published: September 2011

Evaluation of new technologies requires rigorous methods to provide unbiased estimates of the performance and so inform future clinical practice. We review evidence on DNA cytometry reported earlier in this journal and point to the standards for reporting of diagnostic accuracy as a metric against which this article can be evaluated. The cross-sectional nature of the data and incomplete reporting limit the clinical utility of the study. With application of improved reporting standards for diagnostic tests and improved design and evaluation of new technologies for screening, we may better inform practices to improve clinical outcomes and population health. Clin Cancer Res; 17(22); 6971–2. ©2011 AACR.
Reorganization of Motor System in Parkinson’s Disease
Authors: Kalmar Zsuzsanna , Kovacs Norbert , Perlaki Gabor , Nagy Ferenc , Aschermann Zsuzsanna , Kerekes Zsuzsanna , Kaszas Beata , Balas Istvan , Orsi Gergely , Komoly Samuel , Schwarcz Attila , Janszky Jozsef
Published: September 2011

Background/Aims: We investigated adaptive reorganization in Parkinson’s disease (PD) by fMRI using a passive movement task and compared the brain activation patterns of 10 patients with left- versus right-sided dominant symptoms. Five healthy controls were also investigated with the same settings. Methods: We grouped patients according to the predominant side of symptoms; thus, a right-sided dominant and a left-sided dominant group was formed. The paradigm consisted of a 4-finger passive movement task, which altered with resting states. For each subject, this examination was performed twice: on the left and on the right hand separately. Results: In healthy controls, motor-related areas contralateral to the moving fingers showed activation on fMRI. Concerning PD patients, motor-related areas of the ipsilateral hemisphere – including the primary motor cortex, supplementary motor area, and basal ganglia – seemed to be involved in the motor reorganization in PD. However, we could only demonstrate this reorganization in patients with right-sided dominant symptoms. Conclusions: We suggest that the human brain in PD tries to compensate for the failure of the basal ganglia motor loop by employing alternative (ipsilateral) motor pathways, indicating that a complex reorganization can also take place in disorders like PD which affect the whole motor-related network.
Impaired Diastolic Function and Disruption of the Force-Frequency Relationship in the Right Ventricle of Newborn Pigs Resuscitated with 100% Oxygen
Authors: Odland Hans Henrik , Kro Grete A.B. , Edvardsen Thor , Thaulow Erik , Saugstad Ola Didrik
Published: September 2011

Background: Resuscitation with 100% oxygen increases oxidative stress and is detrimental for organ function. Objective: To study the effects of resuscitation with 100% oxygen compared to room-air on myocardial function. Methods: Twenty-eight newborn pigs underwent global hypoxia (8% oxygen/N2) until base excess reached –20 mmol/l. The animals were randomized into two groups and resuscitated with either 100% or room air for 30 min. Myocardial tissue Doppler velocities and acceleration of the mitral and tricuspid valve annuli during systole and diastole were assessed before global hypoxia and after resuscitation together with troponin I. Results: Peak early diastolic velocity (E′) and acceleration (pEac) in the septum and pEac in the lateral tricuspid valve annulus were lower after resuscitation with 100% oxygen, suggesting impaired diastolic relaxation in the right ventricle. Lower systolic velocities and acceleration in the right ventricle relative to heart rate indicate disruption of the right ventricular force-frequency relationship after resuscitation with 100% oxygen. Troponins were higher in the 100% oxygen group, suggesting increased myocardial damage in this group. Conclusion: Resuscitation with 100% oxygen compared to room air induces diastolic dysfunction, disrupts the systolic force-frequency relationship and increases myocardial damage in the newborn pig.
Staging Dementia Using Proxy-Reported Activities of Daily Living
Authors: Jonas Christina , Schiffczyk Claudia , Lahmeyer Constanze , Mueller Friedemann , Riepe Matthias W.
Published: September 2011

Background/Aim: It has been questioned whether cognitive and behavioral scales sufficiently address the impact of dementia on the everyday life of patients. Therefore, other instruments are used, such as scales of activities of daily living (ADL). Our goal was to analyze variables influencing the appraisal of ADL. Method: Prospective cohort study on 202 patients with dementia and their proxies. Results: Two clusters of patients were identified. These clusters differed significantly in their constituting variables and all variables that informants reported regarding the patients. However, severity of dementia and other variables were similar in the two clusters. Conclusion: We conclude that ratings of basic and instrumental ADL by proxy are modulated by the informants’ variables, particularly if these informants are female. Use of ADL scales to assess the impact of dementia or treatment thereof needs to be handled cautiously.
Homozygosity for an Allele Encoding Deacetylated FoxO1 Protects Macrophages From Cholesterol-Induced Inflammation Without Increasing Apoptosis
Authors: Tsuchiya Kyoichiro , Banks Alexander S. , Liang Chien-Ping , Tabas Ira , Tall Alan R. , Accili Domenico
Published: September 2011

Objective—

Insulin resistance renders macrophages more prone to cholesterol-induced apoptosis by promoting nuclear localization of transcription factor forkhead box transcription factor (Fox) O1. However, FoxO1 also decreases macrophage inflammation, raising the question of how the balance between proapoptotic and antiinflammatory effects is determined. We sought to identify the mechanism whereby FoxO1 dampens inflammation without promoting apoptosis. We hypothesized that nutrient-dependent FoxO1 acetylation plays a role in this process.

Methods and Results—

We generated knock-in mice bearing alleles that encode constitutively deacetylated FoxO1 and studied the ex vivo response of primary peritoneal macrophages. We show that macrophages derived from mice homozygous for constitutively deacetylated FoxO1 alleles retain antiinflammatory properties in response to free cholesterol loading, without increasing apoptosis. Deacetylated FoxO1 inhibits free cholesterol–induced Akt phosphorylation and increases levels of the nuclear factor-κB precursor p105, decreasing nuclear translocation of nuclear factor-κB p65 subunit and dampening mitogen-activated protein/extracellular signal-regulated kinase activation to prevent inflammation.

Conclusion—

Deacetylated FoxO1 regulates p105 to prevent macrophage inflammation without causing apoptosis, suggesting a potential novel therapeutic approach to atherosclerosis through FoxO1 deacetylation.
Integrin-Targeted Imaging of Inflammation in Vascular Remodeling
Authors: Razavian Mahmoud , Marfatia Ravi , Mongue-Din Heloise , Tavakoli Sina , Sinusas Albert J. , Zhang Jiasheng , Nie Lei , Sadeghi Mehran M.
Published: September 2011

Objective—

Inflammation plays a key role in the development of vascular diseases. Monocytes and macrophages express α
v
β
3
integrin. We used an α
v
integrin-specific tracer,
99m
Tc-NC100692, to investigate integrin-targeted imaging for detection vessel wall inflammation.

Methods and Results—

The binding of a fluorescent homologue of NC100692 to α
v
β
3
on human monocytes and macrophages was shown by flow cytometry. Vessel wall inflammation and remodeling was induced in murine carotid arteries through adventitial exposure to CaCl
2
. NC100692 micro single photon computed tomography/CT imaging was performed after 2 and 4 weeks and showed significantly higher uptake of the tracer in CaCl
2
-exposed left carotids compared with sham-operated contralateral arteries. Histological analysis at 4 weeks demonstrated significant remodeling of left carotid arteries and considerable macrophage infiltration, which was confirmed by real-time polymerase chain reaction. There was no significant difference in normalized α
v
, β
3
, or β
5
mRNA expression between right and left carotid arteries. Finally, NC100692 uptake strongly correlated with macrophage marker expression in carotid arteries.

Conclusion—

NC100692 imaging can detect vessel wall inflammation in vivo. If further validated, α
v
-targeted imaging may provide a noninvasive approach for identifying patients who are at high risk for vascular events and tracking the effect of antiinflammatory treatments.
Protease-Activated Receptor-2 Modulates Protease-Activated Receptor-1–Driven Neointimal Hyperplasia
Authors: Sevigny Leila M. , Austin Karyn M. , Zhang Ping , Kasuda Shogo , Koukos Georgios , Sharifi Sheida , Covic Lidija , Kuliopulos Athan
Published: September 2011

Objective—

Emerging evidence suggests that protease-activated receptors-1 and -2 (PAR1 and PAR2) can signal together in response to proteases found in the rapidly changing microenvironment of damaged blood vessels. However, it is unknown whether PAR1 and PAR2 promote or mitigate the hyperplastic response to arterial injury. Using cell-penetrating PAR1 pepducins and mice deficient in PAR1 or PAR2, we set out to determine the respective contributions of the receptors to hyperplasia and phenotypic modulation of smooth muscle cells (SMCs) in response to arterial injury.

Methods and Results—

SMCs were strongly activated by PAR1 stimulation, as evidenced by increased mitogenesis, mitochondrial activity, and calcium mobilization. The effects of chronic PAR1 stimulation following vascular injury were studied by performing carotid artery ligations in mice treated with the PAR1 agonist pepducin, P1pal-13. Histological analysis revealed that PAR1 stimulation caused striking hyperplasia, which was ablated in PAR1
−/−
and, surprisingly, PAR2
−/−
mice. P1pal-13 treatment yielded an expression pattern consistent with a dedifferentiated phenotype in carotid artery SMCs. Detection of PAR1-PAR2 complexes provided an explanation for the hyperplastic effects of the PAR1 agonist requiring the presence of both receptors.

Conclusion—

We conclude that PAR2 regulates the PAR1 hyperplastic response to arterial injury leading to stenosis.
Physical Activity and Functional Outcomes From Cerebral Vascular Events in Men
Authors: Rist Pamela M. , Lee I-Min , Kase Carlos S. , Gaziano J. Michael , Kurth Tobias
Published: September 2011

Background and Purpose—

In studies enrolling patients with stroke, higher levels of prestroke physical activity are associated with better functional outcomes. However, prospective studies evaluating this association are sparse. Using a cohort of initially healthy men, we aimed to prospectively assess the association between physical activity and functional outcomes from cerebral vascular events.

Methods—

We conducted a prospective cohort study among 21 794 men enrolled in the Physician's Health Study who provided information on physical activity at baseline and who did not have a history of stroke or transient ischemic attack (TIA). Baseline levels of physical activity were categorized as: vigorous exercise <1, 1, 2 to 4, and ≥5 times/week. Possible functional outcomes included TIA and stroke with modified Rankin Scale score of 0 to 1, 2 to 3, or 5 to 6. Multinomial logistic regression was used to determine the association between physical activity and functional outcomes from cerebral vascular events.

Results—

After a mean of 20.2 years of follow-up, 761 TIAs, 1146 ischemic strokes, 221 hemorrhagic strokes, and 11 strokes of unknown type occurred. Compared with men who did not experience a stroke or TIA and who exercise vigorously <1 time/week, men who exercise vigorously ≥5 times/week had adjusted relative risk (95% CIs) of 0.67 (0.53–0.86) for TIA, 0.84 (0.61–1.14) for stroke with modified Rankin Scale score 0 to 1, 0.85 (0.67–1.08) for modified Rankin Scale score 2 to 3, and 1.12 (0.78–1.60) for modified Rankin Scale score 5 to 6 after total stroke. Other levels of physical activity did not have a significant impact on the risk of our outcomes.

Conclusions—

Physical activity before TIA or stroke does not appear to influence functional outcomes after cerebral vascular events.
Comprehensive Cardiac Rehabilitation for Secondary Prevention After Transient Ischemic Attack or Mild Stroke
Authors: Prior Peter L. , Hachinski Vladimir , Unsworth Karen , Chan Richard , Mytka Sharon , O'Callaghan Christina , Suskin Neville
Published: September 2011

Background and Purpose—

Comprehensive cardiac rehabilitation (CCR), which integrates structured lifestyle interventions and medications, reduces morbidity and mortality among cardiac patients. CCR has not typically been used with cerebrovascular populations, despite important commonalities with heart patients. We tested feasibility and effectiveness of 6-month outpatient CCR for secondary prevention after transient ischemic attack or mild, nondisabling stroke. This article presents risk factors. A future article will discuss psychological outcomes.

Methods—

Consecutive consenting subjects having sustained a transient ischemic attack or mild, nondisabling stroke within the previous 12 months (mean, 11.5 weeks; event-to-CCR entry) with ≥1 vascular risk factor, were recruited from a stroke prevention clinic providing usual care. We measured 6-month CCR outcomes following a prospective cohort design.

Results—

Of 110 subjects recruited from January 2005 to April 2006, 100 subjects (mean age, 64.9 years; 46 women) entered and 80 subjects completed CCR. We obtained favorable, significant intake-to-exit changes in: aerobic capacity (+31.4%;
P
<0.001), total cholesterol (−0.30 mmol/L;
P
=0.008), total cholesterol/high-density lipoprotein (−11.6%;
P
<0.001), triglycerides (−0.27 mmol/L;
P
=0.003), waist circumference (−2.44 cm;
P
<0.001), body mass index (−0.53 kg/m
2
;
P
=0.003), and body weight (−1.43 kg;
P
=0.001). Low-density lipoprotein (−0.24 mmol/L), high-density lipoprotein (+0.06 mmol/L), systolic (−3.21 mm Hg) and diastolic (−2.34 mm Hg) blood pressure changed favorably, but nonsignificantly. A significant shift toward nonsmoking occurred (
P
=0.008). Compared with intake, 11 more individuals (25.6% increase) finished CCR in the lowest-mortality risk category of the Duke Treadmill Score (
P
<0.001).

Conclusions—

CCR is feasible and effective for secondary prevention after transient ischemic attack or mild, nondisabling stroke, offering a promising model for vascular protection across chronic disease entities. We know of no similar previous investigation, and are now conducting a randomized trial.
Lipoprotein (a) and Carotid Atherosclerosis in Young Patients With Stroke
Authors: Nasr Nathalie , Ruidavets Jean Bernard , Farghali Ahmed , Guidolin Brigitte , Perret Bertrand , Larrue Vincent
Published: September 2011

Background and Purpose—

Elevated lipoprotein (a) concentration is associated with carotid atherosclerosis in middle-aged and older patients with ischemic stroke. This association has not been explored in young patients with stroke.

Methods—

A retrospective analysis of data from patients aged 16 to 54 years consecutively treated for acute ischemic stroke in a tertiary stroke unit during 4.5 years was performed. We graded carotid atherosclerosis using carotid duplex as: no atherosclerosis (A); plaque without stenosis (B); or stenosis ≥50% (C).

Results—

One hundred ninety-six patients were included (male/female: 119/77; mean age±SD: 44.3±8.6 years): 115 in Group A; 67 in Group B; and 14 in Group C. Multivariate analysis using polynomial logistic regression showed a graded association of lipoprotein (a) plasma concentration with carotid atherosclerosis (
P
<0.001).

Conclusions—

Our results showed a positive association of lipoprotein (a) plasma concentration with carotid atherosclerosis in young adults with ischemic stroke. This association was strong, graded, and independent of traditional risk factors including cholesterol.
Ethnic and Geographic Variation in Stroke Mortality Trends
Authors: Gillum Richard F. , Kwagyan John , Obisesan Thomas O.
Published: September 2011

Background and Purpose—

Magnitude, geographic, and ethnic variation in trends in stroke within the United States require updating for health services and health disparities research.

Methods—

Data for stroke were analyzed from the US mortality files for 1999 to 2007. Age-adjusted death rates were computed for non-Hispanic African Americans and European Americans aged ≥45 years.

Results—

Between 1999 and 2007, the age-adjusted death rate per 100 000 for stroke declined both in African Americans and in European Americans of both genders. Among African American females, European American females, and European American males, rates declined by at least 2% annually in every division. Among African American males, rates declined little in the East and West South Central divisions where disparities in trends by urbanization level were found.

Conclusions—

Between 1999 and 2007, the rate of decline in stroke mortality varied by geographic region and ethnic group.
Atherosclerosis and Dementia
Authors: Suemoto Claudia K. , Nitrini Ricardo , Grinberg Lea T. , Ferretti Renata E.L. , Farfel José M. , Leite Renata E.P. , Menezes Paulo R. , Fregni Felipe , Jacob-Filho Wilson , Pasqualucci Carlos A. ,   Brazilian Aging Brain Study Group
Published: September 2011

Background and Purpose—

Previous ultrasound-based studies have shown an association between carotid artery atherosclerosis and dementia. Our aim was to investigate this association using postmortem examination.

Methods—

Postmortem morphometric measurements of carotid stenosis and intima-media thickness were performed in individuals with dementia (n=112) and control subjects (n=577). Multivariate logistic regression models were applied.

Results—

High-grade left internal carotid stenosis (≥70%) was associated with increased odds for dementia (OR, 2.30; 95% CI, 1.14–4.74;
P
=0.02). Intima-media thickness was not associated with dementia.

Conclusions—

The likelihood of dementia is increased with high-grade left internal carotid artery atherosclerosis after adjusting for demographic and cardiovascular risk factors.
Semi-Supervised Semantic Role Labeling via Structural Alignment
Authors: Fürstenau Hagen , Lapata Mirella
Published: September 2011

Large-scale annotated corpora are a prerequisite to developing high-performance semantic role labeling systems. Unfortunately, such corpora are expensive to produce, limited in size, and may not be representative. Our work aims to reduce the annotation effort involved in creating resources for semantic role labeling via semi-supervised learning. The key idea of our approach is to find novel instances for classifier training based on their similarity to manually labeled seed instances. The underlying assumption is that sentences that are similar in their lexical material and syntactic structure are likely to share a frame semantic analysis. We formalize the detection of similar sentences and the projection of role annotations as a graph alignment problem, which we solve exactly using integer linear programming. Experimental results on semantic role labeling show that the automatic annotations produced by our method improve performance over using hand-labeled instances alone.
In the Pause and Listening to the Little People
Authors: Robbins Rockey , Hong Ji , Jennings Aaron M.
Published: September 2011

This article employs a qualitative case study approach to describe the views and perspectives of a folk healer (White Bear) regarding spiritual healing. White Bear argues for a mobile, in-the-moment form of diagnosis and a “pause,” in which the mind ceases to tyrannize and the healer is no longer absorbed in his or her emotions. He contends that a healer can benefit from aligning with spirits (he calls them Little People) who can help achieve the necessary states of anonymity and nonjudgment required for healing work. Throughout the study, theoretical and empirical findings in the field of psychology are cited in an effort to support or question rather than validate or invalidate White Bear’s mystical wisdom.
Impulsivity, School Context, and School Misconduct
Authors: Vogel Matt , Barton Michael S.
Published: September 2011

Impulsivity holds a central place in the explanations of adolescent delinquency. Recent research suggests that neighborhood characteristics, particularly SES (socioeconomic status), perceived supervision, and collective efficacy, moderate the association between impulsivity and delinquency. However, findings to date have been equivocal, and the relationships between social context, impulsivity, and delinquency remain an open question. This study builds on the current literature by examining the moderating influence of a second context, the high school, on the relationship between impulsivity and delinquency. The authors focus explicitly on self-reported delinquency that has occurred on school grounds, referred to here as school misconduct. Results of hierarchical logistic regression models using the National Longitudinal Study of Adolescent Health suggest that the relationship between impulsivity and two measures of misconduct vary significantly across schools. Moreover, the relationship between impulsivity and weapon carrying is stronger in schools characterized by a limited sense of connectedness among students.
Hitting the Wall
Authors: Willging Cathleen E. , Quintero Gilbert A. , Lilliott Elizabeth A.
Published: September 2011

We examine the experience of boredom and its relationship to troublemaking and drug use among rural youth in southwestern New Mexico. We draw on qualitative research with area youth to describe what they think about drug use and how they situate it within their social circumstances. We then locate youth drug use within globalized processes affecting this setting, including a local economic environment with limited educational and employment opportunities for youth. Drug use emerges as a common social practice that enables youth to ameliorate boredom, yet only some youth become known as troublemakers. Study findings offer insight into how dominant social institutions—schools and juvenile justice authorities—shape the construction of trouble from the perspectives of youth. We contend that boredom and troublemaking among rural youth are not simply age-appropriate forms of self-expression but instead represent manifestations of social position, political economic realities, and assessments of possible futures.
Revision Stapes Surgery
Authors: Özüer Mehmet Ziya , Olgun Levent , Gültekin Gürol
Published: September 2011

Objectives

Surgery for otosclerosis has a highly satisfactory hearing outcome, for both the patient and the otologic surgeon. However, subsequent conductive hearing loss, dizziness/vertigo, or sound distortion could necessitate revision surgery. The aim of the present study is to evaluate the surgical findings and hearing outcomes of 84 revision stapes surgeries.

Study Design

Case series with chart review.

Setting

Tertiary referral center.

Subjects and Methods

At our institution, 84 revision cases were performed between 1998 and 2009. Conductive hearing loss was the revision indication in 69 cases, severe dizziness/vertigo in 8 patients, sound distortion in 5 cases, and progressive hearing loss with dizziness in 2 patients. Operative findings were noted in every case and evaluated separately.

Results

Surgical intervention revealed problems related to prosthesis in 51 cases, fibrotic bands in 26 cases, adhesions in 13 cases, incus necrosis in 15 cases, perilymphatic fistula in 3 cases, intact footplate in 5 cases, incus‐malleus fixation in 2 cases, and reobliteration in 2 cases. Mean follow‐up period was 19 months (range, 12‐53 months). Successful hearing results (air‐bone gap <10 dB) were reached in 58% of the cases, and satisfactory hearing results (air‐bone gap <20 dB) were reached in 71% of the cases.

Conclusions

The ideal patient for revision stapes surgery is one who benefits from the initial surgery but complained of conductive hearing loss. In the present study, improvement in pure‐tone average was 13.2 dB, and the mean air‐bone gap was 9.6 dB.