bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of Endothelial-Mesenchymal Transition by a Smad3 Inhibitor Delays the Early Development of Streptozotocin-Induced Diabetic Nephropathy
Authors: Li Jinhua , Qu Xinli , Yao Jun , Caruana Georgina , Ricardo Sharon D. , Yamamoto Yasuhiko , Yamamoto Hiroshi , Bertram John F. 
Published: August 2010

OBJECTIVE
A multicenter, controlled trial showed that early blockade of the renin-angiotensin system in patients with type 1 diabetes and normoalbuminuria did not retard the progression of nephropathy, suggesting that other mechanism(s) are involved in the pathogenesis of early diabetic nephropathy (diabetic nephropathy). We have previously demonstrated that endothelial-mesenchymal-transition (EndoMT) contributes to the early development of renal interstitial fibrosis independently of microalbuminuria in mice with streptozotocin (STZ)-induced diabetes. In the present study, we hypothesized that blocking EndoMT reduces the early development of diabetic nephropathy.

RESEARCH DESIGN AND METHODS
EndoMT was induced in a mouse pancreatic microvascular endothelial cell line (MMEC) in the presence of advanced glycation end products (AGEs) and in the endothelial lineage–traceble mouse line Tie2-Cre;Loxp-EGFP by administration of AGEs, with nonglycated mouse albumin serving as a control. Phosphorylated Smad3 was detected by immunoprecipitation/Western blotting and confocal microscopy. Blocking studies using receptor for AGE siRNA and a specific inhibitor of Smad3 (SIS3) were performed in MMECs and in STZ-induced diabetic nephropathy in Tie2-Cre;Loxp-EGFP mice.

RESULTS
Confocal microscopy and real-time PCR demonstrated that AGEs induced EndoMT in MMECs and in Tie2-Cre;Loxp-EGFP mice. Immunoprecipitation/Western blotting showed that Smad3 was activated by AGEs but was inhibited by SIS3 in MMECs and in STZ-induced diabetic nephropathy. Confocal microscopy and real-time PCR further demonstrated that SIS3 abrogated EndoMT, reduced renal fibrosis, and retarded progression of nephropathy.

CONCLUSIONS
EndoMT is a novel pathway leading to early development of diabetic nephropathy. Blockade of EndoMT by SIS3 may provide a new strategy to retard the progression of diabetic nephropathy and other diabetes complications.
Downregulation of AMPK Accompanies Leucine- and Glucose-Induced Increases in Protein Synthesis and Insulin Resistance in Rat Skeletal Muscle
Authors: Saha Asish K. , Xu X. Julia , Lawson Ebony , Deoliveira Rosangela , Brandon Amanda E. , Kraegen Edward W. , Ruderman Neil B. 
Published: August 2010

OBJECTIVE
Branched-chain amino acids, such as leucine and glucose, stimulate protein synthesis and increase the phosphorylation and activity of the mammalian target of rapamycin (mTOR) and its downstream target p70S6 kinase (p70S6K). We examined in skeletal muscle whether the effects of leucine and glucose on these parameters and on insulin resistance are mediated by the fuel-sensing enzyme AMP-activated protein kinase (AMPK).

RESEARCH DESIGN AND METHODS
Rat extensor digitorum longus (EDL) muscle was incubated with different concentrations of leucine and glucose with or without AMPK activators. Muscle obtained from glucose-infused rats was also used as a model.

RESULTS
In the EDL, incubation with 100 or 200 μmol/l leucine versus no added leucine suppressed the activity of the α2 isoform of AMPK by 50 and 70%, respectively, and caused concentration-dependent increases in protein synthesis and mTOR and p70S6K phosphorylation. Very similar changes were observed in EDL incubated with 5.5 or 25 mmol/l versus no added glucose and in muscle of rats infused with glucose in vivo. Incubation of the EDL with the higher concentrations of both leucine and glucose also caused insulin resistance, reflected by a decrease in insulin-stimulated Akt phosphorylation. Coincubation with the AMPK activators AICAR and α-lipoic acid substantially prevented all of those changes and increased the phosphorylation of specific sites of mTOR inhibitors raptor and tuberous sclerosis complex 2 (TSC2). In contrast, decreases in AMPK activity induced by leucine and glucose were not associated with a decrease in raptor or TSC2 phosphorylation.

CONCLUSIONS
The results indicate that both leucine and glucose modulate protein synthesis and mTOR/p70S6 and insulin signaling in skeletal muscle by a common mechanism. They also suggest that the effects of both molecules are associated with a decrease in AMPK activity and that AMPK activation prevents them.
Central Nervous System Delivery of the Antipsychotic Olanzapine Induces Hepatic Insulin Resistance
Authors: Martins Paulo J.F. , Haas Michael , Obici Silvana 
Published: August 2010

OBJECTIVEOlanzapine (OLZ) is an atypical antipsychotic whose clinical efficacy is hampered by side effects including weight gain and diabetes. Recent evidence shows that OLZ alters insulin sensitivity independent of changes in body weight and composition. The present study addresses whether OLZ-induced insulin resistance is driven by its central actions.RESEARCH DESIGN AND METHODSSprague-Dawley rats received an intravenous (OLZ-IV group) or intracerebroventricular (OLZ-ICV group) infusion of OLZ or vehicle. Glucose kinetics were assessed before (basal period) and during euglycemic-hyperinsulinemic clamp studies.RESULTSOLZ-IV caused a transient increase in glycemia and a higher rate of glucose appearance (Ra) in the basal period. During the hyperinsulinemic clamp, the glucose infusion rate (GIR) required to maintain euglycemia and the rate of glucose utilization (Rd) were decreased in OLZ-IV, whereas endogenous glucose production (EGP) rate was increased compared with vehicle-IV. Consistent with an elevation in EGP, the OLZ-IV group had higher hepatic mRNA levels for the enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Phosphorylation of hypothalamic AMP-activated protein kinase (AMPK) was increased in OLZ-IV rats compared with controls. Similarly, an intracerebroventricular infusion of OLZ resulted in a transient increase in glycemia as well as a higher Ra in the basal period. During the hyperinsulinemic period, OLZ-ICV caused a decreased GIR, an increased EGP, but no change in Rd. Furthermore, OLZ-ICV rats had increased hepatic gluconeogenic enzymes and elevated hypothalamic neuropeptide-Y and agouti-related protein mRNA levels.CONCLUSIONSAcute central nervous system exposure to OLZ induces hypothalamic AMPK and hepatic insulin resistance, pointing to a hypothalamic site of action for the metabolic dysregulation of atypical antipsychotics.
Common Variants in 40 Genes Assessed for Diabetes Incidence and Response to Metformin and Lifestyle Intervention in the Diabetes Prevention Program
Authors: Jablonski Kathleen A. , McAteer Jarred B. , de Bakker Paul I.W. , Franks Paul W. , Pollin Toni I. , Hanson Robert L. , Saxena Richa , Fowler Sarah , Shuldiner Alan R. , Knowler William C. , Altshuler David , Florez Jose C. ,   for the Diabetes Prevention Program Research Group
Published: August 2010

OBJECTIVEGenome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions.RESEARCH DESIGN AND METHODSWe selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates.RESULTSWe replicated the association of variants in the metformin transporter gene SLC47A1 with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene STK11, the AMPK subunit genes PRKAA1 and PRKAA2, and a missense SNP in SLC22A1, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene PRKAG2 (hazard ratio 1.24, 95% CI 1.09–1.40, P = 7 × 10−4). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest P values were consistent with experiment-wide 33% false discovery rates.CONCLUSIONSWe have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples.
Lack of Association of C-C Chemokine Receptor 5 Δ32 Deletion Status with Rheumatoid Arthritis, Systemic Lupus Erythematosus, Lupus Nephritis, and Disease Severity
Authors: MARTENS HENK A. , GROSS SACHA , van der STEEGE GERRIT , BROUWER ELISABETH , BERDEN JO H.M. , de SEVAUX RUUD , DERKSEN RONALD H.W.M. , VOSKUYL ALEXANDRE E. , BERGER STEFAN P. , NAVIS GERJAN J. , KALLENBERG CEES G.M. , BIJL MARC 
Published: August 2010

Objective.C-C chemokine receptor 5 (CCR5) plays an important role in inflammation. A 32 base-pair (Δ32) deletion in the CCR5 gene leads to a nonfunctional receptor. This deletion has been reported to have a protective effect on the development and progression of several autoimmune diseases. We investigated whether the Δ32 deletion is associated with disease susceptibility in a population of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and lupus nephritis (LN); and whether it is associated with disease severity.MethodsDNA samples from 405 RA patients, 97 SLE patients, 113 LN patients, and 431 healthy controls were genotyped for the CCR5 Δ32 deletion. Differences in genotype frequencies were tested between patients and controls. Association of genotypes with disease severity was analyzed.ResultsGenotype frequencies of each group were in Hardy-Weinberg equilibrium. The genotype frequencies of patients did not differ significantly from controls (CCR5/Δ32, Δ32/Δ32: RA 18.3% and 1.2%, respectively; SLE 17.5% and 2.1%; LN 13.3% and 1.8%; controls 20.0% and 2.8%). However, there was a trend for lower Δ32 deletion allele frequency in LN patients compared to controls (p = 0.08). There was no significant association between the CCR5 status and disease severity in RA, SLE, or LN.Conclusion.Although an association with LN cannot be excluded, the CCR5 Δ32 deletion does not seem to be a disease susceptibility genotype for RA, SLE, or LN. No significant effect of the Δ32 deletion on disease severity was demonstrated.
Effect of Psychological Distress on Continuation of Anti-Tumor Necrosis Factor Therapy in Patients with Rheumatoid Arthritis
Authors: MATTEY DEREK L. , DAWES PETER T. , HASSELL ANDREW B. , BROWNFIELD ANN , PACKHAM JONATHAN C. 
Published: August 2010

Objective.To investigate the relationship of psychological distress and associated factors with continuation of tumor necrosis factor (TNF) antagonist therapy in patients with rheumatoid arthritis (RA).Methods.Patients about to start therapy with TNF antagonists (n = 166) were assessed for psychological distress using the Hospital Anxiety and Depression Scale (HADS). A core set of demographic and clinical variables, including comorbidities from medical records and cigarette smoking history by questionnaire, were recorded at baseline and regular intervals thereafter. Cox proportional hazards regression analysis was used to assess the likelihood of patients discontinuing therapy over a 36-month followup period.Results.The number of years smoked was associated with anxiety (HADS-A; p for trend = 0.008) and general psychological distress (HADS-Total; p for trend = 0.03). In univariate analyses, earlier discontinuation was associated with these variables at baseline: anxiety (HADS-A), depression (HADS-D), abnormal mood (HADS-Total), smoking history (> 30 pack-yrs), years smoked (> 30 yrs), current smoking, high Disease Activity Score 28-joint count (DAS28), poor patient global assessment, and evidence of cardio/cerebrovascular disease (CVD). In multivariate analyses, the strongest predictors of discontinuation were HADS-Total, smoking history (> 30 pack-yrs), DAS28, and evidence of CVD at baseline.Conclusion.Discontinuation of therapy with TNF antagonists is independently associated with psychological distress, heavy smoking, and CVD at baseline.
Impaired Health-related Quality of Life in Patients Treated for Wegener’s Granulomatosis
Authors: FAURSCHOU MIKKEL , SIGAARD LENE , BJORNER JAKOB BUE , BASLUND BO 
Published: August 2010

Objective.To investigate whether patients with Wegener’s granulomatosis (WG) experience reduced health-related quality of life (HRQOL) after accomplishment of remission, and to study the influence of WG-associated organ damage on HRQOL.Methods.Sixty-eight patients with inactive WG and 680 randomly selected, age- and sex-matched controls of the Danish background population completed the Medical Outcomes Study Short-Form 36 (SF-36) survey for evaluation of HRQOL. Irreversible organ damage attributable to WG and/or its treatment was assessed using the Vasculitis Damage Index (VDI).Results.The median disease duration was 7.5 (range 1–26) years in the WG group, and the median total VDI score was 2.0 (range 0–7). Compared to controls, WG patients reported impaired HRQOL reflected by significantly lower SF-36 physical component summary scores (PCS) and mental component summary scores (MCS) (p < 0.001) and by significantly lower scores in 7 out of 8 SF-36 subscales (p ≤ 0.001). In the WG group, no statistically significant correlations were found between the different SF-36 scores and the total VDI score, number of organ systems affected by damage, disease duration, or number of WG relapses. Patients with organ failure or other major forms of damage did not report significantly lower HRQOL than less severely affected patients.Conclusion.WG patients experience significantly reduced HRQOL even in phases with no apparent vasculitis disease activity. Our data indicate that the level of HRQOL does not correlate well with the extent of vasculitis-associated organ damage in WG.
Levels of Transforming Growth Factor-β Are Low in Systemic Lupus Erythematosus Patients with Active Disease
Authors: BECKER-MEROK ANDREA , EILERTSEN GRO ØSTLI , NOSSENT JOHANNES C. 
Published: August 2010

Objective.Cytokines are central regulators of the immune response but the workings of this complex network in systemic lupus erythematosus (SLE) are not fully understood. We investigated a range of inflammatory and immune-modulating cytokines to determine their value as biomarkers for disease subsets in SLE.Methods.This was a cross-sectional study in 102 patients with SLE (87% women, disease duration 10.6 yrs). Circulating concentrations of interleukin 1β (IL-1β), IL-4, IL-6, IL-10, IL-12, IL-17, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 (MIP-1α), MIP-1β, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and total transforming growth factor-β1 (TGF-β1) were related to disease activity (SLE Disease Activity Index; SLEDAI), lymphocyte subsets, autoantibody levels, accrued damage (Systemic Lupus International Collaborating Clinics/ACR Damage Index; SDI), and concomitant treatment.Results.Patients with SLE had lower levels of TGF-β1 (p = 0.01) and IL-1β (p = 0.0004) compared to controls. TGF-β1 levels were lower in patients with SLEDAI scores 1–10 and SDI > 3; and were correlated with CD4+, CD8+, and natural killer cell counts; and were independent of steroid or cytotoxic drug use. Treatment with cardiovascular drugs was associated with lower IL-12 levels. No consistent disease associations existed for the other cytokines investigated.Conclusion.Lower TGF-β1 was the most consistent cytokine abnormality in patients with SLE. The associations with disease activity, lymphocyte subsets, and damage suggest that TGF-β1 may be a therapeutic target of interest in SLE.
Low Plasma Adiponectin as a Potential Biomarker for Osteonecrosis of the Femoral Head
Authors: SHUAI BO , SHEN LIN , YANG YAN P. , XIE JING , SHOU ZHE X. , WEI BING 
Published: August 2010

Objective.To examine whether plasma adiponectin level is correlated with osteonecrosis of the femoral head (ONFH).Methods.Blood adiponectin level in patients with nontraumatic ONFH (n = 120) was compared with a group of healthy subjects (n = 120). Patients with hip osteoarthritis (OA; n = 30) and traumatic ONFH (n = 45) were included as controls. Potential compounding factors, such as plasma low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1 (apo A1), apolipoprotein B (apo B), total cholesterol (TC), triglycerides (TG), and C-reactive protein (CRP) were also examined.Results.Patients with nontraumatic ONFH had significantly lower plasma levels of adiponectin than the healthy controls (7.14 ± 3.53 vs 10.93 ± 3.41μg/ml, respectively; p < 0.001). Adiponectin level was positively correlated with HDL (r = 0.282, p < 0.001) and age (r = 0.145, p = 0.01), yet negatively correlated with body mass index (r = −0.70, p < 0.001), TG (r = −0.55, p<0.001), LDL/HDL ratio (r = −0.173, p = 0.002), and CRP (r = −0.634, p < 0.001). No correlation was seen with LDL (r = −0.017, p = 0.762). A multiple logistic regression analysis revealed that adiponectin level is an independent predictor of the presence of nontraumatic ONFH (p < 0.001, OR 0.676, 95% CI 0.546 to 0.845).Conclusion.Low adiponectin level is significantly associated with the presence of nontraumatic ONFH. This biomarker may be useful in assessing the potential presence of nontraumatic ONFH.
L'acquisition de la morphologie verbale à travers les langues
Authors: Bassano Dominique , Maillochon Isabelle , Klampfer Sabine , Dressler Wolfgang U. 
Published: August 2010

RÉSUMÉ Bien que l’acquisition de la morphologie verbale à travers les langues ait dernièrement largement suscité l’intérêt, il n’existe guère de travaux qui en aient réalisé une comparaison directe dans des langues contrastées, selon une approche et une méthode commune. Tel est l’objet de la présente recherche, qui, dans un cadre théorique fonctionnaliste, mène une étude contrastive du développement des formes verbales en français et en allemand autrichien depuis le début de la production jusqu’à 3 ans. L’objectif est de définir les séquences de développement des systèmes verbaux dans les deux langues, et de dégager, à partir des similarités et différences observées, les divers facteurs déterminant l’acquisition de la morphologie verbale. Cette recherche fait ici l’objet de deux articles. Le premier – celui-ci même – est consacré à l’exposé des fondements théoriques de l’étude. Nous y présentons l’approche fonctionnaliste de l’acquisition de la grammaire et donnons une description des systèmes verbaux des deux langues. À la lumière de ce double cadre de réflexion, nous recensons les facteurs susceptibles de déterminer l’acquisition de la morphologie verbale : contraintes cognitives générales, telle que la complexité cognitivo-sémantique ; contraintes linguistiques particulières liées aux propriétés des systèmes, telles que la complexité morphologique, la complexité syntaxique, l’homophonie – un facteur peu étudié auquel nous accordons une attention toute particulière. C’est dans le deuxième article, consacré à l’exposé de l’investigation empirique, qu’on trouvera la mise à l’épreuve des hypothèses de développement issues de cet examen.
Caractéristiques phonologiques des noms en fonction de l'âge d'acquisition
Authors: Gayraud Frédérique , Kern Sophie 
Published: August 2010

RÉSUMÉ Ce travail analyse la composition syllabique, l’inventaire phonologique et la longueur des noms acquis précocement par des enfants français d’âge préscolaire et des noms acquis plus tardivement, à partir de l’étude de trois bases de données : l’adaptation française du compte rendu parental de MacArthur-Bates, une base d’âge d’acquisition (AoA) et un corpus de français parlé (Corpaix). Les caractéristiques des noms acquis seront comparées d’une part aux tendances observées dans le babillage, d’autre part à celles du langage adulte dans le but de montrer comment progressivement les mots ne sont plus façonnés par les contraintes articulatoires du babillage mais par les contraintes phonologiques de la langue cible. Les noms acquis à 24 mois présentent les mêmes caractéristiques que le babillage parce qu’ils sont façonnés par les mêmes contraintes articulatoires. Typiquement, ce sont des noms courts, composés de syllabes ouvertes à initiale bilabiale plosive. Par la suite, on observe un ajustement progressif aux spécificités de la langue cible avec une diversification des types syllabiques, des sons notamment à l’initiale et une augmentation de la taille des noms. De plus, quand contraintes motrices développementales convergent vers les caractéristiques phonologiques présentes dans la langue en voie d’acquisition, les noms sont acquis précocement ; dans le cas contraire, on assiste à une apparition plus tardive.
La coopération dyadique entre enfants de 5-6 ans : effets de la complexité cognitive et de l'activité motrice sollicitées par les situations de résolution de problème
Authors: Herbé Dominique , Tremblay Hélène , Mallet Pascal 
Published: August 2010

RÉSUMÉ Ce travail avait pour but de tester les effets de la complexité cognitive des tâches de résolution de problème et de l’activité motrice qu’elles sollicitent sur la coopération des dyades d’âge préscolaire. Nous avons défini la coopération par les actions conjointes, les interactions en dehors des tâches et les échanges émotionnels entre enfants pendant leur tâche de résolution. Trois tâches ont été conçues qui différaient par leurs niveaux de complexité cognitive et de stimulation motrice. Quinze dyades de 5-6 ans ont été filmées pendant trois minutes dans chaque situation. Chaque comportement individuel a été codé par échantillonnage temporel avec un pas de 1 seconde. Après comparaison des deux situations qui variaient exclusivement par leur niveau de stimulation motrice, les résultats attestent que les dyades ont interagi en dehors des tâches, agi conjointement et échangé plus longtemps leurs émotions dans la situation qui stimulait le plus l’activité motrice des dyades. En revanche, nous ne constatons pas de différences en comparant les situations qui variaient exclusivement par leur niveau de complexité cognitive. Ces résultats soulignent l’effet déterminant de la stimulation motrice des situations sur la coopération des dyades alors même que la complexité cognitive des tâches n’aurait pas d’effet sur les variables considérées dans cette classe d’âge. Ces résultats sont discutés en référence à Wallon (1945) qui articule l’expression du mouvement de l’enfant et le développement de ses instruments de pensée.