bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic factors of 10-year radiographic outcome in early rheumatoid arthritis: a prospective study
Authors: Courvoisier Natacha , Dougados Maxime , Cantagrel Alain , Goupille Philippe , Meyer Olivier , Sibilia Jean , Daures Jean Pierre , Combe Bernard 
Published: September 2008

Abstract
Introduction
The objectives of this study were to determine the predictive factors of long-term radiographic outcome of rheumatoid arthritis (RA) and to describe the relationship between joint damage and disability over the course of the disease.

Methods
A cohort of 191 patients with early RA referred from primary care physicians were prospectively followed for 10 years. To determine the predictive factors of radiographic outcome, univariate analysis of the relationship between baseline values and outcome measures was undertaken using a chi-squared or Fisher's exact test. Stepwise multiple logistic regression was also performed to select independent prognostic factors.

Results
From data available for 112 patients, univariate analysis revealed a total Sharp score at 10 years that was significantly correlated with erythrocyte sedimentation rate (ESR), presence and level of IgA rheumatoid factor, presence of an anti-citrullinated protein antibody (ACPA), serum level of matrix metalloproteinase-3 and radiographic score at baseline. Logistic regression identified the baseline erosion score to be the most important baseline parameter as an independent prognostic factor of total radiographic score at 10 years (odds ratio = 5.64; 95% confidence interval = 1.78 to 17.86). After excluding radiographic scores from the entry parameters, the presence of ACPA and ESR were also predictive of the final total Sharp score. The Health Assessment Questionnaire (HAQ) score was strongly correlated with disease activity parameters, such as disease activity score and pain, at baseline and at three, five and 10 years. No correlation was found between total radiographic Sharp score and HAQ score throughout the study.

Conclusions
In this prospective study, baseline radiographic score, ESR and ACPA were the best predictive factors of 10-year radiographic outcome in early RA. HAQ disability was associated with disease activity throughout the 10-year follow-up but not with joint damage. This discrepancy with previous reports may be due in part to the early start of therapy with disease-modifying anti-rheumatic drugs.
The Homeodomain-Interacting Protein Kinase 2 Regulates Insulin Promoter Factor-1/Pancreatic Duodenal Homeobox-1 Transcriptional Activity
Authors: Boucher Marie-Josée , Simoneau Mélanie , Edlund Helena 
Published: September 2008

The homeodomain transcription factor insulin promoter factor (IPF)-1/pancreatic duodenal homeobox (PDX)-1 plays a crucial role in both pancreas development and maintenance of β-cell function. Targeted disruption of the Ipf1/Pdx1 gene in β-cells of mice leads to overt diabetes and reduced Ipf1/Pdx1 gene expression results in decreased insulin expression and secretion. In humans, mutations in the IPF1 gene have been linked to diabetes. Hence, the identification of molecular mechanisms regulating the transcriptional activity of this key transcription factor is of great interest. Herein we analyzed homeodomain-interacting protein kinase (Hipk) 2 expression in the embryonic and adult pancreas by in situ hybridization and RT-PCR. Moreover, we functionally characterized the role of HIPK2 in regulating IPF1/PDX1 transcriptional activity by performing transient transfection experiments and RNA interference. We show that Hipk2 is expressed in the developing pancreatic epithelium from embryonic d 12–15 but that the expression becomes preferentially confined to pancreatic endocrine cells at later developmental stages. Moreover, we show that HIPK2 positively influences IPF1/PDX1 transcriptional activity and that the kinase activity of HIPK2 is required for this effect. We also demonstrate that HIPK2 directly phosphorylates the C-terminal portion of IPF1/PDX1. Taken together, our data provide evidence for a new mechanism by which IPF1/PDX1 transcriptional activity, and thus possibly pancreas development and/or β-cell function, is regulated.Homeodomain-interacting protein kinase 2 phosphorylates the C-terminal portion of IPF1/PDX1 as well as positively regulating IPF1/PDX1 transcriptional activity.
Antiandrogen Exposure in Utero Disrupts Expression of Desert Hedgehog and Insulin-Like Factor 3 in the Developing Fetal Rat Testis
Authors: Brokken Leon J. S. , Adamsson Annika , Paranko Jorma , Toppari Jorma 
Published: September 2008

Testicular development is an androgen-dependent process, and fetal exposure to antiandrogens disrupts male sexual differentiation. A variety of testicular disorders may result from impaired development of fetal Leydig and Sertoli cells. We hypothesized that antiandrogenic exposure during fetal development interferes with desert hedgehog (Dhh) signaling in the testis and results in impaired Leydig cell differentiation. Fetal rats were exposed in utero to the antiandrogen flutamide from 10.5 d post conception (dpc) until they were killed or delivery. Fetal testes were isolated at different time points during gestation and gene expression levels of Dhh, patched-1 (Ptc1), steroidogenic factor 1 (Sf1), cytochrome P450 side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (Hsd3b1), and insulin-like factor 3 (Insl3) were analyzed. To study direct effects of hedgehog signaling on testicular development, testes from 14.5 dpc fetuses were cultured for 3 d in the presence of cyclopamine, sonic hedgehog, or vehicle, and gene expression levels and testosterone secretion were analyzed. Organ cultures were also analyzed histologically, and cleaved-caspase 3 immunohistochemistry was performed to assess apoptosis. In utero exposure to flutamide decreased expression levels of Dhh, Ptc1, Sf1, P450scc, Hsd3b1, and Insl3, particularly from 17.5 dpc onward. Inhibition of hedgehog signaling in testis cultures resulted in similar effects on gene expression levels. Apoptosis in Wolffian ducts was increased by cyclopamine compared with sonic hedgehog- or vehicle-treated cultures. We conclude that exposure to the antiandrogen flutamide interferes with Dhh signaling resulting in an impaired differentiation of the fetal Leydig cells and subsequently leading to abnormal testicular development and sexual differentiation.Antiandrogenic exposure of rat fetuses in utero affects genes that are involved in sexual differentiation of the testis and suppresses sexual maturation.
Superoxide and Respiratory Coupling in Mitochondria of Insulin-Deficient Diabetic Rats
Authors: Herlein Judith A. , Fink Brian D. , O'Malley Yunxia , Sivitz William I. 
Published: September 2008

Mitochondrial reactive oxygen species have been implicated in both diabetic complications and the progression of the underlying diabetic state. However, it is not clear whether mitochondria of diabetic origin are intrinsically altered to generate excess reactive oxygen species independent of the surrounding diabetic milieu. Mitochondria were isolated from gastrocnemius, heart, and liver of 2-wk and 2-month streptozotocin diabetic rats and controls. We rigidly quantified mitochondrial superoxide, respiration and ATP production, respiratory coupling, the expression of several proteins with antioxidant properties, and the redox state of glutathione. Both fluorescent assessment and electron paramagnetic spectroscopy revealed that superoxide production was unchanged or reduced in the 2-month diabetic mitochondria compared with controls. Kinetic analysis of the proton leak showed that diabetic heart and muscle mitochondria were actually more coupled compared with control despite an approximate 2- to 4-fold increase in uncoupling protein-3 content. Adenine nucleotide translocator type 1 expression was reduced by approximately 50% in diabetic muscle mitochondria. Catalase was significantly up-regulated in muscle and heart tissue and in heart mitochondria, whereas glutathione peroxidase expression was increased in liver mitochondria of diabetic rats. We conclude that gastrocnemius, heart, and liver mitochondria of streptozotocin diabetic rats are not irrevocably altered toward excess superoxide production either by complex I or complex III. Moreover, gastrocnemius and heart mitochondria demonstrate increased, not decreased, respiratory coupling. Mitochondria of insulin-deficient diabetic rats do show signs of adaptation to antecedent oxidative stress manifested as tissue-specific enzyme and uncoupling protein expression but remain remarkably robust with respect to superoxide production.Mitochondria of streptozotocin-diabetic rats do not generate excess superoxide, manifest decreased or unchanged respiratory coupling, and show adaptation to antecedent in vivo oxidative stress.
Aldose Reductase Regulates High Glucose-Induced Ectodomain Shedding of Tumor Necrosis Factor (TNF)-α via Protein Kinase C-δ and TNF-α Converting Enzyme in Vascular Smooth Muscle Cells
Authors: Reddy Aramati B. M. , Ramana Kota V. , Srivastava Sanjay , Bhatnagar Aruni , Srivastava Satish K. 
Published: September 2008

Chronic low-grade inflammation has emerged as a key contributor to the cardiovascular complications of diabetes, however, the mechanisms by which diabetes increases inflammation remain poorly understood. Here, we report that exposure to high glucose (HG) stimulates ectodomain shedding of TNF-α from rat aortic smooth muscle cells in culture. Our results show that exposure to HG decreases membrane-associated TNF-α. This decrease in unprocessed TNF-α was prevented by the aldose reductase (AR) inhibitor sorbinil and AR small interference RNA. Treatment with HG, but not equimolar mannitol or 3-O-methyl glucose, resulted in phosphorylation and activation of TNF-α converting enzyme (TACE) (ADAM17), which were attenuated by sorbinil or AR-specific small interference RNA. HG-induced TACE phosphorylation and TNF-α processing were also prevented by TNF-α protease inhibitor-1, an inhibitor of TACE. Inhibition of protein kinase C (PKC)-δ by rottlerin prevented HG-induced TACE activation and the accumulation of unprocessed TNF-α. Treatment with sorbinil decreased elevated levels of circulating TNF-α in streptozotocin-treated diabetic rats. Sorbinil treatment also decreased the expression of TNF-α, matrix metalloproteinase-2, matrix metalloproteinase-9, and increased tissue inhibitor of metalloproteinase-3 in vascular smooth muscle cells treated with HG and in balloon-injured carotid arteries of diabetic rats. These results indicate that HG-induced TNF-α shedding could be attributed to TACE activation, which is regulated, in part, by PKC-δ and AR. Therefore, inhibition of TACE by TNF-α protease inhibitor-1, or pharmacological inhibition of PKC-δ or AR may represent useful strategies for treating vascular inflammation associated with diabetes.In adrenocortical cells high versus low levels of steroidogenic factor 1 (SF-1) differentially regulates the expression of aldosterone synthase and aldosterone production.
Lysophosphatidic Acid Signaling during Embryo Development in Sheep: Involvement in Prostaglandin Synthesis
Authors: Liszewska Ewa , Reinaud Pierrette , Billon-Denis Emmanuelle , Dubois Olivier , Robin Philippe , Charpigny Gilles 
Published: September 2008

We investigated the lysophosphatidic acid (LPA) pathway during early pregnancy in sheep. LPA was detected in the uteri of early-stage pregnant ewes. Using quantitative RT-PCR, the expression of autotaxin, the LPA-generating enzyme, was found in the endometrium and conceptus. In the latter autotaxin, transcript levels were low on d 12–14 and increased on d 15–16, in parallel with the level of LPA. Autotaxin was localized in the luminal epithelium and superficial glands of the endometrium and in trophectoderm cells of the conceptus. The expression of G protein-coupled receptors for LPA was also examined in the ovine conceptus. LPA receptor LPAR1 and LPAR3 transcripts were expressed during early pregnancy and displayed a peak on d 14, whereas the highest level of protein for both receptors was observed at d 17. LPAR1 was localized in cellular membranes and nuclear compartments of the trophectoderm cells, whereas LPAR3 was revealed only in membranes. LPA activated phosphorylation of the MAPK ERK1/2 in ovine trophectoderm-derived cells. Moreover, the bioactive lipid increased the proliferation of trophectoderm cells in culture, as shown by thymidine and bromodeoxyuridine incorporation. Furthermore, LPA induced changes to the organization of β-actin and α-tubulin, suggesting a role for it in rearrangement of trophectoderm cells cytoskeleton. Because a link had previously been established between prostaglandin and LPA pathways, we analyzed the effect of LPA on prostaglandin synthesis. LPA induced an increase in the release of prostaglandin F2α and prostaglandin E2, with no significant modifications to cytosolic phospholipase A2α and prostaglandin synthase-2 expression. Taken together, our results suggest a new role for LPA-mediated signaling in the ovine conceptus at the time of implantation.Lysophosphatidic acid (LPA) receptor 1 (R1) and LPAR3 mediate signaling of lysophosphatidic acid produced by autotaxin and induce prostaglandin biosynthesis and cytoskeleton changes in ovine trophectoderm cells at implantation time.
Identification of Novel Biphenyl Carboxylic Acid Derivatives as Novel Antiresorptive Agents that Do Not Impair Parathyroid Hormone-Induced Bone Formation
Authors: Idris Aymen I. , Greig Iain R. , Bassonga-Landao Euphemie , Ralston Stuart H. , van 't Hof Rob J. 
Published: September 2008

Bisphosphonates are widely used in the treatment of osteoporosis, but they inhibit bone formation and blunt the anabolic effect of PTH. Here we describe a novel series of compounds that have potent antiresorptive effects in vitro and in vivo that do not adversely affect osteoblast function. The effects of the compounds on osteoclast formation and survival were studied on mouse osteoclasts generated from bone marrow macrophages and on osteoblast function using primary mouse calvarial osteoblast cultures and bone nodule cultures. Studies were performed in vivo using sham-operated or ovariectomized mice. The most potent compound tested was ABD350, a halogen-substituted derivative of the parent compound ABD56 in which the labile ester bond was replaced by a reduced ketone link, with IC50 osteoclast formation at a concentration of 1.3 μm. All compounds inhibited receptor activator of nuclear factor-κB ligand-induced inhibitor of nuclear factor κB phosphorylation and caused osteoclast apoptosis but no inhibitory effects on osteoblast function were observed at concentrations of up to 20μm. ABD350 prevented ovariectomy-induced bone loss when given ip (5 mg/kg · d), whereas ABD56 was only partially effective at this dose. In contrast to the bisphosphonate alendronate, ABD350 had no inhibitory effect on PTH-induced bone formation in ovariectomized mice. In conclusion, the biphenyl carboxylic acid derivatives like ABD350 represent a new class of antiresorptive drugs that inhibit osteoclast activity but have no significant inhibitory effects on osteoblast activity in vitro or PTH-induced bone formation in vivo.
The biphenyl-carboxylate ABD350 inhibits osteoclast formation in vitro and in vivo and, unlike the bisphosphonate Alendronate, does not inhibit the bone anabolic effects of PTH.
Hematological changes associated with egg production: direct evidence for changes in erythropoiesis but a lack of resource dependence?
Authors: Wagner Emily C. , Stables Christine A. , Williams Tony D. 
Published: September 2008

SUMMARYReductions in hematological parameters among laying birds are well reported, but the cause of this anemia is not known. We tested specific predictions generated from several, non-mutually exclusive hypotheses for mechanisms underlying reproductive anemia associated with egg production(hemodilution, transient suppression of erythropoiesis, resource dependence)in relation to (1) the time-course of development and recovery from anemia,(2) changes in specific hematological traits, and (3) the effect of diet quality, in female zebra finches (Taeniopygia guttata). Female zebra finches showed marked decreases in hematocrit (∼6%), red blood cell counts(∼8%), and plasma hemoglobin concentration (∼9%) during egg production, even on a high-quality ad libitum diet, consistent with an effect of hemodilution associated with yolk precursor production. However,our results provide strong support for the hypothesis that erythropoiesis is transiently suppressed during egg-laying and that the recovery from anemia is relatively long-lasting, extending through incubation and hatching periods. Decreased hematocrit, red blood cell counts, and hemoglobin concentration did not recover at clutch completion, but showed evidence of recovery to baseline pre-breeding levels at hatching. More importantly, there was significant time-dependent variation in the proportion of reticulocytes, which increased at clutch completion but peaked at hatching 10–12 days after clutch completion, and in mean red blood cell volume, which showed a significant increase at clutch completion; consistent with enhanced production and release of larger immature cells into the circulation following suppression of erythropoiesis. Finally, we found no evidence for resource dependence of anemia associated with egg production in relation to diet quality, i.e. exogenous lipid and protein resources available to the laying female. This study demonstrates that transient suppression of erythropoiesis and,subsequently, increased reticulocytosis, are key components of reproductive anemia in egg-laying females.
The near and far wake of Pallas' long tongued bat (Glossophaga soricina)
Authors: Johansson L. Christoffer , Wolf Marta , von Busse Rhea , Winter York , Spedding Geoffrey R. , Hedenström Anders 
Published: September 2008

SUMMARYThe wake structures of a bat in flight have a number of characteristics not associated with any of the bird species studied to this point. Unique features include discrete vortex rings generating negative lift at the end of the upstroke at medium and high speeds, each wing generating its own vortex loop,and a systematic variation in the circulation of the start and stop vortices along the wingspan, with increasing strength towards the wing tips. Here we analyse in further detail some previously published data from quantitative measurements of the wake behind a small bat species flying at speeds ranging from 1.5 to 7 m s–1 in a wind tunnel. The data are extended to include both near- and far-wake measurements. The near-/far-wake comparisons show that although the measured peak vorticity of the start and stop vortices decreases with increasing downstream distance from the wing, the total circulation remains approximately constant. As the wake evolves, the diffuse stop vortex shed at the inner wing forms a more concentrated vortex in the far wake. Taken together, the results show that studying the far wake,which has been the standard procedure, nevertheless risks missing details of the wake. Although study of the far wake alone can lead to the misinterpretation of the wake topology, the net, overall circulation of the main wake vortices can be preserved so that approximate momentum balance calculations are not unreasonable within the inevitably large experimental uncertainties.
Fish and chips: functional genomics of social plasticity in an African cichlid fish
Authors: Renn Susan C. P. , Aubin-Horth Nadia , Hofmann Hans A. 
Published: September 2008

SUMMARY
Behavior and physiology are regulated by both environment and social context. A central goal in the study of the social control of behavior is to determine the underlying physiological, cellular and molecular mechanisms in the brain. The African cichlid fish Astatotilapia burtoni has long been used as a model system to study how social interactions regulate neural and behavioral plasticity. In this species, males are either socially dominant and reproductively active or subordinate and reproductively suppressed. This phenotypic difference is reversible. Using an integrative approach that combines quantitative behavioral measurements, functional genomics and bioinformatic analyses, we examine neural gene expression in dominant and subordinate males as well as in brooding females. We confirm the role of numerous candidate genes that are part of neuroendocrine pathways and show that specific co-regulated gene sets (modules), as well as specific functional gene ontology categories, are significantly associated with either dominance or reproductive state. Finally, even though the dominant and subordinate phenotypes are robustly defined, we find a surprisingly high degree of individual variation in the transcript levels of the very genes that are differentially regulated between these phenotypes. The results of the present study demonstrate the molecular complexity in the brain underlying social behavior, identify novel targets for future studies, validate many candidate genes and exploit individual variation in order to gain biological insights.
Urea loading enhances freezing survival and postfreeze recovery in a terrestrially hibernating frog
Authors: Costanzo Jon P. , Lee Richard E. 
Published: September 2008

SUMMARY
We tested the hypothesis that urea, an osmolyte accumulated early in hibernation, functions as a cryoprotectant in the freeze-tolerant wood frog, Rana sylvatica. Relative to saline-treated, normouremic (10 μmol ml–1) frogs, individuals rendered hyperuremic (70 μmol ml–1) by administration of an aqueous urea solution exhibited significantly higher survival (100% versus 64%) following freezing at–4°C, a potentially lethal temperature. Hyperuremic frogs also had lower plasma levels of intracellular proteins (lactate dehydrogenase, creatine kinase, hemoglobin), which presumably escaped from damaged cells, and more quickly recovered neurobehavioral functions following thawing. Experimental freezing–thawing did not alter tissue urea concentrations, but did elevate glucose levels in the blood and organs of all frogs. When measured 24 h after thawing commenced, glucose concentrations were markedly higher in urea-loaded frogs as compared to saline-treated ones, possibly because elevated urea retarded glucose clearance. Like other low-molecular-mass cryoprotectants, urea colligatively reduces both the amount of ice forming within the body and the osmotic dehydration of cells. In addition, by virtue of certain non-colligative properties, it may bestow additional protection from freeze–thaw damage not afforded by glucose.