bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and review of the voluntary phase of a national BVD eradication programme in Ireland
Authors: Graham D. A. , Lynch M. , Coughlan S. , Doherty M. L. , O'Neill R. , Sammin D. , O'Flaherty J. 
Published: January 2014

The voluntary phase of an industry‐led national Bovine Viral Diarrhoea (BVD) eradication programme began in Ireland on January 1, 2012 with the goal of progressing to a compulsory programme in 2013. The development and implementation of the programme in 2012 was informed by a review of current and prior eradication programmes elsewhere in Europe and extensive stakeholder consultation. The programme was based on tissue tag testing of newborn calves in participating herds, with the status of the mothers of calves with positive or inconclusive results requiring clarification. Participating herd owners were required to comply with a series of guidelines, including not selling cattle suspected of being persistently infected. For herds compliant with the guidelines, the results from 2012 counted as one of three years of tag testing anticipated in the compulsory phase of the programme. Testing was carried out in laboratories designated for this purpose by the cross‐industry BVD Implementation Group that oversees the programme. Results were reported to a central database managed by the Irish Cattle Breeding Federation, and the majority of results were reported to farmers’ mobile telephones by SMS message. A detailed review of the programme was conducted, encompassing the period between January 1, 2012 and July 15, 2012, based on results from approximately 500,000 calves. This paper describes the establishment and structure of the programme, and the outcomes of the review, including findings at herd and animal level.
Impact of Vagal Nerve Stimulation on Left Atrial Structure and Function in a Canine High-Rate Pacing Model
Authors: Kusunose Kenya , Zhang Youhua , Mazgalev Todor N. , Van Wagoner David R. , Thomas James D. , Popović Zoran B. 
Published: January 2014

Background—
Cervical vagal nerve stimulation (VNS) can improve left ventricular dysfunction in the setting of heart failure (HF). However, little is known about the impact of VNS on left atrial (LA) function. The aim of this study was to compare LA mechanics and histology between control and VNS-treated animals during HF development.

Methods and Results—

Fifteen mongrel dogs were randomized into control (n=7) and VNS (n=8) groups. All dogs underwent 8 weeks of high-rate ventricular pacing (at 220 beats per minute for the first 4 weeks to develop HF and another 4 weeks at 180 beats per minute to maintain HF). LA contractile function (LA negative peak strain), conduit function (LA positive peak strain), and reservoir function (LA total strain) were measured from speckle tracking in 2 groups. At the end of the terminal study, the LA appendage was obtained. Baseline LA strains were comparable in the control and VNS-treated dogs. At 4 and 8 weeks of ventricular pacing, all LA strains were decreased and LA volumes were increased in the control group compared with the VNS group (
P
<0.05). Histological evaluation of the left atrium revealed that percent fibrosis was significantly lower in the VNS versus the control group (8±1% versus 13±1%;
P
<0.001). Finally, transmitral flow showed decreased atrial contribution to left ventricular filling in the control group (
P
<0.05).

Conclusions—
VNS improved LA function and volumes and suppressed LA fibrosis in the canine high-rate ventricular pacing model. VNS is a novel and potentially useful therapy for improving LA function during HF.
Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura
Authors: Jiang Yang , McIntosh Jennifer J. , Reese Jessica A. , Deford Cassandra C. , Kremer Hovinga Johanna A. , Lämmle Bernhard , Terrell Deirdra R. , Vesely Sara K. , Knudtson Eric J. , George James N. 
Published: January 2014

Key Points
Recurrent TTP complicating a subsequent pregnancy may be uncommon; most pregnancies result in normal children. The frequency of preeclampsia may be increased in pregnancies following recovery from TTP.
Surgical treatment of an invasive thymoma extending into the superior vena cava and right atrium
Authors: Dong Yong-Qiang , Liang Jiang-Shui , Zhang Xiao-Ming , Zhu Shui-Bo , Xu Jia-Hang , Ji Tao , Yin Gui-Lin 
Published: January 2014

Abstract
Although invasive thymoma commonly infiltrates neighbouring mediastinal structures, its extension into the superior vena cava (SVC) and consequent SVC occlusion are rare. In such cases, the urgent removal of the thymoma and radical resection of the infiltrated SVC representreasonable options, since induction therapy is time-consuming and useless for symptom resolution. A case of invasive thymoma extending into the SVC and right atrium (RA) with SVC syndrome is reported. The patient underwent a combined resection of the invasive tumor and SVC under cardiopulmonary bypass (CPB), and the SVC and bilateral brachiocephalic vein (BCV) were reconstructed with an autologous pericardial ‘Y’ conduit. After 40 months of follow-up, the patient showed a patent graft and no tumor recurrence.
Antiresorptive Treatment of Postmenopausal Osteoporosis: Comparison of Study Designs and Outcomes in Large Clinical Trials with Fracture as an Endpoint
Authors: Marcus Robert , Wong Mayme , Heath Hunter , Stock John L. 
Published: January 2014

AbstractAntiresorptive treatments for postmenopausal osteoporosis have been studied extensively, but due to the volume of published data and lack of head-to-head trials, it is difficult to evaluate and compare their fracture reduction efficacy. The objective of this review is to summarize the results from clinical trials that have fracture as an endpoint and to discuss the factors in study design and populations that can affect the interpretation of the results. Although there are numerous observational studies suggesting that estrogen and hormone replacement therapies may reduce the risk of vertebral and nonvertebral fractures, there is no large, prospective, randomized, placebo-controlled, double-blind clinical trial demonstrating fracture efficacy. The effects of raloxifene, alendronate, risedronate, and salmon calcitonin on increasing bone mineral density (BMD) and decreasing fracture risk have been shown in randomized, placebo-controlled, double-blind clinical trials of postmenopausal women with osteoporosis. Although the increases in lumbar spine BMD vary greatly in these trials, the decrease in relative risk of vertebral fractures is similar among therapies. However, nonvertebral fracture efficacy has not been consistently demonstrated. Combined administration of two antiresorptive therapies results in greater BMD increases, but the effects on fracture risk are unknown. Direct comparisons of clinical trial results should be considered carefully, given the differences in study design and populations. Differences in study design that may influence the efficacy of fracture risk reduction include calcium and vitamin D supplementation, primary fracture endpoints, definition of vertebral deformity or fracture, discontinuation rates, and statistical power. Factors in the study population that may influence fracture efficacy include the age of the population and the proportion of subjects with prevalent fractures. The use of surrogate endpoints such as BMD to predict fracture risk should be approached with caution, as the relationship between BMD changes and fracture risk reduction with antiresorptive therapies is uncertain. Consideration of these results from clinical trials can contribute to clinical judgment in selecting the best treatment option for postmenopausal osteoporosis.
Fasting-Induced Hepatic Production of DHEA is Regulated by PGC-1α, ERRα and HNF4α
Authors: Grasfeder Linda L. , Gaillard Stephanie , Hammes Stephen R. , Ilkayeva Olga , Newgard Christopher B. , Hochberg Richard B. , Dwyer Mary A. , Chang Ching-yi , McDonnell Donald P. 
Published: January 2014

ABSTRACT
The transcriptional coactivator PGC-1α is involved in the coordinate induction of changes in gene expression in the liver that enable a homeostatic response to alterations in metabolic state, environmental cues and nutrient availability. In exploring the specific pathways under PGC-1α regulation in the liver, we have made the surprising observation that this coactivator can induce the expression of CYP11A1 and CYP17A1, key rate limiting enzymes involved in the initial steps of steroidogenesis. Both of these enzymes function to produce C19-steroids, converting cholesterol into pregnenolone, and then to DHEA. ERRa mediates PGC-1α’s induction of CYP11A1 and binds within the first intron of the CYP11A1 gene. Both ERRa and HNF4a are required for PGC-1α-mediated induction of CYP17A1 and specific binding sites for these receptors have been identified in the regulatory regions of this gene. The potential physiological significance of these observations was highlighted in rats where fasting induced hepatic expression of PGC-1α and CYP17A1 and was associated with an increase in hepatic levels of DHEA. These data suggest that DHEA could be playing a role as an intracellular signaling molecule involved in modulating hepatic activity in response to fasting conditions.
Pegylated Leptin Antagonist Is a Potent Orexigenic Agent: Preparation and Mechanism of Activity
Authors: Elinav Eran , Niv-Spector Leonora , Katz Meirav , Price Tulin O. , Ali Mohammed , Yacobovitz Michal , Solomon Gili , Reicher Shay , Lynch Jessica L. , Halpern Zamir , Banks William A. , Gertler Arieh 
Published: January 2014

ABSTRACT
Leptin, a pleiotropic adipokine, is a central regulator of appetite and weight and a key immunomodulatory protein. Although inborn leptin deficiency causes weight gain, it is unclear whether induced leptin deficiency in adult wild-type animals would be orexigenic. Previous work with a potent competitive leptin antagonist did not induce a true metabolic state of leptin deficiency in mice because of a short circulating half-life. In this study, we increased the half-life of the leptin antagonist by pegylation, which resulted in significantly increased bioavailability and retaining of antagonistic activity. Mice administered the pegylated antagonist showed a rapid and dramatic increase in food intake with weight gain. Resulting fat was confined to the mesenteric region with no accumulation in the liver. Serum cholesterol, triglyceride, and hepatic aminotransferases remained unaffected. Weight changes were reversible on cessation of leptin antagonist treatment. The mechanism of severe central leptin deficiency was found to be primarily caused by blockade of transport of circulating leptin across the blood-brain barrier with antagonisms at the arcuate nucleus playing a more minor role. Altogether we introduce a novel compound that induces central and peripheral leptin deficiency. This compound should be useful in exploring the involvement of leptin in metabolic and immune processes and could serve as a therapeutic for the treatment of cachexia.
Role of Insulin-Like Growth Factor-Binding Protein 5 (IGFBP5) in Organismal and Pancreatic β-Cell Growth
Authors: Gleason Catherine E. , Ning Yun , Cominski Tara P. , Gupta Rana , Kaestner Klaus H. , Pintar John E. , Birnbaum Morris J. 
Published: January 2014

Abstract
A family of IGF-binding proteins (IGFBP) exerts biological actions both dependent on and independent of IGF-I. A major effector of the insulin/IGF-I signaling pathway, the serine/threonine protein kinase Akt, mediates cellular processes such as glucose uptake, protein synthesis, cell survival, and growth. IGF-I is required for normal organismal growth, and in the pancreatic β-cell, the insulin/IGF-I signaling pathway is critical for normal and adaptive maintenance of β-cell mass. Expression of myrAkt1, an activated form of Akt, in the endocrine pancreas drives β-cell expansion through dramatic increases in both islet and β-cell size and number. Herein we present a comparative expression profiling of myrAkt1 transgenic islets that demonstrates the increased abundance of transcripts encoding proteins associated with growth, suppression of apoptosis, RNA processing, and metabolism. Although IGFBP5 is identified as a gene induced by Akt1 activation in the β-cell, Igfbp5 expression is not necessary for myrAkt1 to augment β-cell size or mass in vivo. However, in the absence of Igfbp5, mice demonstrate an increase in size and mild glucose intolerance. This is accentuated during diet-induced obesity, when Igfbp5-deficient mice have increased adiposity compared with wild-type mice on the same diet. These studies reveal a novel role for Igfbp5 in the control of growth and metabolism.
Acute Tissue Injury Caused by Subcutaneous Fat Biopsies Produces Endoplasmic Reticulum Stress
Authors: Boden Guenther , Silviera Matthew , Smith Brian , Cheung Peter , Homko Carol 
Published: January 2014

Abstract

Background
It is not known whether acute tissue injury is associated with endoplasmic reticulum (ER) stress.

Objective
Our objective was to determine whether open, sc fat biopsies cause ER stress.

Approach
Five healthy subjects underwent three open sc fat biopsies. The first biopsy, taken from the lateral aspect of a thigh, was followed 4 h later by a second biopsy from the same incision site and a third biopsy from the contralateral leg. Expression markers of ER stress, inflammation, hypoxia, and adipokines were measured in these fat biopsies. In addition, we tested for signs of systemic ER stress and inflammation in plasma and in circulating monocytes.

Results
mRNA/18s ratios of IL-6, monocyte chemoattractant protein-1, CD-14, hypoxia-induced factor 1-α, the spliced form of Xbox protein-1, glucose-regulated protein 78, CEBP homologous protein, and activating factor-4 were all severalfold higher, whereas mRNA/18s ratios of adiponectin and leptin were lower in fat biopsies taken from the same site 4 h after the first biopsy but were unchanged in the second biopsy that was taken from the contralateral site. The biopsies were not associated with changes in plasma and monocyte IL-6 concentrations or in monocyte ER stress markers. Also, whole-body insulin-stimulated glucose uptake was the same in 15 subjects who had biopsies compared with 15 different subjects who did not.

Conclusion
Open, sc fat biopsies produced inflammation, hypoxia, ER stress, and decreased expression of adiponectin and leptin. These changes remained confined to the biopsy site for at least 4 h.
Precursor Cells in Mouse Islets Generate New β-Cells in Vivo during Aging and after Islet Injury
Authors: Liu H. , Guz Y. , Kedees M. H. , Winkler J. , Teitelman G. 
Published: January 2014

ABSTRACT
Whereas it is believed that the pancreatic duct contains endocrine precursors, the presence insulin progenitor cells residing in islets remain controversial. We tested whether pancreatic islets of adult mice contain precursor β-cells that initiate insulin synthesis during aging and after islet injury. We used bigenic mice in which the activation of an inducible form of cAMP response element recombinase by a one-time pulse of tamoxifen results in the permanent expression of a floxed human placental alkaline phosphatase (PLAP) gene in 30% of pancreatic β-cells. If islets contain PLAP− precursor cells that differentiate into β-cells (PLAP−IN+), a decrease in the percentage of PLAP+IN+ cells per total number of IN+ cells would occur. Conversely, if islets contain PLAP+IN− precursors that initiate synthesis of insulin, the percentage of PLAP+IN+ cells would increase. Confocal microscope analysis revealed that the percentage of PLAP+IN+ cells in islets increased from 30 to 45% at 6 months and to 60% at 12 months. The augmentation in the level of PLAP in islets with time was confirmed by real time-PCR. Our studies also demonstrate that the percentage of PLAP+IN+ cells in islets increased after islet injury and identified putative precursors in islets. We postulate that PLAP+IN− precursors differentiate into insulin-positive cells that participate in a slow renewal of the β-cell mass during aging and replenish β-cells eliminated by injury.
Minireview: A Tiny Touch: Activation of Cell Signaling Pathways with Magnetic Nanoparticles
Authors: Sniadecki Nathan J. 
Published: January 2014

ABSTRACT
Magnetic nanoparticles can be coated with specific ligands that enable them to bind to receptors on a cell’s surface. When a magnetic field is applied, it pulls on the particles so that they deliver nanoscale forces at the ligand-receptor bond. It has been observed that mechanical stimulation in this manner can activate cellular signaling pathways that are known as mechanotransduction pathways. Integrin receptors, stretch-activated ion channels, focal adhesions, and the cytoskeleton are key players in activating these pathways, but there is still much we do not know about how these mechanosensors work. Current evidence indicates that applied forces at these structures can activate Ca2+ signaling, Src family protein kinase, MAPK, and RhoGTPase pathways. The techniques of magnetic twisting and magnetic tweezers, which use magnetic particles to apply forces to cells, afford a fine degree of control over how cells are stimulated and hold much promise in elucidating the fundamentals of mechanotransduction. The particles are generally not harmful to cellular health, and their nanoscale dimensions make them advantageous for probing a cell’s molecular-scale sensory structures. This review highlights the basic aspects of magnetic nanoparticles, magnetic particle techniques and the structures and pathways that are involved in mechanotransduction.
A Novel Bile Acid-Activated Vitamin D Receptor Signaling in Human Hepatocytes
Authors: Han Shuxin , Li Tiangang , Ellis Ewa , Strom Steven , Chiang John Y. L. 
Published: January 2014

ABSTRACT
Vitamin D receptor (VDR) is activated by natural ligands, 1α, 25-dihydroxy-vitamin D3 (1α, 25(OH)2-D3) and lithocholic acid (LCA). Our previous study shows that VDR is expressed in human hepatocytes, and VDR ligands inhibit bile acid synthesis and transcription of the gene encoding cholesterol 7α-hydroxylase (CYP7A1). Primary human hepatocytes were used to study LCA and 1α, 25(OH)2-D3 activation of VDR signaling. Confocal immunofluorescent microscopy imaging and immunoblot analysis showed that LCA and 1α, 25(OH)2-D3 induced intracellular translocation of VDR from the cytosol to the nucleus, and also plasma membrane where VDR co-localized with caveolin-1. VDR ligands induced tyrosine phosphorylation of c-Src and VDR, and their interaction. Inhibition of c-Src abrogated VDR ligand-dependent inhibition of CYP7A1 mRNA expression. Kinase assays showed that VDR ligands specifically activated the c-Raf/MEK1/2/ERK1/2 pathway, which stimulates serine phosphorylation of VDR and HNF4α, and their interaction. Mammalian two-hybrid assays showed a VDR ligand dependent interaction of nuclear receptor corepressor-1 (NCoR-1) and silencing mediator of retinoid and thyroid (SMRT) with VDR/RXRα. Chromatin immunoprecipitation assays revealed that an ERK1/2 inhibitor reversed VDR ligand-induced recruitment of VDR, RXRα and corepressors to human CYP7A1 promoter. In conclusion, VDR ligands activate membrane VDR signaling to activate the MEK1/2/ERK1/2 pathway, which stimulates nuclear VDR/RXRα recruitment of co-repressors to inhibit CYP7A1 gene transcription in human hepatocytes. This membrane VDR signaling pathway may be activated by bile acids to inhibit bile acid synthesis as a rapid response to protect hepatocytes from cholestatic liver injury.
Novel Corticosteroid-Binding Globulin Variant That Lacks Steroid Binding Activity
Authors: Perogamvros I. , Underhill C. , Henley D. E. , Hadfield K. D. , Newman W. G. , Ray D. W. , Lightman S. L. , Hammond G. L. , Trainer P. J. 
Published: January 2014

Abstract

Background:
Corticosteroid-binding globulin (CBG) is the principal carrier for glucocorticoids in the circulation and a regulator of their bioavailability. Inherited CBG deficiencies are rarely reported, and only three causative mutations in four families have been described.

Patients, Methods, and Results:
In a 26-yr-old female with hypotension, fatigue, and undetectable serum cortisol at presentation, we have identified a novel homozygous c.776g&gt;t transversion in exon 3 of the CBG (SERPINA6) gene. This results in a p.Gly237Val substitution that is predicted to influence the positioning of two β-sheets that constitute part of the CBG steroid-binding site. Two siblings were also homozygous for the variant, whereas her mother and an unaffected sibling were heterozygous. No other symptomatic family members were identified apart from the proband. Individuals homozygous for the variant had serum CBG levels below the reference range when measured by RIA, but CBG was unmeasurable in cortisol-binding capacity assays. In the same individuals, we observed very low baseline and stimulated serum cortisol levels but normal free serum and salivary cortisol and plasma ACTH. In a study of ultradian cortisol pulsatility, increased pulse frequency was only observed in the proband.

Conclusion:
We describe a novel CBG variant that lacks steroid binding. All mutant homozygotes have very low serum cortisol, but normal free cortisol levels. The only biochemical feature to distinguish the symptomatic subject was increased cortisol pulsatility, and we suggest that this may influence glucocorticoid signaling and contribute to symptoms previously associated with CBG deficiency.
Familial Glucocorticoid Resistance Caused by a Novel Frameshift Glucocorticoid Receptor Mutation
Authors: Trebble P. , Matthews L. , Blaikley J. , Wayte A. W. O. , Black G. C. M. , Wilton A. , Ray D. W. 
Published: January 2014

ABSTRACT

Context
Familial glucocorticoid resistance is a rare condition with a typical presentation of women with hirsutism and hypertension, with or without hypokalemia.

Objective
The aim was to determine the cause of apparent glucocorticoid resistance in a young woman.

Patients and Methods
We studied a family with a novel glucocorticoid receptor (GR) mutation and a surprisingly mild phenotype. Their discovery resulted from serendipitous measurement of serum cortisol with little biochemical or clinical evidence for either hyperandrogenism or mineralocorticoid excess.

Results
The causative mutation was identified as a frameshift mutation in exon 6. Transformed peripheral blood lymphocytes were generated to analyze GR expression in vitro. Carriers of the mutation had less full-length GR, but the predicted mutant GR protein was not detected. However, this does not exclude expression in vivo, and so the mutant GR (D612GR) was expressed in vitro. Simple reporter gene assays suggested that Δ612GR has dominant negative activity. Δ612GR was not subject to ligand-dependent Ser211 phosphorylation or to ligand-dependent degradation. A fluorophore-tagged construct showed that Δ612GR did not translocate to the nucleus in response to ligand and retarded translocation of the wild-type GR. These data suggest that Δ612GR is not capable of binding ligand and exerts dominant negative activity through heterodimerization with wild-type GR.

Conclusion
Therefore, we describe a novel, naturally occurring GR mutation that results in familial glucocorticoid resistance. The mutant GR protein, if expressed in vivo, is predicted to exert dominant negative activity by impairing wild-type GR nuclear translocation.