bluuebunny/crossref_metadata_2025_split huggingface dataset:
A site-specific PEGylated analog of exendin-4 with improved pharmacokinetics and pharmacodynamics in vivo
Authors: Gao Mingming , Jin Yuhao , Tong Yue , Tian Hong , Gao Xiangdong , Yao Wenbing 
Published: June 2012

Abstract

Objectives
Our aim was to improve the in vivo pharmacokinetics and pharmacodynamics of exendin-4 by using site-specific PEGylation.

Methods
We designed the PEGylated peptide based on its structure and activity relationship and prepared the conjugate by two steps of chromatographic purification. After obtained the conjugate we confirmed its glucose-lowering activity in normal mice and determined its half-life in SD rats. Then we evaluated its anti-diabetic activity in a multiple low-dose Streptozocin (STZ)-induced diabetic mice model.

Key findings
With the process established in this study the product conjugate was obtained with a yield of over 60% and purity of above 99%. The conjugate maintained its original conformation after modification. In SD rats its half-life was prolonged to 27.12 ± 5.75 h which was 17.61-fold longer than that of the natural exendin-4 for which the half-life was only 1.54 ± 0.47 h. Its anti-diabetic activity was significantly improved in the diabetic mice.

Conclusions
Compare with native exendin-4, the C-terminal site-specific PEGylated analog of exendin-4 obtained in this study has an improved pharmacokinetics and pharmacodynamics in vivo and could be regarded as a potential candidate for the future development of anti-diabetic drugs.
Drosophila melanogaster as a Model Organism for Bluetongue Virus Replication and Tropism
Authors: Shaw Andrew E. , Veronesi Eva , Maurin Guillemette , Ftaich Najate , Guiguen Francois , Rixon Frazer , Ratinier Maxime , Mertens Peter , Carpenter Simon , Palmarini Massimo , Terzian Christophe , Arnaud Frederick 
Published: June 2012

ABSTRACT

Bluetongue virus (BTV) is the etiological agent of bluetongue (BT), a hemorrhagic disease of ruminants that can cause high levels of morbidity and mortality. BTV is an arbovirus transmitted between its ruminant hosts by
Culicoides
biting midges (Diptera: Ceratopogonidae). Recently, Europe has experienced some of the largest BT outbreaks ever recorded, including areas with no known history of the disease, leading to unprecedented economic and animal welfare issues. The current lack of genomic resources and genetic tools for
Culicoides
restricts any detailed study of the mechanisms involved in the virus-insect interactions. In contrast, the genome of the fruit fly (
Drosophila melanogaster
) has been successfully sequenced, and it is used extensively as a model of molecular pathways due to the existence of powerful genetic technology. In this study,
D. melanogaster
is investigated as a model for the replication and tropism of BTV. Using reverse genetics, a modified BTV-1 that expresses the fluorescent mCherry protein fused to the viral nonstructural protein NS3 (BTV-1/NS3mCherry) was generated. We demonstrate that BTV-1/NS3mCherry is not only replication competent as it retains many characteristics of the wild-type virus but also replicates efficiently in
D. melanogaster
after removal of the bacterial endosymbiont
Wolbachia pipientis
by antibiotic treatment. Furthermore, confocal microscopy shows that the tissue tropism of BTV-1/NS3mCherry in
D. melanogaster
resembles that described previously for BTV in
Culicoides
. Overall, the data presented in this study demonstrate the feasibility of using
D. melanogaster
as a genetic model to investigate BTV-insect interactions that cannot be otherwise addressed in vector species.
Modulation of Translation Initiation Efficiency in Classical Swine Fever Virus
Authors: Friis Martin Barfred , Rasmussen Thomas Bruun , Belsham Graham J. 
Published: June 2012

ABSTRACT

Modulation of translation initiation efficiency on classical swine fever virus (CSFV) RNA can be achieved by targeted mutations within the internal ribosome entry site (IRES). In this study, cDNAs corresponding to the wild-type (wt) or mutant forms of the IRES of CSFV strain Paderborn were amplified and inserted into dicistronic reporter plasmids encoding Fluc and Rluc under the control of a T7 promoter. The mutations were within domains II, IIId
1
, and IIIf of the IRES. The plasmids were transfected into baby hamster kidney (BHK) cells infected with recombinant vaccinia virus vTF7-3, which expresses the T7 RNA polymerase. IRES mutants with different levels of IRES activity were identified and then introduced by homologous recombination into bacterial artificial chromosomes (BACs) containing CSFV Paderborn cDNA downstream of a T7 promoter. From the wt and mutant BACs, full-length CSFV RNA transcripts were produced
in vitro
and electroporated into porcine PK15 cells. Rescued mutant viruses were obtained from RNAs that contained mutations within domain IIIf which retained more than 75% of the wt translation efficiency. Sequencing of cDNA generated from these rescued viruses verified the maintenance of the introduced changes within the IRES. The growth characteristics of each rescued mutant virus were compared to those of the wt virus. It was shown that viable mutant viruses with reduced translation initiation efficiency can be designed and generated and that viruses containing mutations within domain IIIf of the IRES have reduced growth in cell culture compared to the wt virus.
A Vesiculovirus Showing a Steepened Transcription Gradient and Dominant
trans
-Repression of Virus Transcription
Authors: Hodges Erin N. , Heinrich Bianca S. , Connor John H. 
Published: June 2012

ABSTRACT

Vesicular stomatitis virus (VSV) is a prototype nonsegmented, negative-sense virus used to examine viral functions of a broad family of viruses, including human pathogens. Here we demonstrate that S
2
VSV, an isolate with a small plaque phenotype compared to other Indiana strain viruses, has a transcription defect resulting in an altered pattern and rapid decline of transcription. The S
2
VSV transcription gradient is dominant over the wild-type transcription in a coinfection. This is the first characterization of an altered gradient of transcription not dependent on RNA template sequence or host response and may provide insight into new approaches to viral attenuation.
Self-reported cocaine use, emergency physician testing and outcomes in suspected acute coronary syndromes: a nested matched case–control study
Authors: Wang Yang , Lindsell Christopher J , Pollack Charles V , Hollander Judd , Diercks Deborah B , Kirk J Douglas , Anantharaman Venkataraman , Gibler W Brian , Hoekstra James , Peacock W Frank 
Published: June 2012

ObjectivesThe primary purpose was to compare the odds of acute coronary syndrome-pertinent diagnostic testing between self-reported cocaine users and non-users at the turn of the century. The secondary purpose was to compare the odds of acute coronary syndrome outcomes between cocaine users and non-users.DesignNested matched case–control study using data from the Internet Tracking Registry of Acute Coronary Syndromes.SettingExtracted data of patients from eight US institutions composed of six academic and two community hospitals, with census varying between 10 000 and 160 000 visits per year.Participants249 cases of self-reported cocaine users and 249 matched controls. Matching was based on age, race, sex and any history of known coronary artery disease. Exclusion criteria were new ST elevations on initial ECG and initial physician impression of acute myocardial infarction.Primary and secondary outcome measuresPrimary outcome was the conditional odds of undergoing non-invasive and invasive testing for coronary artery disease. Secondary outcome was the occurrences of adverse cardiac outcomes within 30 days.ResultsCocaine users underwent diagnostic testing at similar rates compared with non-users (9.6% vs 8.0%, OR 1.24, CI 0.65 to 2.34). Adverse cardiovascular outcomes occurred in four (1.6%) cocaine users and in seven (2.8%) controls.ConclusionsThere was no increase in tendency for testing associated with self-reported history of cocaine use between 1999 and 2001. This suggests that even 10 years ago, cocaine use already had only a limited role in the Emergency Department (ED) physician's decision-making process. Similar data analyses of detailed registries can offer important contextual information that can better direct resources for future comparative effectiveness research.
The utility of injury narratives for prioritising future prevention activities in small and medium enterprises in rural Vietnam
Authors: Marucci-Wellman Helen , Willetts Joanna L , Diep Nguyen Bich , Binh Ta Thi Tuyet 
Published: June 2012

ObjectivesInjuries are a leading cause of work-related disability and death in rapidly developing countries such as Vietnam. The authors' objective was to demonstrate the utility of detailed injury narratives, derived from a household survey, in providing information on the determinants of work-related injuries to inform potential intervention targets.MethodsIn a cross-sectional survey administered to 2615 households of a rapidly developing community of Vietnam where many workers engage in both agriculture and industrial work, the authors collected information about self-reported work-related injuries, annual hours worked in each industry and narrative text describing the circumstances of each injury. The authors used a customised coding taxonomy to describe injury scenarios.ResultsSeveral intervention themes emerged, including the implementation of machine guarding, the use of cut resistant gloves and safety glasses which would benefit the small- and medium-sized enterprises. Calculation of incidence rates using full-time equivalents, stratified by work group, provided some unexpected observations of the risks of working in agriculture; workers who work in agriculture in addition to another industry are at an increased risk of fatigue or overexertion and other consequences ofworking too hardin their agricultural activities.ConclusionsA lack of aggregate injury statistics makes it difficult for the owners of small- and medium-sized enterprises to recognise a priori the most effective safety interventions. This analysis of detailed injury narratives with an appropriate taxonomic basis offers the ability to focus on the level of cause, activity and source and may inform the choice of various potential interventions at the workplace or enterprise level.
Combined surgical and endovascular treatment of complex cerebrovascular diseases in the hybrid operating room
Authors: Murayama Yuichi , Arakawa Hideki , Ishibashi Toshihiro , Kawamura Daichi , Ebara Masaki , Irie Koreaki , Takao Hiroyuki , Ikeuchi Satoshi , Ogawa Takeki , Kato Masataka , Kajiwara Ikki , Nishimura Shingo , Abe Toshiaki 
Published: June 2012

BackgroundAlthough most neurovascular diseases can be treated either by microsurgical or endovascular means, a subset of patients may require a combined approach. Patient transfer from the operating room (OR) to the angiosuite has been a fundamental drawback of this type of approach.ObjectiveThe purpose of this study is to report our clinical experience performing combined surgical and endovascular procedures for neurovascular diseases in the hybrid OR.Methods29 patients with neurovascular diseases underwent combined endovascular and surgical procedures in a single session: 16 were scheduled combined treatment and 13 were emergency combined procedures. Of the emergency cases, three were rescue surgeries after endovascular complications. Three patients had ruptured intracranial aneurysms, eight had unruptured intracranial aneurysms, eight had arteriovenous malformations and eight had arteriovenous fistulae; two patients had either a spinal tumor or dural arteriovenous fistulae.ResultsAll combined procedures were performed in a single session without changing the patient's surgical position. In cases of ruptured arteriovenous malformations or aneurysms with hematoma, an emergency embolization was performed to assist the surgical procedure. Combined superficial temporal artery–middle cerebral artery (STA–MCA) bypass followed by endovascular parent artery trapping were successfully performed for complex large or giant aneurysms. There were two periprocedural ischemic complications. Of the three patients who underwent surgical rescue after endovascular complications, two remained intact and one died despite immediate surgical procedures.ConclusionA combined endovascular and surgical approach conducted in a hybrid OR provides a new strategy for the treatment of complex neurovascular diseases.
Molecular Profiling Reveals Low- and High-Grade Forms of Primary Melanoma
Authors: Harbst Katja , Staaf Johan , Lauss Martin , Karlsson Anna , Måsbäck Anna , Johansson Iva , Bendahl Pär-Ola , Vallon-Christersson Johan , Törngren Therese , Ekedahl Henrik , Geisler Jürgen , Höglund Mattias , Ringnér Markus , Lundgren Lotta , Jirström Karin , Olsson Håkan , Ingvar Christian , Borg Åke , Tsao Hensin , Jönsson Göran 
Published: June 2012

Abstract
Purpose: For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome.
Experimental Design: We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data.
Results: Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between “high” and “low” grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P &lt; 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84–8.59), and overall (HR = 3.66; 95% CI, 2.40–5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets.
Conclusions: We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease. Clin Cancer Res; 18(15); 4026–36. ©2012 AACR.
The CIRCE Simulations: Regional Climate Change Projections with Realistic Representation of the Mediterranean Sea
Authors: Gualdi S. , Somot S. , Li L. , Artale V. , Adani M. , Bellucci A. , Braun A. , Calmanti S. , Carillo A. , Dell'Aquila A. , Déqué M. , Dubois C. , Elizalde A. , Harzallah A. , Jacob D. , L'Hévéder B. , May W. , Oddo P. , Ruti P. , Sanna A. , Sannino G. , Scoccimarro E. , Sevault F. , Navarra A. 
Published: June 2012

In this article, the authors describe an innovative multimodel system developed within the Climate Change and Impact Research: The Mediterranean Environment (CIRCE) European Union (EU) Sixth Framework Programme (FP6) project and used to produce simulations of the Mediterranean Sea regional climate. The models include high-resolution Mediterranean Sea components, which allow assessment of the role of the basin and in particular of the air–sea feedbacks in the climate of the region.
The models have been integrated from 1951 to 2050, using observed radiative forcings during the first half of the simulation period and the Intergovernmental Panel on Climate Change (IPCC) Special Report on Emissions Scenarios (SRES) A1B scenario during the second half.
The projections show a substantial warming (about 1.5°–2°C) and a significant decrease of precipitation (about 5%) in the region for the scenario period. However, locally the changes might be even larger. In the same period, the projected surface net heat loss decreases, leading to a weaker cooling of the Mediterranean Sea by the atmosphere, whereas the water budget appears to increase, leading the basin to lose more water through its surface than in the past. Overall, these results are consistent with the findings of previous scenario simulations, such as the Prediction of Regional Scenarios and Uncertainties for Defining European Climate Change Risks and Effects (PRUDENCE), Ensemble-Based Predictions of Climate Changes and Their Impacts (ENSEMBLES), and phase 3 of the Coupled Model Intercomparison Project (CMIP3). The agreement suggests that these findings are robust to substantial changes in the configuration of the models used to make the simulations.
Finally, the models produce a 2021–50 mean steric sea level rise that ranges between +7 and +12 cm, with respect to the period of reference.
Estimation of the costs of cervical cancer screening, diagnosis and treatment in rural Shanxi Province, China: a micro-costing study
Authors: Shi Ju-Fang , Chen Jun-Feng , Canfell Karen , Feng Xiang-Xian , Ma Jun-Fei , Zhang Yong-Zhen , Zhao Fang-Hui , Li Rong , Ma Li , Li Zhi-Fang , Lew Jie-Bin , Ning Yan , Qiao You-Lin 
Published: June 2012

AbstractBackgroundCost estimation is a central feature of health economic analyses. The aim of this study was to use a micro-costing approach and a societal perspective to estimate aggregated costs associated with cervical cancer screening, diagnosis and treatment in rural China.MethodsWe assumed that future screening programs will be organized at a county level (population ~250,000), and related treatments will be performed at county or prefecture hospitals; therefore, this study was conducted in a county and a prefecture hospital in Shanxi during 2008–9. Direct medical costs were estimated by gathering information on quantities and prices of drugs, supplies, equipment and labour. Direct non-medical costs were estimated via structured patient interviews and expert opinion.ResultsUnder the base case assumption of a high-volume screening initiative (11,475 women screened annually per county), the aggregated direct medical costs of visual inspection, self-sampledcareHPV (Qiagen USA) screening, clinician-sampledcareHPV, colposcopy and biopsy were estimated as US$2.64,$7.49,$7.95,$3.90 and $5.76, respectively. Screening costs were robust to screening volume (<5% variation if 2,000 women screened annually), but costs of colposcopy/biopsy tripled at the lower volume. Direct medical costs of Loop Excision, Cold-Knife Conization and Simple and Radical Hysterectomy varied from $61–544, depending on the procedure and whether conducted at county or prefecture level. Direct non-medical expenditure varied from $0.68–$3.09 for screening/diagnosis and $83–$494 for pre-cancer/cancer treatment.ConclusionsDiagnostic costs were comparable to screening costs for high-volume screening but were greatly increased in lower-volume situations, which is a key consideration for the scale-up phase of new programs. The study’s findings will facilitate cost-effectiveness evaluation and budget planning for cervical cancer prevention initiatives in China.
Validation of a new tool to assess health-related quality of life in psoriasis: the PSO-LIFE questionnaire
Authors: Dauden Esteban , Herrera Enrique , Puig Lluis , Sánchez-Carazo José Luis , Toribio Jaime , Caloto Ma Teresa , Nocea Gonzalo , Roset Montse , Lara Nuria 
Published: June 2012

AbstractBackgroundSeveral questionnaires have been used to measure health related quality of life (HRQoL) in patients with psoriasis, few have been adapted for use in Spain; none of them was developed specifically for the Spanish population. The purpose of the study was to validate and assess the sensitivity to change of a new questionnaire to measure HRQOL in patients with psoriasis (PSO-LIFE).MethodsObservational, prospective, multicenter study performed in centers around Spain. Patients with active or inactive psoriasis completed the PSO-LIFE together with other Dermatology Quality of Life Index (DLQI) and Psoriasis Disability Index (PDI). A control group of patients with urticaria or atopic dermatitis was also included. Internal consistency and test-retest reliability of the PSO-LIFE were assessed by calculating Cronbach’s alpha and Intraclass Correlation Coefficient (ICC). Validity was assessed by examining factorial structure, the capacity to discriminate between groups, and correlations with other measures. Sensitivity to change was measured using effect sizes.ResultsThe final sample included for analysis consisted of 304 patients and 56 controls. Mean (SD) age of psoriasis patients was 45.3 (14.5) years compared to 38.8 (14) years for controls (p < 0.01). Cronbach’s alpha for the PSO-LIFE was 0.95 and test-retest reliability using the ICC was 0.98. Factor analysis showed the questionnaire to be unidimensional. Mean (SD) PSO-LIFE scores differed between patients with psoriasis and controls (64.9 [22.5] vs 69.4 [17.3]; p < 0.05), between those with active and inactive disease (57.4 [20.4] vs 76.4 [20.6]; p < 0.01), and between those with visible and non-visible lesions (63.0 [21.9] vs. 74.8 [23.9]; p < 0.01). The correlation between PSO-LIFE and PASI scores was moderate (r = −0.43) while correlations with DLQI and PDI dimensions ranged from moderate to high (between 0.4 and 0.8). Effect size on the PSO-LIFE in patients reporting ‘much improved’ health status at study completion was 1.01 (large effect size).ConclusionsThe present results provide substantial support for the reliability, validity, and responsiveness of the PSO-LIFE questionnaire in the population for which it was designed.