bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating cognitive outcome measures for MS clinical trials: what is a clinically meaningful change?
Authors: Benedict Ralph HB , Walton Marc K 
Published: July 2012

Brief cognitive assessments are increasingly emphasized in MS treatment studies and clinical care. While much is known about the reliability of several widely-used neuropsychological tests, interpretation of the changes in individual patients is inadequate. The FDA offers guidance on the issue, as related to patient-reported outcomes. Unfortunately, cognitive ability is only weakly correlated with the frequency and severity of self-reported cognitive problems. In this review, we critically examined the psychometrics of neuropsychological testing in MS, emphasizing statistical and anchor-based approaches to interpreting clinically meaningful change. We suggest that there are two paths forward that should be currently pursued. First, to employ co-primary outcomes, including a brief cognitive test and a clinician or observer’s impression on a scale of change, where successful treatment would require showing significant improvement in both measures. Secondly, to work toward showing that when reliable brief cognitive tests are employed, increments of statistically-relevant change would correlate with changes in clinically-relevant anchors (such as vocational disability or clinical relapses with cognitive impairment). The latter goal will allow a more parsimonious and scientifically efficient approach of utilizing only the brief cognitive test as a primary outcome. While some progress has been made in this direction, more research is needed. We are of the opinion that data from both the statistical and clinically meaningful approaches will be necessary to develop valid definitions of meaningful change on cognitive outcome measures, and that it would be best to pursue research using tests that already have well-established reliability and validity.
Self-perceived need for interpreter among immigrants in Denmark
Authors: Harpelund Lars , Nielsen Signe Smith , Krasnik Allan 
Published: July 2012

Aim: Starting in June 2011, immigrants who have lived for more than 7 years in Denmark have to pay a user-fee for interpreters in GP consultations and when hospitalised. We do not know yet how many immigrants will be affected by this amendment to the Danish Health Act and which socioeconomic factors characterise the immigrants who might be affected. To shed light on this, we investigated self-perceived need for interpreter (SNI) in GP consultations among participants from the largest non-Western immigrant groups in Denmark, the association between socioeconomic factors and SNI, and the characteristics of the immigrants potentially affected by the act amendment. Methods: Survey data on 2866 immigrants from former Yugoslavia, Iraq, Iran, Lebanon, Pakistan, Somalia, and Turkey, linked to registry information on socioeconomic factors were examined. We compared unadjusted proportions of SNI by country of birth. Logistic regression analyses were performed to investigate associations between SNI and socioeconomic factors. Results: Overall, 20% of immigrants living longer than 3 years in Denmark and 15% after 7 years reported a need for interpretation in their encounters with GPs. Of the latter group, the majority were outside the labour force (72.3%) and reported poor health (56%). Sex, age, length of stay, education, employment and household income were important factors for SNI. Conclusions: The amendment to the Health Act will primarily affect immigrants with modest household income, poor health and who are outside the labour force, thereby contributing and creating ethnic and social inequalities in access to health care in Denmark.
SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes
Authors: Visconte Valeria , Rogers Heesun J. , Singh Jarnail , Barnard John , Bupathi Manoj , Traina Fabiola , McMahon James , Makishima Hideki , Szpurka Hadrian , Jankowska Anna , Jerez Andres , Sekeres Mikkael A. , Saunthararajah Yogen , Advani Anjali S. , Copelan Edward , Koseki Haruhiko , Isono Kyoichi , Padgett Richard A. , Osman Sami , Koide Kazunori , O'Keefe Christine , Maciejewski Jaroslaw P. , Tiu Ramon V. 
Published: July 2012

AbstractWhole exome/genome sequencing has been fundamental in the identification of somatic mutations in the spliceosome machinery in myelodysplastic syndromes (MDSs) and other hematologic disorders. SF3B1, splicing factor 3b subunit 1 is mutated in 60%-80% of refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T), 2 distinct subtypes of MDS and MDS/myeloproliferative neoplasms (MDSs/MPNs). An idiosyncratic feature of RARS/RARS-T is the presence of abnormal sideroblasts characterized by iron overload in the mitochondria, called RS. Based on the high frequency of mutations of SF3B1 in RARS/RARS-T, we investigated the consequences of SF3B1 alterations. Ultrastructurally, SF3B1 mutants showed altered iron distribution characterized by coarse iron deposits compared with wild-type RARS patients by transmission electron microscopy. SF3B1 knockdown experiments in K562 cells resulted in down-regulation of U2-type intron-splicing by RT-PCR. RNA-sequencing analysis of SF3B1 mutants showed differentially used genes relevant in MDS pathogenesis, such as ASXL1, CBL, EZH, and RUNX families. A SF3B pharmacologic inhibitor, meayamycin, induced the formation of RS in healthy BM cells. Further, BM aspirates of Sf3b1 heterozygous knockout mice showed RS by Prussian blue. In conclusion, we report the first experimental evidence of the association between SF3B1 and RS phenotype. Our data suggest that SF3B1 haploinsufficiency leads to RS formation.
Clinical implications of plasma Epstein-Barr virus DNA in early-stage extranodal nasal-type NK/T-cell lymphoma patients receiving primary radiotherapy
Authors: Wang Zhao-Yang , Liu Qing-Feng , Wang Hua , Jin Jing , Wang Wei-Hu , Wang Shu-Lian , Song Yong-Wen , Liu Yue-Ping , Fang Hui , Ren Hua , Wu Run-Ye , Chen Bo , Zhang Xi-Mei , Lu Ning-Ning , Zhou Li-Qiang , Li Ye-Xiong 
Published: July 2012

Abstract
The clinical value of plasma Epstein-Barr virus (EBV) DNA has not been evaluated in patients with early-stage extranodal nasal-type NK/T-cell lymphoma (NKTCL) receiving primary radiotherapy. Fifty-eight patients with stage I disease and 11 with stage II disease were recruited. High pretreatment EBV-DNA concentrations were associated with B-symptoms, elevated lactate dehydrogenase levels, and a high International Prognostic Index score. EBV-DNA levels significantly decreased after treatment. The 3-year overall survival (OS) rate was 82.6% for all patients. Stage I or II patients with a pretreatment EBV-DNA level of ≤ 500 copies/mL had 3-year OS and progression-free survival (PFS) rates of 97.1% and 79.0%, respectively, compared with 66.3% (P = .002) and 52.2% (P = .045) in patients with EBV-DNA levels of > 500 copies/mL. The 3-year OS and PFS rates for patients with undetectable EBV-DNA after treatment was significantly higher than patients with detectable EBV-DNA (OS, 92.0% vs 69.8%, P = .031; PFS, 77.5% vs 50.7%, P = .028). Similar results were observed in stage I patients. EBV-DNA levels correlate with tumor load and a poorer prognosis in early-stage NKTCL. The circulating EBV-DNA level could serve both as a valuable biomarker of tumor load for the accurate classification of early-stage NKTCL and as a prognostic factor.
Short read sequence typing (SRST): multi-locus sequence types from short reads
Authors: Inouye Michael , Conway Thomas C , Zobel Justin , Holt Kathryn E 
Published: July 2012

Abstract

Background
Multi-locus sequence typing (MLST) has become the gold standard for population analyses of bacterial pathogens. This method focuses on the sequences of a small number of loci (usually seven) to divide the population and is simple, robust and facilitates comparison of results between laboratories and over time. Over the last decade, researchers and population health specialists have invested substantial effort in building up public MLST databases for nearly 100 different bacterial species, and these databases contain a wealth of important information linked to MLST sequence types such as time and place of isolation, host or niche, serotype and even clinical or drug resistance profiles. Recent advances in sequencing technology mean it is increasingly feasible to perform bacterial population analysis at the whole genome level. This offers massive gains in resolving power and genetic profiling compared to MLST, and will eventually replace MLST for bacterial typing and population analysis. However given the wealth of data currently available in MLST databases, it is crucial to maintain backwards compatibility with MLST schemes so that new genome analyses can be understood in their proper historical context.

Results
We present a software tool, SRST, for quick and accurate retrieval of sequence types from short read sets, using inputs easily downloaded from public databases. SRST uses read mapping and an allele assignment score incorporating sequence coverage and variability, to determine the most likely allele at each MLST locus. Analysis of over 3,500 loci in more than 500 publicly accessible Illumina read sets showed SRST to be highly accurate at allele assignment. SRST output is compatible with common analysis tools such as eBURST, Clonal Frame or PhyloViz, allowing easy comparison between novel genome data and MLST data. Alignment, fastq and pileup files can also be generated for novel alleles.

Conclusions
SRST is a novel software tool for accurate assignment of sequence types using short read data. Several uses for the tool are demonstrated, including quality control for high-throughput sequencing projects, plasmid MLST and analysis of genomic data during outbreak investigation. SRST is open-source, requires Python, BWA and SamTools, and is available from http://srst.sourceforge.net.
Bioluminescence imaging to track bacterial dissemination of Yersinia pestis using different routes of infection in mice
Authors: Gonzalez Rodrigo J , Weening Eric H , Frothingham Richard , Sempowski Gregory D , Miller Virginia L 
Published: July 2012

Abstract

Background
Plague is caused by Yersinia pestis, a bacterium that disseminates inside of the host at remarkably high rates. Plague bacilli disrupt normal immune responses in the host allowing for systematic spread that is fatal if left untreated. How Y. pestis disseminates from the site of infection to deeper tissues is unknown. Dissemination studies for plague are typically performed in mice by determining the bacterial burden in specific organs at various time points. To follow bacterial dissemination during plague infections in mice we tested the possibility of using bioluminescence imaging (BLI), an alternative non-invasive approach. Fully virulent Y. pestis was transformed with a plasmid containing the luxCDABE genes, making it able to produce light; this lux-expressing strain was used to infect mice by subcutaneous, intradermal or intranasal inoculation.

Results
We successfully obtained images from infected animals and were able to follow bacterial dissemination over time for each of the three different routes of inoculation. We also compared the radiance signal from animals infected with a wild type strain and a Δcaf1 ΔpsaA mutant that we previously showed to be attenuated in colonization of the lymph node and systemic dissemination. Radiance signals from mice infected with the wild type strain were larger than values obtained from mice infected with the mutant strain (linear regression of normalized values, P < 0.05).

Conclusions
We demonstrate that BLI is useful for monitoring dissemination from multiple inoculation sites, and for characterization of mutants with defects in colonization or dissemination.
Genetic structure and mating system of wild cowpea populations in West Africa
Authors: Kouam Eric B , Pasquet Remy S , Campagne Pascal , Tignegre Jean-Baptiste , Thoen Kevin , Gaudin Remi , Ouedraogo Jeremy T , Salifu Abdulai B , Muluvi Geoffrey M , Gepts Paul 
Published: July 2012

AbstractBackgroundCowpea is a highly inbred crop. It is part of a crop-weed complex, whose origin and dynamics is unknown, which is distributed across the African continent. This study examined outcrossing rates and genetic structures in 35 wild cowpea (Vigna unguiculata ssp. unguiculata var. spontanea) populations from West Africa, using 21 isozyme loci, 9 of them showing polymorphism.ResultsOutcrossing rates ranged from 1% to 9.5% (mean 3.4%), which classifies the wild cowpea breeding system as primarily selfing, though rare outcrossing events were detected in each population studied. Furthermore, the analyses of both the genetic structure of populations and the relationships between the wild and domesticated groups suggest possibilities of gene flow that are corroborated by field observations.ConclusionsAs expected in a predominantly inbred breeding system, wild cowpea shows high levels of genetic differentiation and low levels of genetic diversity within populations. Gene flow from domesticated to wild cowpea does occur, although the lack of strong genetic swamping and modified seed morphology in the wild populations suggest that these introgressions should be rare.
Hashimoto’s encephalopathy cases: Chinese experience
Authors: Tang Yi , Xing Yi , Lin Michael T , Zhang Jin , Jia Jianping 
Published: July 2012

Abstract

Background
Hashimoto’s encephalopathy is a poorly understood syndrome consisting of heterogeneous neurological symptoms and high serum antithyroid antibody titers, typically responding to steroids. More clinical series studies are required to characterize the clinical, laboratory and imaging features, and outcomes, especially in the Chinese population.

Methods
We analyzed the clinical, laboratory, and imaging features and outcomes of thirteen consecutive patients with Hashimoto’s encephalopathy diagnosed in Xuan Wu Hospital, Beijing from 2005 to 2010 retrospectively.

Results
Cognitive impairment (84.6%) and psychiatric symptoms (38.5%) were the most frequent symptoms. Seizures (30.8%) and myoclonus (7.7%) were less common than previously described. Three (23.1%) patients showed abnormal signals in hippocampus or temporal lobe, which were believed related to their memory disorders or seizures. MRI changes showed resolution paralleling clinical improvement in one patient. Among eight patients who received steroid therapy, five patients recovered, one patient improved with residual deficits, and two patients relapsed or had no effect. Among five non-steroid treated patients, three patients experienced stable remission with antiepileptic drugs or general neurotrophic therapy, and two patients experienced continuous deterioration.

Conclusions
Most patients with Hashimoto’s encephalopathy showed good response to steroids. Some patients improved without steroid therapy. Considering its reversible course, we recommend that Hashimoto’s encephalopathy should always be in the differential diagnosis while evaluating disorders of the central nervous system.
Optimization and comparison of knockdown efficacy between polymerase II expressed shRNA and artificial miRNA targeting luciferase and Apolipoprotein B100
Authors: Maczuga Piotr , Koornneef Annemart , Borel Florie , Petry Harald , van Deventer Sander , Ritsema Tita , Konstantinova Pavlina 
Published: July 2012

Abstract

Background
Controlling and limiting the expression of short hairpin RNA (shRNA) by using constitutive or tissue-specific polymerase II (pol II) expression can be a promising strategy to avoid RNAi toxicity. However, to date detailed studies on requirements for effective pol II shRNA expression and processing are not available. We investigated the optimal structural configuration of shRNA molecules, namely: hairpin location, stem length and termination signal required for effective pol II expression and compared it with an alternative strategy of avoiding toxicity by using artificial microRNA (miRNA) scaffolds.

Results
Highly effective shRNAs targeting luciferase (shLuc) or Apolipoprotein B100 (shApoB1 and shApoB2) were placed under the control of the pol II CMV promoter and expressed at +5 or +6 nucleotides (nt) with reference to the transcription start site (TSS). Different transcription termination signals (TTS), namely minimal polyadenylation (pA), poly T (T5) and U1 were also used. All pol II- expressed shRNA variants induced mild inhibition of Luciferase reporters carrying specific targets and none of them showed comparable efficacy to their polymerase III-expressed H1-shRNA controls, regardless of hairpin position and termination signal used. Extending hairpin stem length from 20 basepairs (bp) to 21, 25 or 29 bp yielded only slight improvement in the overall efficacy. When shLuc, shApoB1 and shApoB2 were placed in an artificial miRNA scaffold, two out of three were as potent as the H1-shRNA controls. Quantification of small interfering RNA (siRNA) molecules showed that the artificial miRNA constructs expressed less molecules than H1-shRNAs and that CMV-shRNA expressed the lowest amount of siRNA molecules suggesting that RNAi processing in this case is least effective. Furthermore, CMV-miApoB1 and CMV-miApoB2 were as effective as the corresponding H1-shApoB1 and H1-shApoB2 in inhibiting endogenous ApoB mRNA.

Conclusion
Our results demonstrate that artificial miRNA have a better efficacy profile than shRNA expressed either from H1 or CMV promoter and will be used in the future for RNAi therapeutic development.
Immunological response in mice bearing LM3 breast tumor undergoing Pulchellin treatment
Authors: de Matos Djamile Cordeiro , de Ribeiro Lívia Carolina Abreu , Tansini Aline , Ferreira Lucas Souza , Placeres Marisa Campos Polesi , Colombo Lucas Luis , Carlos Iracilda Zeppone 
Published: July 2012

Abstract

Background
Ribosome-inactivating proteins (RIP) have been studied in the search for toxins that could be used as immunotoxins for cancer treatment. Pulchellin, a type 2 RIP, is suggested to induce immune responses that have a role in controlling cancer.

Methods
The percentage of dendritic cells and CD4+ and CD8+ T cells in the spleen (flow cytometry), cytokines’ release by PECs and splenocytes (ELISA) and nitric oxide production by PECs (Griess assay) were determined from tumor-bearing mice injected intratumorally with 0.1 ml of pulchellin at 0.75 μg/kg of body weight. Statistical analysis was performed by one-way ANOVA with Tukey’s post hoc test.

Results
Pulchellin-treated mice showed significant immune system activation, characterized by increased release of IFN-γ and Th2 cytokines (IL-4 and IL-10), while IL-6 and TGF-β levels were decreased. There was also an increase in macrophage’s activation, as denoted by the higher percentage of macrophages expressing adhesion and costimulatory molecules (CD54 and CD80, respectively).

Conclusions
Our results suggest that pulchellin is promising as an adjuvant in breast cancer treatment.
Effectiveness of interventions for hypertension care in the community – a meta-analysis of controlled studies in China
Authors: Lu Zuxun , Cao Shiyi , Chai Yun , Liang Yuan , Bachmann Max , Suhrcke Marc , Song Fujian 
Published: July 2012

Abstract

Background
Hypertension is a serious public health problem in China and in other developing countries. Our aim is to conduct a systematic review of studies on the effectiveness of community interventions for hypertension management in China.

Methods
China National Knowledge Infrastructure, PubMed, and references of retrieved articles were searched to identify randomised or quasi-randomised controlled studies that evaluated community hypertension care in mainland China. One reviewer extracted and a second reviewer checked data from the included studies.

Results
We included 94 studies, 93 of which were in Chinese language, that evaluated the following interventions: health education, improved monitoring, family-support, self-management, healthcare management changes and training of providers. The study quality was generally poor, with high risk of biased outcome reporting and significant heterogeneity between studies. When reported, the vast majority of the included studies reported statistically significantly improved outcomes in the intervention group. By assuming zero treatment effects for missing outcomes, the weighted reduction in the intervention group was 6∙9 (95% CI: 4∙9 to 8∙9) mm Hg for systolic BP, and 3∙8 (95% CI: 2∙6 to 5∙0) mm Hg for diastolic BP. Exploratory subgroup analyses found no significant differences between different interventions.

Conclusions
After taking account of possible reporting biases, a wide range of community interventions for hypertension care remain effective. The findings have implications for China and other low and middle income countries facing similar challenges. Because of significant heterogeneity and high risk of bias in the available studies, further well designed studies should be conducted in China to provide high quality evidence to inform policy decisions on hypertension control.
Alterations of specific biomarkers of metabolic pathways in vascular tree from patients with Type 2 diabetes
Authors: Rosa Bernal-Lopez M , Vicenta Llorente-Cortes , Victor Gomez-Carrillo , Dolores Lopez-Carmona , Fernando Calleja , Ricardo Gomez-Huelgas , Lina Badimon , J Tinahones Francisco 
Published: July 2012

Abstract
The aims of this study were to check whether different biomarkers of inflammatory, apoptotic, immunological or lipid pathways had altered their expression in the occluded popliteal artery (OPA) compared with the internal mammary artery (IMA) and femoral vein (FV) and to examine whether glycemic control influenced the expression of these genes. The study included 20 patients with advanced atherosclerosis and type 2 diabetes mellitus, 15 of whom had peripheral arterial occlusive disease (PAOD), from whom samples of OPA and FV were collected. PAOD patients were classified based on their HbA1c as well (HbA1c ≤ 6.5) or poorly (HbA1c > 6.5) controlled patients. Controls for arteries without atherosclerosis comprised 5 IMA from patients with ischemic cardiomyopathy (ICM). mRNA, protein expression and histological studies were analyzed in IMA, OPA and FV. After analyzing 46 genes, OPA showed higher expression levels than IMA or FV for genes involved in thrombosis (F3), apoptosis (MMP2, MMP9, TIMP1 and TIM3), lipid metabolism (LRP1 and NDUFA), immune response (TLR2) and monocytes adhesion (CD83). Remarkably, MMP-9 expression was lower in OPA from well-controlled patients. In FV from diabetic patients with HbA1c ≤6.5, gene expression levels of BCL2, CDKN1A, COX2, NDUFA and SREBP2 were higher than in FV from those with HbA1c >6.5.
The atherosclerotic process in OPA from diabetic patients was associated with high expression levels of inflammatory, lipid metabolism and apoptotic biomarkers. The degree of glycemic control was associated with gene expression markers of apoptosis, lipid metabolism and antioxidants in FV. However, the effect of glycemic control on pro-atherosclerotic gene expression was very low in arteries with established atherosclerosis.