bluuebunny/crossref_metadata_2025 huggingface dataset:
Matter, politics and the sacred: insurgent ecologies of citizenship
Authors: Latta Alex
Published: August 2013

In light of recent explorations into the interface between human agency and the agentic qualities of matter, the article revisits Michele Serres’ notion of a natural contract to explore the relationships between materiality, environmental politics and citizenship. In a break from conventional renderings of environmental citizenship, the article argues that nature enters into politics alongside human subjects, through insurgent socio-ecological assemblages. In a case study of the 2008 Ecuadorian constitution, with its organizing principle of buen vivir and provisions enshrining the rights of nature, the idea of a natural contract proves a useful heuristic device for probing the political intertwining of human and nonhuman. At the same time, it falls short in characterizing the dynamic socionatural insurgencies that transgress dominant orders and perform alternate modes of being, ultimately leading to such things as formal constitutional change. Moreover, the secular contractual language of the Ecuadorian constitution tends to efface the spiritual content of the indigenous cosmovisions that significantly inform its principles. In light of this, the second part of the analysis probes the way human actors attach meaning to their involvement in socionatural insurgence, with an emphasis on the sacred as an important and often overlooked dimension of political-ecological struggle. Taking the Latin American movement for water justice as its empirical referent, the article locates the spiritual dimension as a vital ontological and discursive bridge facilitating human actors’ embodied engagements with their ecological surroundings. In this way the sacred makes key contributions to assembling human and more-than-human elements within the insurgent ecologies of citizenship.
Current Update on the Status of Totally Percutaneous Aneurysm Repair
Authors: Mousa Albeir Y. , Abu-Halimah Shadi , Nanjundappa Aravinda , AbuRahma Ali F. , Richmond Bryan K.
Published: August 2013

The evolution of minimally invasive procedures to treat aortic aneurysms has expanded to include access interventions as well. Traditionally, groin exposures have been the standard approach for common femoral artery exposure with open cutdown; however, inherent and related complications to that approach have paved the road to the percutaneous approach. Current available evidence from the literature supports the feasibility and the safety of percutaneous endovascular aneurysm repair (PEVAR); however, predictors of success are not well defined. We should examine all available studies (both prospective and retrospective) in order to draw a conclusion and evidence-based outcome for selecting patients who would benefit the most from PEVAR.
Sumatriptan/naproxen sodium combination versus its components administered concomitantly for the acute treatment of migraine: a pragmatic, crossover, open-label outcomes study
Authors: Landy Stephen , Hoagland Rebecca , Hoagland Dakota , Saiers Jane , Reuss Gena
Published: August 2013

Objective:

Efficacy and tolerability profiles of Treximet [sumatriptan/naproxen sodium combination tablet (SNC)] have been established in clinical trials but have to date been virtually unstudied in pragmatic research. The primary objective of this study was to compare the overall satisfaction of SNC to its monotherapy components, S/N [one 100 mg Imitrex tablet (S) and two Aleve (naproxen sodium) 220 mg tablets, total dose 440 mg (N)] administered concomitantly using the Patient Perception of Migraine Questionnaire –Revised (PPMQ-R).

Methods:

Adults with migraine ( n = 50) without ‘medication overuse headache’ were treated for up to 18 migraine attacks per 3-month study period with study medication; SNC during one study period and S/N during the other study period. For all endpoints, differences between treatments were compared with paired t tests.

Results:

The percentage of patients reporting satisfied/very satisfied for Overall Satisfaction of SNC versus S/N (primary endpoint) was 85% versus 72% respectively ( p = 0.054). For Overall Effectiveness, the results were 82% for SNC versus 73% for S/N ( p = 0.159); and for Overall Side Effects the results were 86% for SNC versus 69% for S/N ( p = 0.005). Mean PPMQ-R scores reflect greater satisfaction with SNC than S/N for Total score and for each of four subscales. The difference between SNC and S/N was significant for the Ease of Use subscale ( p = 0.004) and met the criterion of being clinically meaningful for both the Total score and Ease of Use. SNC did not differ from S/N with respect to pain-free response 2 h post dose, pain relief 2 h post dose, sustained 24 h pain-free response, or sustained 24 h pain relief.

Conclusion:

Although the primary endpoint only just failed, the results of this pragmatic outcomes study demonstrate SNC to have benefits over its concomitantly administered components in the acute treatment of migraine.
Relieving the Burdens of Secrecy
Authors: Slepian Michael L. , Masicampo E. J. , Ambady Nalini
Published: August 2013

Recent work demonstrates that harboring secrets influences perceptual judgments and actions. Individuals carrying secrets make judgments consistent with the experience of being weighed down, such as judging a hill as steeper and judging distances to be farther. In the present article, two studies examined whether revealing a secret would relieve the burden of secrecy. Relative to a control condition, thinking about a secret led to the judgments of increased hill slant, whereas revealing a secret eliminated that effect (Study 1). Additionally, relative to a control condition, thinking about a secret led to judgments of increased distance, and again, revealing a secret eliminated that effect (Study 2). Sharing secrets with others might relieve the perceived physical burden from secrecy.
A reliable method for intracranial electrode implantation and chronic electrical stimulation in the mouse brain
Authors: Jeffrey Melanie , Lang Min , Gane Jonathan , Wu Chiping , Burnham W McIntyre , Zhang Liang
Published: August 2013

Background

Electrical stimulation of brain structures has been widely used in rodent models for kindling or modeling deep brain stimulation used clinically. This requires surgical implantation of intracranial electrodes and subsequent chronic stimulation in individual animals for several weeks. Anchoring screws and dental acrylic have long been used to secure implanted intracranial electrodes in rats. However, such an approach is limited when carried out in mouse models as the thin mouse skull may not be strong enough to accommodate the anchoring screws. We describe here a screw-free, glue-based method for implanting bipolar stimulating electrodes in the mouse brain and validate this method in a mouse model of hippocampal electrical kindling.

Methods

Male C57 black mice (initial ages of 6–8 months) were used in the present experiments. Bipolar electrodes were implanted bilaterally in the hippocampal CA3 area for electrical stimulation and electroencephalographic recordings. The electrodes were secured onto the skull via glue and dental acrylic but without anchoring screws. A daily stimulation protocol was used to induce electrographic discharges and motor seizures. The locations of implanted electrodes were verified by hippocampal electrographic activities and later histological assessments.

Results

Using the glue-based implantation method, we implanted bilateral bipolar electrodes in 25 mice. Electrographic discharges and motor seizures were successfully induced via hippocampal electrical kindling. Importantly, no animal encountered infection in the implanted area or a loss of implanted electrodes after 4–6 months of repetitive stimulation/recording.

Conclusion

We suggest that the glue-based, screw-free method is reliable for chronic brain stimulation and high-quality electroencephalographic recordings in mice. The technical aspects described this study may help future studies in mouse models.
A receptor-like kinase gene (GbRLK) from Gossypium barbadense enhances salinity and drought-stress tolerance in Arabidopsis
Authors: Zhao Jun , Gao Yulong , Zhang Zhiyuan , Chen Tianzi , Guo Wangzhen , Zhang Tianzhen
Published: August 2013

Background

Cotton (Gossypiumspp.) is widely cultivated due to the important economic value of its fiber. However, extreme environmental degradation impedes cotton growth and production. Receptor-like kinase (RLK) proteins play important roles in signal transduction and participate in a diverse range of processes in response to plant hormones and environmental cues. Here, we introduced an RLK gene (GbRLK) from cotton intoArabidopsisand investigated its role in imparting abiotic stress tolerance.

Results

GbRLKtranscription was induced by exogenously supplied abscisic acid (ABA), salicylic acid, methyl jasmonate, mock drought conditions and high salinity. We cloned the promoter sequence of this geneviaself-formed adaptor PCR. Sequence analysis revealed that the promoter region contains manycis-acting stress-responsive elements such as ABRE, W-Box, MYB-core, W-Box core, TCA-element and others. We constructed a vector containing a 1,890-bp sequence in the 5′ region upstream of the initiation codon of this promoter and transformed it intoArabidopsis thaliana. GUS histochemical staining analysis showed thatGbRLKwas expressed mainly in leaf veins, petioles and roots of transgenicArabidopsis, but not in the cotyledons or root hairs.GbRLKpromoter activity was induced by ABA, PEG, NaCl andVerticillium dahliae.TransgenicArabidopsiswith constitutive overexpression ofGbRLKexhibited a reduced rate of water loss in leavesin vitro, along with improved salinity and drought tolerance and increased sensitivity to ABA compared with non-transgenic Col-0Arabidopsis. Expression analysis of stress-responsive genes inGbRLK Arabidopsisrevealed that there was increased expression of genes involved in the ABA-dependent signaling pathway (AtRD20, AtRD22andAtRD26) and antioxidant genes (AtCAT1, AtCCS, AtCSD2andAtCSD1) but not ion transporter genes (AtNHX1, AtSOS1).

Conclusions

GbRLKis involved in the drought and high salinity stresses pathway by activating or participating in the ABA signaling pathway. Overexpression ofGbRLKmay improve stress tolerance by regulating stress-responsive genes to reduce water loss.GbRLKmay be employed in the genetic engineering of novel cotton cultivars in the future. Further studying ofGbRLKwill help elucidate abiotic stress signaling pathways.
Sequencing-based variant detection in the polyploid crop oilseed rape
Authors: Wells Rachel , Trick Martin , Fraser Fiona , Soumpourou Eleni , Clissold Leah , Morgan Colin , Pauquet Jérôme , Bancroft Ian
Published: August 2013

Background

The detection and exploitation of genetic variation underpins crop improvement. However, the polyploid nature of the genomes of many of our most important crops represents a barrier, particularly for the analysis of variation within genes. To overcome this, we aimed to develop methodologies based on amplicon sequencing that involve the incorporation of barcoded amplification tags (BATs) into PCR products.

Results

A protocol was developed to tag PCR products with 5’ 6-base oligonucleotide barcode extensions before pooling for sequencing library production using standard Illumina adapters. A computational method was developed for the de-convolution of products and the robust detection and scoring of sequence variants. Using this methodology, amplicons targeted to gene sequences were screened across a B. napus mapping population and the resulting allele scoring strings for 24 markers linkage mapped to the expected regions of the genome. Furthermore, using one-dimensional 8-fold pooling, 4608 lines of a B. napus mutation population were screened for induced mutations in a locus-specific amplicon (an orthologue of GL2.b) and mixed product of three co-amplified loci (orthologues of FAD2), identifying 10 and 41 mutants respectively.

Conclusions

The utilisation of barcode tags to de-convolute pooled PCR products in multiplexed, variation screening via Illumina sequencing provides a cost effective method for SNP genotyping and mutation detection and, potentially, markers for causative changes, even in polyploid species. Combining this approach with existing Illumina multiplexing workflows allows the analysis of thousands of lines cheaply and efficiently in a single sequencing run with minimal library production costs.
Comparison of the risk factors effects between two populations: two alternative approaches illustrated by the analysis of first and second kidney transplant recipients
Authors: Trébern-Launay Katy , Giral Magali , Dantal Jacques , Foucher Yohann
Published: August 2013

Background

Whereas the prognosis of second kidney transplant recipients (STR) compared to the first ones has been frequently analyzed, no study has addressed the issue of comparing the risk factor effects on graft failure between both groups.

Methods

Here, we propose two alternative strategies to study the heterogeneity of risk factors between two groups of patients:(i) a multiplicative-regression model for relative survival (MRS) and(ii) a stratified Cox model (SCM) specifying the graft rank as strata and assuming subvectors of the explicatives variables. These developments were motivated by the analysis of factors associated with time to graft failure (return-to-dialysis or patient death) in second kidney transplant recipients (STR) compared to the first ones. Estimation of the parameters was based on partial likelihood maximization. Monte-Carlo simulations associated with bootstrap re-sampling was performed to calculate the standard deviations for the MRS.

Results

We demonstrate, for the first time in renal transplantation, that:(i) male donor gender is a specific risk factor for STR,(ii) the adverse effect of recipient age is enhanced for STR and(iii) the graft failure risk related to donor age is attenuated for STR.

Conclusion

While the traditional Cox model did not provide original results based on the renal transplantation literature, the proposed relative and stratified models revealed new findings that are useful for clinicians. These methodologies may be of interest in other medical fields when the principal objective is the comparison of risk factors between two populations.
The association between cecal insertion time and colorectal neoplasm detection
Authors: Yang Moon Hee , Cho Juhee , Rampal Sanjay , Choi Eun Kyung , Choi Yoon-Ho , Lee Jun Haeng , Kim Young-Ho , Chang Dong Kyung , Rhee Poong-Lyul , Kim Jae J , Guallar Eliseo , Rhee Jong Chul , Son Hee Jung
Published: August 2013

Background

Information on the impact of cecal insertion time on colorectal neoplasm detection is limited. Our objective was to determine the association between cecal insertion time and colorectal neoplasm detection rate in colonoscopy screening.

Methods

We performed a cross-sectional study of 12,679 consecutive subjects aged 40–79 years undergoing screening colonoscopy in routine health check-ups at the Center for Health Promotion of the Samsung Medical Center from December 2007 to June 2009. Fixed effects logistic regression conditioning on colonoscopist was used to eliminate confounding due to differences in technical ability and other characteristics across colonoscopists.

Results

The mean cecal insertion time was 5.9 (SD, 4.4 minutes). We identified 4,249 (33.5%) participants with colorectal neoplasms, of whom 1,956 had small single adenomas (<5 mm), 595 had medium single adenomas (5–9 mm), and 1,699 had multiple adenomas or advanced colorectal neoplasms. The overall rates of colorectal neoplasm detection by quartiles of cecal insertion time were 36.8%, 33.4%, 32.7%, and 31.0%, respectively (p trend <0.001).The odds for small single colorectal adenoma detection was 16% lower (adjusted OR 0.84; 95% CI 0.71 to 0.99) in the fourth compared to the first quartile of insertion time (p trend 0.005). Insertion time was not associated with the detection rate of single adenomas ≥5 mm, multiple adenomas or advanced colorectal neoplasms.

Conclusion

Shorter insertion times were associated with increased rates of detection of small colorectal adenomas <5 mm. Cecal insertion time may be clinically relevant as missed small colorectal adenomas may progress to more advanced lesions.
Dietary quality in a sample of adults with type 2 diabetes mellitus in Ireland; a cross-sectional case control study
Authors: Murray Alison E , McMorrow Aoibheann M , O’Connor Eamonn , Kiely Catherine , Mac Ananey Oscar , O'Shea Donal , Egaña Mikel , Lithander Fiona E
Published: August 2013

Background

A number of dietary quality indices (DQIs) have been developed to assess the quality of dietary intake. Analysis of the intake of individual nutrients does not reflect the complexity of dietary behaviours and their association with health and disease. The aim of this study was to determine the dietary quality of individuals with type 2 diabetes mellitus (T2DM) using a variety of validated DQIs.

Methods

In this cross-sectional analysis of 111 Caucasian adults, 65 cases with T2DM were recruited from the Diabetes Day Care Services of St. Columcille’s and St. Vincent’s Hospitals, Dublin, Ireland. Forty-six controls did not have T2DM and were recruited from the general population. Data from 3-day estimated diet diaries were used to calculate 4 DQIs.

Results

Participants with T2DM had a significantly lower score for consumption of a Mediterranean dietary pattern compared to the control group, measured using the Mediterranean Diet Score (Range 0–9) and the Alternate Mediterranean Diet Score (Range 0–9) (mean ± SD) (3.4 ± 1.3 vs 4.8 ± 1.8, P < 0.001 and 3.3 ± 1.5 vs 4.2 ± 1.8, P = 0.02 respectively). Participants with T2DM also had lower dietary quality than the control population as assessed by the Healthy Diet Indicator (Range 0–9) (T2DM; 2.6 ± 2.3, control; 3.3 ± 1.1, P = 0.001). No differences between the two groups were found when dietary quality was assessed using the Alternate Healthy Eating Index. Micronutrient intake was assessed using the Micronutrient Adequacy Score (Range 0–8) and participants with T2DM had a significantly lower score than the control group (T2DM; 1.6 ± 1.4, control; 2.3 ± 1.4, P = 0.009). When individual nutrient intakes were assessed, no significant differences were observed in macronutrient intake.

Conclusion

Overall, these findings demonstrate that T2DM was associated with a lower score when dietary quality was assessed using a number of validated indices.
Combined p21-activated kinase and farnesyltransferase inhibitor treatment exhibits enhanced anti-proliferative activity on melanoma, colon and lung cancer cell lines
Authors: Porcu Giampiero , Parsons Ainslie B , Di Giandomenico Daniele , Lucisano Giuseppe , Mosca Maria Giovanna , Boone Charles , Ragnini-Wilson Antonella
Published: August 2013

Background

Farnesyltransferase inhibitors (FTIs) are anticancer agents with a spectrum of activity in Ras-dependent and independent tumor cellular and xenograph models. How inhibition of protein farnesylation by FTIs results in reduced cancer cell proliferation is poorly understood due to the multiplicity of potential FTase targets. The low toxicity and oral availability of FTIs led to their introduction into clinical trials for the treatment of breast cancer, hematopoietic malignancy, advanced solid tumor and pancreatic cancer treatment, and Hutchinson-Gilford Progeria Syndrome. Although their efficacy in combinatorial therapies with conventional anticancer treatment for myeloid malignancy and solid tumors is promising, the overall results of clinical tests are far below expectations. Further exploitation of FTIs in the clinic will strongly rely on understanding how these drugs affect global cellular activity.

Methods

Using FTase inhibitor I and genome-wide chemical profiling of the yeast barcoded deletion strain collection, we identified genes whose inactivation increases the antiproliferative action of this FTI peptidomimetic. The main findings were validated in a panel of cancer cell lines using FTI-277 in proliferation and biochemical assays paralleled by multiparametric image-based analyses.

Results

ABC transporter Pdr10 or p-21 activated kinase (PAK) gene deletion increases the antiproliferative action of FTase inhibitor I in yeast cells. Consistent with this, enhanced inhibition of cell proliferation by combining group I PAK inhibition, using IPA3, with FTI-277 was observed in melanoma (A375MM), lung (A549) and colon (HT29), but not in epithelial (HeLa) or breast (MCF7), cancer cell lines. Both HeLa and A375MM cells show changes in the nuclear localization of group 1 PAKs in response to FTI-277, but up-regulation of PAK protein levels is observed only in HeLa cells.

Conclusions

Our data support the view that group I PAKs are part of a pro-survival pathway activated by FTI treatment, and group I PAK inactivation potentiates the anti-proliferative action of FTIs in yeast as well as in cancer cells. These findings open new perspectives for the use of FTIs in combinatorial strategies with PAK inhibitors in melanoma, lung and colon malignancy.
Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells
Authors: Di Cello Francescopaolo , Flowers V Lynn , Li Huili , Vecchio-Pagán Briana , Gordon Brent , Harbom Kirsten , Shin James , Beaty Robert , Wang Wei , Brayton Cory , Baylin Stephen B , Zahnow Cynthia A
Published: August 2013

Background

Recent epidemiological studies demonstrate that both active and involuntary exposure to tobacco smoke increase the risk of breast cancer. Little is known, however, about the molecular mechanisms by which continuous, long term exposure to tobacco smoke contributes to breast carcinogenesis because most previous studies have focused on short term treatment models. In this work we have set out to investigate the progressive transforming effects of tobacco smoke on non-tumorigenic mammary epithelial cells and breast cancer cells using in vitro and in vivo models of chronic cigarette smoke exposure.

Results

We show that both non-tumorigenic (MCF 10A, MCF-12A) and tumorigenic (MCF7) breast epithelial cells exposed to cigarette smoke acquire mesenchymal properties such as fibroblastoid morphology, increased anchorage-independent growth, and increased motility and invasiveness. Moreover, transplantation experiments in mice demonstrate that treatment with cigarette smoke extract renders MCF 10A cells more capable to survive and colonize the mammary ducts and MCF7 cells more prone to metastasize from a subcutaneous injection site, independent of cigarette smoke effects on the host and stromal environment. The extent of transformation and the resulting phenotype thus appear to be associated with the differentiation state of the cells at the time of exposure. Analysis by flow cytometry showed that treatment with CSE leads to the emergence of a CD44hi/CD24low population in MCF 10A cells and of CD44+ and CD49f + MCF7 cells, indicating that cigarette smoke causes the emergence of cell populations bearing markers of self-renewing stem-like cells. The phenotypical alterations induced by cigarette smoke are accompanied by numerous changes in gene expression that are associated with epithelial to mesenchymal transition and tumorigenesis.

Conclusions

Our results indicate that exposure to cigarette smoke leads to a more aggressive and transformed phenotype in human mammary epithelial cells and that the differentiation state of the cell at the time of exposure may be an important determinant in the phenotype of the final transformed state.
A rare case of bilateral sequential spermatocytic seminoma
Authors: Xu Ning , Li Fubiao , Tian Runhui , Shao Mingming , Liu Lingyun , Guo Kaimin
Published: August 2013

Spermatocytic seminoma (SS) is a rare testicular neoplasm characterized by a palpable, painless, slowly enlarging mass in the testis. Even more rare is a synchronous bilateral presentation. Only eight cases of bilateral SS have been reported in the literature, of which three cases were present with synchronous testis enlargement, and five were sequential. Here, we report an additional case of synchronous bilateral SS and present a comprehensive relevant literature review concerning clinical features, histopathology, and treatment.
Inverse spectral problems for non-selfadjoint second-order differential operators with Dirichlet boundary conditions
Authors: Buterin Sergey A , Shieh Chung-Tsun , Yurko Vjacheslav A
Published: August 2013

We study the inverse problem for non-selfadjoint Sturm-Liouville operators on a finite interval with possibly multiple spectra. We prove the uniqueness theorem and obtain constructive procedures for solving the inverse problem along with the necessary and sufficient conditions of its solvability and also prove the stability of the solution.

MSC:34A55, 34B24, 47E05.
Identification of novel key amino acids at the interface of the transmembrane domains of human BST-2 and HIV-1 Vpu
Authors: Pang Xiaojing , Hu Siqi , Li Jian , Xu Fengwen , Mei Shan , Zhou Jinming , Cen Shan , Jin Qi , Guo Fei
Published: August 2013

Background

BST-2 (bone marrow stromal cell antigen 2) is an interferon-inducible protein that inhibits virus release by tethering viral particles to the cell surface. This antiviral activity of BST-2 is antagonized by HIV-1 accessory protein Vpu. Vpu physically interacts with BST-2 through their mutual transmembrane (TM) domains. In this study, we utilized the BRET assay and molecular dynamics (MD) simulation method to further characterize the interaction of BST-2 and Vpu.

Results

Amino acids I34, L37, P40 and L41 in the TM domain of BST-2, and L11, A18 and W22 in the TM domain of Vpu were identified to be critical for the interaction between BST-2 and Vpu. The residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu were shown, for the first time, to be important for their interaction. Furthermore, triple-amino-acid substitutions, 14–16 (AII to VAA) and 26–28 (IIE to AAA) in Vpu TM, not the single-residue mutation, profoundly disrupted BST-2/Vpu interaction. The results of MD simulation revealed significant conformational changes of the BST-2/Vpu complex as a result of mutating P40 of BST-2 and L11, 14–16 (AII to VAA) and 26–28 (IIE to AAA) of Vpu. In addition, disrupting the interaction between BST-2 and Vpu rendered BST-2 resistant to Vpu antagonization.

Conclusions

Through use of the BRET assay, we identified novel key residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu that are important for their interaction. These results add new insights into the molecular mechanism behind BST-2 antagonization by HIV-1 Vpu.
What supports do health system organizations have in place to facilitate evidence-informed decision-making? a qualitative study
Authors: Ellen Moriah E , Léon Gregory , Bouchard Gisèle , Lavis John N , Ouimet Mathieu , Grimshaw Jeremy M
Published: August 2013

Background

Decisions regarding health systems are sometimes made without the input of timely and reliable evidence, leading to less than optimal health outcomes. Healthcare organizations can implement tools and infrastructures to support the use of research evidence to inform decision-making.

Objectives

The purpose of this study was to profile the supports and instruments (i.e., programs, interventions, instruments or tools) that healthcare organizations currently have in place and which ones were perceived to facilitate evidence-informed decision-making.

Methods

In-depth semi-structured telephone interviews were conducted with individuals in three different types of positions (i.e., a senior management team member, a library manager, and a ‘knowledge broker’) in three types of healthcare organizations (i.e., regional health authorities, hospitals and primary care practices) in two Canadian provinces (i.e., Ontario and Quebec). The interviews were taped, transcribed, and then analyzed thematically using NVivo 9 qualitative data analysis software.

Results

A total of 57 interviews were conducted in 25 organizations in Ontario and Quebec. The main findings suggest that, for the healthcare organizations that participated in this study, the following supports facilitate evidence-informed decision-making: facilitating roles that actively promote research use within the organization; establishing ties to researchers and opinion leaders outside the organization; a technical infrastructure that provides access to research evidence, such as databases; and provision and participation in training programs to enhance staff’s capacity building.

Conclusions

This study identified the need for having a receptive climate, which laid the foundation for the implementation of other tangible initiatives and supported the use of research in decision-making. This study adds to the literature on organizational efforts that can increase the use of research evidence in decision-making. Some of the identified supports may increase the use of research evidence by decision-makers, which may then lead to more informed decisions, and hopefully to a strengthened health system and improved health.
Genotype-phenotype correlations in recessive RYR1-related myopathies
Authors: Amburgey Kimberly , Bailey Angela , Hwang Jean H , Tarnopolsky Mark A , Bonnemann Carsten G , Medne Livija , Mathews Katherine D , Collins James , Daube Jasper R , Wellman Gregory P , Callaghan Brian , Clarke Nigel F , Dowling James J
Published: August 2013

Background

RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed.

Methods

In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n = 14) and previously reported (n = 92) recessive RYR1 cases.

Results

Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non-hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore.

Conclusions

These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of genotype-phenotype associations in recessive RYR1-myopathies.
1q25.2-q31.3 Deletion in a female with mental retardation, clinodactyly, minor facial anomalies but no growth retardation
Authors: Hu Ping , Wang Yan , Meng Lu-lu , Qin Ling , Ma Ding-yuan , Yi Long , Xu Zheng-feng
Published: August 2013

The reports of 1q25-32 deletion cases are rare. We reported here an 11-year-old Chinese Han female with an interstitial 1q25 deletion displaying mental retardation, clinodactyly of the 5th finger and minor facial anomalies. Notably, the patient did not present growth retardation which is quite common in patients with 1q25-32 deletion encompassing LHX4. The heterozygous deletion in this patient was characterized as 46,XX,del(1)(q25.2-q31.3) with a length of 20.5 Mb according to SNP-array test results. STRP (Short Tandem Repeat Polymorphism) analysis of the family trio indicated the genomic abnormality was de novo with paternal origin. After a genotype-phenotype analysis, we proposed here the loss of a 3.1 Mb critical region including 24 genes within 1q25.2 (chr1:174.5-177.6 Mb, build 36) may account for the mental retardation in patients with 1q25-32 deletion.
Identification and systematic annotation of tissue-specific differentially methylated regions using the Illumina 450k array
Authors: Slieker Roderick C , Bos Steffan D , Goeman Jelle J , Bovée Judith VMG , Talens Rudolf P , van der Breggen Ruud , Suchiman H Eka D , Lameijer Eric-Wubbo , Putter Hein , van den Akker Erik B , Zhang Yanju , Jukema J Wouter , Slagboom P Eline , Meulenbelt Ingrid , Heijmans Bastiaan T
Published: August 2013

Background

DNA methylation has been recognized as a key mechanism in cell differentiation. Various studies have compared tissues to characterize epigenetically regulated genomic regions, but due to differences in study design and focus there still is no consensus as to the annotation of genomic regions predominantly involved in tissue-specific methylation. We used a new algorithm to identify and annotate tissue-specific differentially methylated regions (tDMRs) from Illumina 450k chip data for four peripheral tissues (blood, saliva, buccal swabs and hair follicles) and six internal tissues (liver, muscle, pancreas, subcutaneous fat, omentum and spleen with matched blood samples).

Results

The majority of tDMRs, in both relative and absolute terms, occurred in CpG-poor regions. Further analysis revealed that these regions were associated with alternative transcription events (alternative first exons, mutually exclusive exons and cassette exons). Only a minority of tDMRs mapped to gene-body CpG islands (13%) or CpG islands shores (25%) suggesting a less prominent role for these regions than indicated previously. Implementation of ENCODE annotations showed enrichment of tDMRs in DNase hypersensitive sites and transcription factor binding sites. Despite the predominance of tissue differences, inter-individual differences in DNA methylation in internal tissues were correlated with those for blood for a subset of CpG sites in a locus- and tissue-specific manner.

Conclusions

We conclude that tDMRs preferentially occur in CpG-poor regions and are associated with alternative transcription. Furthermore, our data suggest the utility of creating an atlas cataloguing variably methylated regions in internal tissues that correlate to DNA methylation measured in easy accessible peripheral tissues.
Behavioral profile of adults with Prader-Willi syndrome: correlations with individual and environmental variables
Authors: Jauregi Joseba , Laurier Virginie , Copet Pierre , Tauber Maithé , Thuilleaux Denise
Published: August 2013

Background

Maladaptive behavior has been reported as a phenotypical feature in Prader–Willi syndrome (PWS). It severely limits social adaptation and the quality of life of children and adults with the syndrome. Different factors have been linked with the intensity and form of these behavioral disturbances but there is no consensus about the cause. Consequently, there is still controversy regarding management strategies and there is a need for new data.

Methods

The behavior of 100 adults with PWS attending a dedicated center was assessed using the Developmental Behavior Checklist for Adults (DBC-A) and the PWS-specific Hyperphagia Questionnaire. The DBC-A was completed separately by trained caregivers at the center and relatives or caregivers in a natural setting. Genotype, gender, age, degree of obesity and cognitive impairment were analyzed as variables with a hypothetical influence on behavioral features.

Results

Patients showed a relatively high rate of behavioral disturbances other than hyperphagia. Disruptive and social relating were the highest scoring DBC-A subscales whereas anxiety/antisocial and self-absorbed were the lowest. When hospital caregiver and natural caregiver scores were compared, scores for the latter were higher for all subscales except for disruptive and anxiety/antisocial. These effects of institutional management were underlined. In the DBC-A, 22 items have descriptive indications of PWS behavior and were used for further comparisons and correlation analysis. In contrast to previous reports, rates of disturbed behavior were lower in patients with a deletion genotype. However, the behavioral profile was similar for both genotypes. No differences were found in any measurement when comparing type I and type II deletions. The other analyzed variables showed little relevance.

Conclusions

Significant rates of behavioral disorders were highlighted and their typology described in a large cohort of adults with PWS. The deletion genotype was related to a lower severity of symptoms. Some major behavioral problems, such as hyperphagia, may be well controlled if living circumstances are adapted to the specific requirements of individuals with PWS.
Production of ethanol from hemicellulose fraction of cocksfoot grass using pichia stipitis
Authors: Njoku Stephen Ikechukwu , Iversen Jens Asmus , Uellendahl Hinrich , Ahring Birgitte Kiær
Published: August 2013

Background

In this study, cocksfoot grass (Dactylis glomerata), an abundant lignocellulosic biomass was pretreated using different operational parameters using wet explosion (WEx) pretreatment for accessing the bioethanol potential of the hemicellulose fraction. Utilization of the hemicellulose liquid hydrolysate to ethanol is essential for economically feasible cellulosic ethanol processes. Fermentation of the separated hemicellulose liquid hydrolysates obtained after the WEx pretreatment was done by Pichia stipitis CBS 6054 (Scheffersomyces stipitis).

Results

The fermentation of the WEx liquid hydrolysate from the pretreatment at higher severity (180°C, 15 min, 87 psi oxygen and 190°C, 15 min, 0.2% sulfuric acid) was fully inhibited probable by the presence of higher concentrations of inhibitory compounds such as furfural, HMF and acetic acid. The ethanol yield among other WEx conditions was in the range of 89 to 158 mL/kg DM, with the highest yield (92% of theoretical maximum value) found for the lower pretreatment severity at 160°C, 15 min, 87 psi oxygen.

Conclusions

Our findings from this present study demonstrated that the release of hemicellulose sugars in the liquid hydrolysate is maximal when a lower pretreatment severity is applied. This is evident as the highest ethanol yields were found under the pretreatment conditions at lower severity.
Routine use of Staphylococcus aureus rapid diagnostic test in patients with suspected ventilator-associated pneumonia
Authors: Leone Marc , Malavieille François , Papazian Laurent , Meyssignac Bertrand , Cassir Nadim , Textoris Julien , Antonini François , La Scola Bernard , Martin Claude , Allaouchiche Bernard , Hraiech Sami ,   for the AzuRea Network
Published: August 2013

Introduction

In patients with ventilator-associated pneumonia (VAP), administration of an appropriate empirical antimicrobial treatment is associated with improved outcomes, leading to the prescription of broad-spectrum antibiotics, including a drug active against methicillin resistant Staphylococcus aureus (MRSA). In order to avoid the overuse of antibiotics, the present study aimed to evaluate the technical characteristics of a rapid diagnostic test (Cepheid Xpert assay) in patients with suspected VAP.

Methods

From June 2011 to June 2012, in patients with suspected VAP, a sample from the bronchialalveolar lavage (BAL) or miniBAL was tested in a point-of-care laboratory for a rapid diagnostic test of methicillin susceptible Staphylococcus aureus (MSSA) and MRSA. Then, the result was compared to the quantitative culture with a threshold at 104 colony-forming units per milliliter for bronchoalveolar lavage and 103 colony-forming units per milliliter for minibronchoalveolar lavage. The study was performed in three intensive care units at two institutions.

Results

Four hundred, twenty-two samples from 328 patients were analyzed. The culture of 6 (1.1%) and 28 (6.5%) samples were positive for MRSA and MSSA. The test was not interpretable in 41 (9.3%) patients. The negative predictive values of the rapid detection test were 99.7% (98.1 to 99.9%) and 99.8% (98.7 to 99.9%) for MSSA and MRSA, respectively.

Conclusion

The rapid diagnostic test is reliable in excluding the presence of MSSA and MRSA in the samples of patients with suspected VAP. Its utility should be regarded depending on the prevalence of MRSA.
Second Allograft for Hematologic Relapse of Acute Leukemia After First Allogeneic Stem-Cell Transplantation From Related and Unrelated Donors: The Role of Donor Change
Authors: Christopeit Maximilian , Kuss Oliver , Finke Jürgen , Bacher Ulrike , Beelen Dietrich Wilhelm , Bornhäuser Martin , Schwerdtfeger Rainer , Bethge Wolfgang Andreas , Basara Nadezda , Gramatzki Martin , Tischer Johanna , Kolb Hans-Jochem , Uharek Lutz , Meyer Ralf G. , Bunjes Donald , Scheid Christof , Martin Hans , Niederwieser Dietger , Kröger Nicolaus , Bertz Hartmut , Schrezenmeier Hubert , Schmid Christoph
Published: August 2013

Purpose

To evaluate the role of a second allogeneic hematopoietic stem-cell transplantation (HSCT2) given for relapsed acute leukemia (AL) after related or unrelated first hematopoietic stem-cell transplantation (HSCT1) and to analyze the role of donor change for HSCT2 in both settings.

Patients and Methods

We performed a retrospective registry study on 179 HSCT2s given for relapse after HSCT1 from matched related donors (n = 75) or unrelated donors (n = 104), using identical or alternative donors for HSCT2. Separate analyses were performed according to donor at HSCT1.

Results

Independent of donor, 74% of patients achieved complete remission after HSCT2, and half of these patients experienced relapse again. Overall survival (OS) at 2 years was 25% ± 4% (39% ± 7% after related HSCT2; 19% ± 4% after unrelated HSCT2). Long-term survivors were observed even after two unrelated HSCT2s. Multivariate analysis for OS from HSCT2 confirmed established risk factors (remission duration after HSCT1: hazard ratio [HR], 2.37; 95% CI, 1.61 to 3.46; P < .001; stage at HSCT2: HR, 0.53; 95% CI, 0.34 to 0.83; P = .006). Outcome of HSCT2 was better after related HSCT1 than after unrelated HSCT1 (2-year OS: 37% ± 6% v 16% ± 4%, respectively; HR, 0.68; 95% CI, 0.47 to 0.98; P = .042, multivariate Cox regression). After both related and unrelated HSCT1, selecting a new donor for HSCT2 did not result in a relevant improvement in OS compared with HSCT2 from the original donor; however, donor change was not detrimental either.

Conclusion

After relapse from allogeneic HSCT1, HSCT2 can induce 2-year OS in approximately 25% of patients. Unrelated HSCT2 is feasible after related and unrelated HSCT1. Donor change for HSCT2 is a valid option. However, a clear advantage in terms of OS could not be demonstrated.
Randomized Controlled Trial of Mindfulness-Based Cancer Recovery Versus Supportive Expressive Group Therapy for Distressed Survivors of Breast Cancer (MINDSET)
Authors: Carlson Linda E. , Doll Richard , Stephen Joanne , Faris Peter , Tamagawa Rie , Drysdale Elaine , Speca Michael
Published: August 2013

Purpose

To compare the efficacy of the following two empirically supported group interventions to help distressed survivors of breast cancer cope: mindfulness-based cancer recovery (MBCR) and supportive-expressive group therapy (SET).

Patients and Methods

This multisite, randomized controlled trial assigned 271 distressed survivors of stage I to III breast cancer to MBCR, SET, or a 1-day stress management control condition. MBCR focused on training in mindfulness meditation and gentle yoga, whereas SET focused on emotional expression and group support. Both intervention groups included 18 hours of professional contact. Measures were collected at baseline and after intervention by assessors blind to study condition. Primary outcome measures were mood and diurnal salivary cortisol slopes. Secondary outcomes were stress symptoms, quality of life, and social support.

Results

Using linear mixed-effects models, in intent-to-treat analyses, cortisol slopes were maintained over time in both SET (P = .002) and MBCR (P = .011) groups relative to the control group, whose cortisol slopes became flatter. Women in MBCR improved more over time on stress symptoms compared with women in both the SET (P = .009) and control (P = .024) groups. Per-protocol analyses showed greater improvements in the MBCR group in quality of life compared with the control group (P = .005) and in social support compared with the SET group (P = .012).

Conclusion

In the largest trial to date, MBCR was superior for improving stress levels, quality of life, and social support for distressed survivors of breast cancer. Both SET and MBCR also resulted in more normative diurnal cortisol profiles than the control condition. The clinical implications of this finding require further investigation.
Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma
Authors: Ascierto Paolo A. , Minor David , Ribas Antoni , Lebbe Celeste , O'Hagan Anne , Arya Niki , Guckert Mary , Schadendorf Dirk , Kefford Richard F. , Grob Jean-Jacques , Hamid Omid , Amaravadi Ravi , Simeone Ester , Wilhelm Tabea , Kim Kevin B. , Long Georgina V. , Martin Anne-Marie , Mazumdar Jolly , Goodman Vicki L. , Trefzer Uwe
Published: August 2013

Purpose

Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAFV600E/K mutation–positive metastatic melanoma (mut+ MM).

Patients and Methods

Histologically confirmed patients with stage IV BRAFV600E/K mut+ MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAFV600E mut+ MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome.

Results

Seventy-six patients with BRAFV600E and 16 patients with BRAFV600K mut+ MM were enrolled onto the study. In the BRAFV600E group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAFV600K mut+ MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAFV600E and BRAFV600K groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAFV600E mut+ MM patients.

Conclusion

Dabrafenib was well tolerated and clinically active in patients with BRAFV600E/K mut+ MM. cfDNA may be a useful prognostic and response marker in future studies.