bluuebunny/crossref_metadata_2025 huggingface dataset:
Does Student Research Require a Lower Standard of Ethical Scrutiny?
Authors: Humphreys Stephen J
Published: January 2012

Recognizing that students are fundamentally engaged in a process of learning and self-development, ethical review of sub-doctoral student research should be proportionate to that objective. A student's tutor has the pedagogical role and an ethics committee should not interfere with that relationship other than to seek to avoid harms unforeseen by either the student or tutor. Underpowered or other statistically or methodologically flawed sub-doctoral research should not however, in general, be regarded as ethically concerning. With the proviso that no subject is harmed the student can be allowed to learn such lessons as their mistakes may afford them.
Assessing Clinical Trial Informed Consent Comprehension in Non-Cognitively-Impaired Adults: A Systematic Review of Instruments
Authors: Buccini Laura D. , Iverson Don , Caputi Peter , Jones Caroline , Gho Sheridan
Published: January 2012

This systematic review identifies and critically evaluates instruments that have been developed to measure clinical trial informed consent comprehension in non-cognitively-impaired adults.

Literature searches were carried out on Medline (Ovid), PsycInfo, CINHAL, ERIC, ScienceDirect, and Cochrane Library for English language articles published between January 1980 and September 2008. Instruments were excluded if they focused on consent onto paediatric trials, the construct under study was primarily capacity or competency, or the instrument was developed specifically for psychiatric or cognitively-impaired populations. Instruments selected for review were evaluated against the following criteria: (1) method of item generation; (2) type and format of test items; (3) administration and interpretation of test results; and (4) psychometric properties.

Three instruments met our defined inclusion criteria: the Deaconess Informed Consent Comprehension Test (DICCT), the Quality of Informed Consent (QuIC) questionnaire and the Brief Informed Consent Protocol (BICEP). Each instrument varied in terms of content measured. Significantly, these are the first standardized instruments developed to assess comprehension in non-cognitively-impaired adults. Yet, each instrument had its own set of limitations such as the lack of generalizability and the absence of details pertaining to how test results should be used to guide clinical decision-making.

Standardized clinical trial informed consent comprehension assessments have been developed to identify gaps in research participants' understanding and ensure that respect for patient autonomy is satisfied.
Ethical Issues in Researching People with Mental Health Problems: Commentary
Authors: McGee Paula
Published: January 2012

This study appeared in full in the last issue of Research Ethics Review (2008; 4 (4): 160). DS is researching the experiences of black Caribbean and black African people who use mental health services. The mental healthcare organization serves a diverse catchment area and senior members of staff are keen to show that they are taking the views of black services users seriously. They have, therefore appointed DS to undertake a three-year research project about black people's experiences in the catchment area. DS is planning to survey statutory and voluntary organizations to map the services they provide and then use focus groups to ascertain the views and experiences of users and carers. The aim is to identify what they find most helpful, what is not helpful and how services could be improved to become more culturally-competent.
Research Ethics Committees and the Legality of the Protocol: A Rejoinder and a Challenge to the Department of Health
Authors: Roy-Toole Christopher
Published: January 2012

This article is a response to the letter from the Department of Health that was published in the previous edition of the Research Ethics Review upon the matter of the legal duty of the research ethics committees. It also deals briefly with the article published in the current edition of Research Ethics Review by Colin Parker on what appears to be the same topic.
Ethical Issues in the Use of In-Depth Interviews: Literature Review and Discussion
Authors: Allmark Peter , Boote Jonathan , Chambers Eleni , Clarke Amanda , McDonnell Ann , Thompson Andrew , Tod Angela Mary
Published: January 2012

This paper reports a literature review on the topic of ethical issues in in-depth interviews. The review returned three types of article: general discussion, issues in particular studies, and studies of interview-based research ethics. Whilst many of the issues discussed in these articles are generic to research ethics, such as confidentiality, they often had particular manifestations in this type of research. For example, privacy was a significant problem as interviews sometimes probe unexpected areas. For similar reasons, it is difficult to give full information of the nature of a particular interview at the outset, hence informed consent is problematic. Where a pair is interviewed (such as carer and cared-for) there are major difficulties in maintaining confidentiality and protecting privacy. The potential for interviews to harm participants emotionally is noted in some papers, although this is often set against potential therapeutic benefit. As well as these generic issues, there are some ethical issues fairly specific to in-depth interviews. The problem of dual role is noted in many papers. It can take many forms: an interviewer might be nurse and researcher, scientist and counsellor, or reporter and evangelist. There are other specific issues such as taking sides in an interview, and protecting vulnerable groups. Little specific study of the ethics of in-depth interviews has taken place. However, that which has shows some important findings. For example, one study shows participants are not averse to discussing painful issues provided they feel the study is worthwhile. Some papers make recommendations for researchers. One such is that they should consider using a model of continuous (or process) consent rather than viewing consent as occurring once, at signature, prior to the interview. However, there is a need for further study of this area, both philosophical and empirical.
Making our Own Decisions: Researching the Process of ‘Being Informed’ with People with Learning Difficulties
Authors: Cook Tina , Inglis Pamela
Published: January 2012

Historically people with learning difficulties1 have been either included in research without their consent or excluded from research that affects their treatment and care. Over the last 20 years, however, it has been recognised that to exclude the voice of people with learning difficulties (and other so called vulnerable groups) in research that reflects their lived experiences challenges our notion of ethical practice. Cognitive ability has traditionally been one of the key factors in determining ability to consent. This paper identifies, through work with a group of men with learning difficulties, the impact of different ways of presenting information to prospective participants on their ability to understand key issues in relation to participation in research and hence their ability to give informed consent2.
Does Attendance of Students and Supervisors at Meetings Affect the Opinions of NHS Research Ethics Committees of Student Projects?
Authors: Heasman Peter , Preshaw Philip , Turnock Chris , Gray Janine
Published: January 2012

The current practice for UK research ethics committees (RECs) is to invite researchers to attend meetings at which their applications are to be considered and for student-based research the National Research Ethics Service recommends supervisors to attend. This study aims to identify the extent to which students and their supervisors attend NHS REC meetings and whether attendance is associated with the initial outcomes of RECs.
Bloodless DNA
Authors: Humphreys Stephen J
Published: January 2012

Although pharmaceutical practice tends to prefer to take DNA samples from whole blood, this could be both unnecessary and even unethical. The buccal swabbing method offers to provide an adequate and reliable sample less invasively and with the necessary minimal risk to the subject that virtually all ethical guidelines advocate.
Methodological Considerations in Ethical Review — 4. Research Conduct
Authors: Roberts Sa , Brabin L , Vail A , Tully Mp , McNamee R
Published: January 2012

This is the final paper in a four-part series which addresses the methodology of research studies under ethical review. The focus is on study conduct, governance and peer review. The nature and adequacy of peer review as a mechanism for assessing the study design and analysis are discussed. The paper argues that a properly constituted and functioning research team is crucial to the ethical conduct of a study and that an ethical review of methodology should extend beyond study design and analysis to a concern with data collection, storage and availability, and publication. While ethical review committees cannot monitor study conduct, they can ensure that the protocol pays sufficient attention to appropriate monitoring structures and personnel.
Research Ethics Committees: The Business of Society and Medicine
Authors: Emmerich Nathan
Published: January 2012

Whilst Colin Parker and I are in broad disagreement we would nevertheless agree that RECs have both political and ethical functions, albeit to differing degrees, and that a proper account of ethical expertise needs to be given. The uses RECs make of ethical experts and expertise and the way in which this might be recognised remains, from my perspective, open for debate. My only conclusion is that it should be recognised.
The Role of the REC in considering Changes to the Protocol: Commentary
Authors: McGee Paula
Published: January 2012

This study appeared in full in the last issue of Research Ethics Review (2009; 5(3): 127). Three submitted protocol amendments were presented for consideration of REC action. JG submitted a change in methodology, ST a project extension, and MJ wished to extend recruitment to include children and young people.
The Problem of Proliferation: Guidelines for Improving the Security of Qualitative Data in a Digital Age
Authors: Aldridge Judith , Medina Juanjo , Ralphs Robert
Published: January 2012

High profile breaches of data security in government and other organizations are becoming an increasing concern amongst members of the public. Academic researchers have rarely discussed data security issues as they affect research, and this is especially the case for qualitative social researchers, who are sometimes disinclined to technical solutions. This paper describes 14 guidelines developed to help qualitative researchers improve the security of their digitally-created and stored data. We developed these procedures after the theft of a laptop computer containing highly sensitive data from the home of a fieldworker. This paper introduces the ‘principle of proliferation’: digitally-created and stored files (like voice recordings of interviews and text files of their transcriptions) tend to proliferate during the course of a research project by virtue of fact that they can and are copied and shared as research progresses from data collection through to analysis and archive. Our guidelines were designed as concrete strategies that researchers embarking on a project can employ, particularly researchers working in teams, to accommodate this proliferation and reduce it where possible.
Finding New People to Join the REC: Discussion
Authors: Humphreys Stephen
Published: January 2012

This study appeared in full in the last issue of Research Ethics Review (2009; 5 (4): 159). There are three vacancies on the REC; one member has retired and left the area, a second has resigned because of pressures at work, and the third left because he was unable to attend the meetings. A fourth member will shortly be unavailable for several months because she is about to have her first baby. The day's agenda begins with a discussion about how to attract new members. SG suggests that maybe members of the public should be invited to observe a meeting. DL feels that he can recommend two individuals who would be interested.
How Should We Teach Research Ethics?
Authors: Davies Hugh
Published: January 2012

Socrates (SO) is strolling along in the Agora to buy some fruit for his wife Xanthippe. He meets Corecticus (CR), a teacher of research ethics.
Dealing with Complaints to the REC: Discussion
Authors: Humphreys Stephen
Published: January 2012

This study appeared in full in the last issue of Research Ethics Review (2010; 6 (1): 22). JM's research focuses on chronic pain and the evidence to support the effectiveness of current interventions. His current proposal has two dimensions in which mixed quantitative and qualitative methods will be used. One examines professionals' beliefs and the evidence on which they draw to support these. The other focusses on patients' experiences of the interventions and their views about what is most helpful in achieving pain relief.

JM is an experienced researcher. He has used a similar design in previous work. Before submitting his application he consulted with the key professionals and patient representatives in the pain team and elsewhere. Everyone has supported the study and senior colleagues are of the opinion that it is well designed and appropriate.

JM attended the REC meeting and found it an uncomfortable experience. No one was introduced. Questioning was hostile and some of the questions raised seemed to suggest that the application had not been read very carefully, if at all. He has now received a letter stating that a favourable opinion cannot be issued. A completely different methodology is put forward as essential. The REC advises that ‘the study would be more successful if it were conducted in a different type of setting, eg out-patients, and based on a questionnaire alone’.

JM is very angry about this.
What Constitutes Research Ethics in Sport and Exercise Science?
Authors: West Julia , Bill Karen , Martin Louise
Published: January 2012

Prior to any research data collection a proposal outlining methods and protocols is required to undergo ethical scrutiny. The issues surrounding a research ethics review process within sport and exercise science departments are not dissimilar to other subject areas. In particular, the ethical review process may be unclear to the researcher and can either present a difficult and time-consuming challenge or be merely perceived as a tick-box exercise. The aim of this study was to explore and compare research ethics processes and decisions within sport and exercise science departments and institutions across the UK.

Participants were asked to provide decisions and justification of those decisions on ten typical sports and exercise science proposals. Results found that all respondents cited evidence of informed consent and subject information sheets, detailed methodology and data protection procedures as highly important across all scenarios. Additionally it was found that similar processes occur regarding research ethical scrutiny and similar decisions are made at the departmental level. However, confidence fluctuates for individuals when reviewing in non-specialist subject areas and qualitative data collected calls for more research ethics training.
The Role, Remit and Function of the Research Ethics Committee — 4. Limits to Consent?
Authors: Edwards Sarah JL
Published: January 2012

This is the fourth in a series of five papers on the role, remit and function of research ethics committees which are intended to provide for REC members a broad understanding of the most important issues in research ethics and governance. This paper explores the role of ethics committees in reviewing proposed conditions for recruiting human subjects and in checking the intended procedures for gaining consent. In so doing the paper will reiterate the conditions which are traditionally thought to make consent valid, identify a number of limitations to meeting these conditions, and show when consent, however broadly construed or indeterminately focused, may be unnecessary.
Perceptions of Research Assistants on How Their Research Participants View Informed Consent and Its Documentation in Africa
Authors: Araali Bagamba B.
Published: January 2012

This paper discusses the issue of informed consent from an African perspective with a particular emphasis on the problems posed by the documentation of consent in the African socio-cultural environment. The paper presents two small-scale surveys which typify and exemplify the African perspective with regard to procedures for obtaining consent (agreement) and for documenting it. To avoid causing moral pain to African research participants and the feeling of having been used as mere sources of data, this paper suggests, as a short-term solution, that African cultural values be incorporated in the procedures and regulations aimed at protecting their human rights. As a long-term solution, the paper encourages universities and research institutions operating in Africa to come up with clear guidelines of ethical conduct which would satisfy both the interests of ordinary Africans (particularly the rural and uneducated population) and legal requirements to which Western research institutions and funding agencies are subjected.
Passing the Buck: How the Academy of Medical Sciences's ‘New Pathway for the Regulation and Governance of Health Research’ Shifts the Regulatory Burden but Fails to Improve the Quality of Research Governance
Authors: Roy-Toole Christopher
Published: January 2012

In this paper the author argues that the Academy of Medical Sciences's ‘Review of the regulation and governance of medical research’ has produced a set of muddled recommendations that could increase complexity and uncertainty in research governance rather than reduce it. Issues discussed in the paper include the additional legal burden placed upon the newly proposed Health Research Agency by the plan for a National Research Governance Service and its system of centralized permissions, the consequences that this may have for the research ethics committees in the discharge of their legal duty, and the unanswered questions surrounding the TGN1412 incident.
Unwarranted Participant Questions and Virtuous Researcher Lies
Authors: Davis Paul
Published: January 2012

Most writing on research ethics is about researcher treatment of participants. This essay considers a participant threat to researcher privacy and integrity. It is based partly upon a real-life sport research case, and discusses a participant request to know if the researcher supports a particular and popular football team. The researcher does support this team, but felt disinclined to answer truthfully, and so lied. It is argued, with the help of analogous cases, that the participant question is what Borge calls ‘unwarranted’, despite the football fan culture of allegiance disclosure. It is further argued, again following Borge, that refusal of the question would have generated a conversational admitture, resulting in the participant truly believing what the researcher correctly believes he has no right to know. The researcher is therefore justified in lying. This justification is buttressed by Swanton's virtue ethical account of right action, according to which an action is right if it is ‘overall virtuous’ (OV), and that entails that it is the (a) best possible action in the circumstances. Here, actions which are typically right, such as truth-telling, are sometimes not, and may even on occasion be wrong-making qualities of actions. It is argued, however, that honesty retains a positive moral value and dishonesty a positive moral disvalue, and it is therefore to be regretted that the OV course of action involves lying. The researcher should therefore regret the OV lie, should ponder if he could have done anything to prevent the situation, and should consider what he can do to prevent its recurrence. A global prescription to protect researchers is probably out of reach, but one suggestion for this sort of case is that the researcher tells the participant at the outset, in appropriately hospitable tones, that he is unable to disclose anything of his own affections.
IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid mouse progenitors
Authors: Becker Amy M. , Michael Drew G. , Satpathy Ansuman T. , Sciammas Roger , Singh Harinder , Bhattacharya Deepta
Published: January 2012

While most blood lineages are assumed to mature through a single cellular and developmental route downstream of HSCs, dendritic cells (DCs) can be derived from both myeloid and lymphoid progenitors in vivo. To determine how distinct progenitors can generate similar downstream lineages, we examined the transcriptional changes that accompany loss of in vivo myeloid potential as common myeloid progenitors differentiate into common DC progenitors (CDPs), and as lymphoid-primed multipotent progenitors (LMPPs) differentiate into all lymphoid progenitors (ALPs). Microarray studies revealed that IFN regulatory factor 8 (IRF-8) expression increased during each of these transitions. Competitive reconstitutions using Irf8−/− BM demonstrated cell-intrinsic defects in the formation of CDPs and all splenic DC subsets. Irf8−/− common myeloid progenitors and, unexpectedly, Irf8−/− ALPs produced more neutrophils in vivo than their wild-type counterparts at the expense of DCs. Retroviral expression of IRF-8 in multiple progenitors led to reduced neutrophil production and increased numbers of DCs, even in the granulocyte-macrophage progenitor (GMP), which does not normally possess conventional DC potential. These data suggest that IRF-8 represses a neutrophil module of development and promotes convergent DC development from multiple lymphoid and myeloid progenitors autonomously of cellular context.
Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma
Authors: Klapper Wolfram , Kreuz Markus , Kohler Christian W. , Burkhardt Birgit , Szczepanowski Monika , Salaverria Itziar , Hummel Michael , Loeffler Markus , Pellissery Shoji , Woessmann Wilhelm , Schwänen Carsten , Trümper Lorenz , Wessendorf Swen , Spang Rainer , Hasenclever Dirk , Siebert Reiner ,   for the Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe
Published: January 2012

Diffuse large B-cell lymphoma is the most frequent type of B-cell lymphoma in adult patients but also occurs in children. Patients are currently assigned to therapy regimens based on arbitrarily chosen age limits only (eg, 18 or 60 years) and not biologically justified limits. A total of 364 diffuse large B-cell lymphomas and related mature aggressive B-cell lymphomas other than Burkitt lymphoma from all age groups were analyzed by comprehensive molecular profiling. The probability of several biologic features previously reported to be associated with poor prognosis in diffuse large B-cell lymphoma, such as ABC subtype, BCL2 expression, or cytogenetic complexity, increases with age at diagnosis. Similarly, various genetic features, such as IRF4 translocations, gains in 1q21, 18q21, 7p22, and 7q21, as well as changes in 3q27, including gains and translocations affecting the BCL6 locus, are significantly associated with patient age, but no cut-offs between age groups could be defined. If age was incorporated in multivariate analyses, genetic complexity lost its prognostic significance, whereas the prognostic impact of ABC subtype and age were additive. Our data indicate that aging is a major determinant of lymphoma biology. They challenge current concepts regarding both prognostic biomarkers and treatment stratification based on strict age cut-offs.
FIXing Factor VIII inhibitors
Authors: Ponder Katherine P.
Published: January 2012

In this issue of Blood, Milanov and colleagues demonstrate that a Factor IX (FIX) variant that does not require activated Factor VIII (FVIIIa) for activity induces coagulation in hemophilia A mice with FVIII inhibitors.1 This protein might be developed as a bypass agent.
Relaxin' with endothelial progenitor cells
Authors: Wang Alice , Karumanchi S. Ananth
Published: January 2012

Segal and colleagues in this issue of Blood report their findings about an additional new function for the hormone relaxin: turning on bone marrow–derived endothelial progenitor cells to sites of neoangiogenesis.1
The beauty of TLR agonists for CTCL
Authors: Rook Alain H.
Published: January 2012

It is barely more than a decade since Toll-like receptors (TLRs) were linked to the innate immune response.1 Yet substantial data are now emerging that indicate that TLR agonists may have a significant role in the therapy of mycosis fungoides and Sezary syndrome.2,3
Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML
Authors: Hirabayashi Shinsuke , Flotho Christian , Moetter Jessica , Heuser Michael , Hasle Henrik , Gruhn Bernd , Klingebiel Thomas , Thol Felicitas , Schlegelberger Brigitte , Baumann Irith , Strahm Brigitte , Stary Jan , Locatelli Franco , Zecca Marco , Bergstraesser Eva , Dworzak Michael , van den Heuvel-Eibrink Marry M. , De Moerloose Barbara , Ogawa Seishi , Niemeyer Charlotte M. , Wlodarski Marcin W. ,   on behalf of the European Working Group of MDS in Childhood
Published: January 2012

Somatic mutations of the spliceosomal machinery occur frequently in adult patients with myelodysplastic syndrome (MDS). We resequenced SF3B1, U2AF35, and SRSF2 in 371 children with MDS or juvenile myelomonocytic leukemia. We found missense mutations in 2 juvenile myelomonocytic leukemia cases and in 1 child with systemic mastocytosis with MDS. In 1 juvenile myelomonocytic leukemia patient, the SRSF2 mutation that initially coexisted with an oncogenic NRAS mutation was absent at relapse, whereas the NRAS mutation persisted and a second, concomitant NRAS mutation later emerged. The patient with systemic mastocytosis and MDS carried both mutated U2AF35 and KIT in a single clone as confirmed by clonal sequencing. In the adult MDS patients sequenced for control purposes, we detected previously reported mutations in 7/30 and a novel SRSF2 deletion (c.284_307del) in 3 of 30 patients. These findings implicate that spliceosome mutations are rare in pediatric MDS and juvenile myelomonocytic leukemia and are unlikely to operate as driver mutations.
Type IV fimbrial subunit protein ApfA contributes to protection against porcine pleuropneumonia
Authors: Sadilkova Lenka , Nepereny Jiri , Vrzal Vladimir , Sebo Peter , Osicka Radim
Published: January 2012

Porcine pleuropneumonia caused by Actinobacillus pleuropneumoniae accounts for serious economic losses in the pig farming industry worldwide. We examined here the immunogenicity and protective efficacy of the recombinant type IV fimbrial subunit protein ApfA as a single antigen vaccine against pleuropneumonia, or as a component of a multi-antigen preparation comprising five other recombinant antigens derived from key virulence factors of A. pleuropneumoniae (ApxIA, ApxIIA, ApxIIIA, ApxIVA and TbpB). Immunization of pigs with recombinant ApfA alone induced high levels of specific serum antibodies and provided partial protection against challenge with the heterologous A. pleuropneumoniae serotype 9 strain. This protection was higher than that engendered by vaccination with rApxIVA or rTbpB alone and similar to that observed after immunization with the tri-antigen combination of rApxIA, rApxIIA and rApxIIIA. In addition, rApfA improved the vaccination potential of the penta-antigen mixture of rApxIA, rApxIIA, rApxIIIA, rApxIVA and rTbpB proteins, where the hexa-antigen vaccine containing rApfA conferred a high level of protection on pigs against the disease. Moreover, when rApfA was used for vaccination alone or in combination with other antigens, such immunization reduced the number of pigs colonized with the challenge strain. These results indicate that ApfA could be a valuable component of an efficient subunit vaccine for the prevention of porcine pleuropneumonia.
Engineered myocardial tissues constructed in vivo using cardiomyocyte-like cells derived from bone marrow mesenchymal stem cells in rats
Authors: Xing Yujie , Lv Anlin , Wang Li , Yan Xuebo , Zhao Wei , Cao Feng
Published: January 2012

Background

To explore the feasibility of constructing engineered myocardial tissues (EMTs) in vivo, using polylactic acid -co-glycolic acid (PLGA) for scaffold and cardiomyocyte-like cells derived from bone marrow mesenchymal stem cells (BMMSCs) for seeded cells.

Methods

BMMSCs were isolated from femur and tibia of Sprague-Dawley (SD) rats by density-gradient centrifugation. The third passage cells were treated with 10 μmol/L 5-azacytidine (5-aza) and 0.1 μmol/L angiotensin II (Ang II) for 24 h, followed by culturing in complete medium for 3 weeks to differentiated into cardiomyocyte-like cells. The cardiomyocyte-like cells were seeded into PLGA scaffolds to form the grafts. The grafts were cultured in the incubator for three days and then implanted into the peritoneal cavity of SD rats. Four weeks later, routine hematoxylin-eosin (HE) staining, immunohistochemical staining for myocardium-specific cardiac troponin I (cTnI), scanning electron microscopy and transmission electron microscopy were used to analyze the morphology and microconstruction of the EMTs in host rats.

Results

HE staining showed that the cardiomyocyte-like cells distributed equally in the PLGA scaffold, and the nuclei arranged in the spindle shape. Immunohistochemical staining revealed that majority of engrafted cells in the PLGA -Cardiomyocyte-like cells group were positive for cTnI. Scanning electron microscopy showed that the inoculated cells well attached to PLGA and grew in 3 dimensions in construct. Transmission electron microscopy showed that the EMTs contained well arranged myofilaments paralleled to the longitudinal cell axis, the cells were rich in endoplasmic reticulum and mitochondria, while desmosomes, gap junction and Z line-like substances were also can be observed as well within the engrafted cells.

Conclusion

We have developed an in vivo method to construct engineered myocardial tissue. The in vivo microenvironment helped engrafted cells/tissue survive and share similarities with the native heart tissue.
An integrative variant analysis suite for whole exome next-generation sequencing data
Authors: Challis Danny , Yu Jin , Evani Uday S , Jackson Andrew R , Paithankar Sameer , Coarfa Cristian , Milosavljevic Aleksandar , Gibbs Richard A , Yu Fuli
Published: January 2012

Background

Whole exome capture sequencing allows researchers to cost-effectively sequence the coding regions of the genome. Although the exome capture sequencing methods have become routine and well established, there is currently a lack of tools specialized for variant calling in this type of data.

Results

Using statistical models trained on validated whole-exome capture sequencing data, the Atlas2 Suite is an integrative variant analysis pipeline optimized for variant discovery on all three of the widely used next generation sequencing platforms (SOLiD, Illumina, and Roche 454). The suite employs logistic regression models in conjunction with user-adjustable cutoffs to accurately separate true SNPs and INDELs from sequencing and mapping errors with high sensitivity (96.7%).

Conclusion

We have implemented the Atlas2 Suite and applied it to 92 whole exome samples from the 1000 Genomes Project. The Atlas2 Suite is available for download at http://sourceforge.net/projects/atlas2/. In addition to a command line version, the suite has been integrated into the Genboree Workbench, allowing biomedical scientists with minimal informatics expertise to remotely call, view, and further analyze variants through a simple web interface. The existing genomic databases displayed via the Genboree browser also streamline the process from variant discovery to functional genomics analysis, resulting in an off-the-shelf toolkit for the broader community.
COPD exacerbations in general practice: variability in oral prednisolone courses
Authors: de Vries Marianne , Berendsen Annette J , Bosveld Henk EP , Kerstjens Huib AM , van der Molen Thys
Published: January 2012

Background

The use of oral corticosteroids as treatment of COPD exacerbations in primary care is well established and evidence-based. However, the most appropriate dosage regimen has not been determined and remains controversial. Corticosteroid therapy is associated with a number of undesirable side effects, including hyperglycaemias, so differences in prescribing might be relevant. This study examines the differences between GPs in dosage and duration of prednisolone treatment in patients with a COPD exacerbation. It also investigates the number of general practitioners (GPs) who adjust their treatment according to the presence of diabetic co-morbidity.

Methods

Cross-sectional study among 219 GPs and 25 GPs in training, located in the Northern part of the Netherlands.

Results

The response rate was 69%. Nearly every GP prescribed a continuous dose of prednisolone 30 mg per day. Among GPs there were substantial differences in treatment duration. GPs prescribed courses of five, seven, ten, or fourteen days. A course of seven days was most common. The duration of treatment depended on exacerbation and disease severity. A course of five days was especially prescribed in case of a less severe exacerbation. In a more severe exacerbation duration of seven to fourteen days was more common. Hardly any GP adjusted treatment to the presence of diabetic co-morbidity.

Conclusion

Under normal conditions GPs prescribe prednisolone quite uniformly, within the range of the current Dutch guidelines. There is insufficient guidance regarding how to adjust corticosteroid treatment to exacerbation severity, disease severity and the presence of diabetic co-morbidity. Under these circumstances, there is a substantial variation in treatment duration.
LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Giα dependent PI-3kinase signalling
Authors: Ngkelo Anta , Meja Koremu , Yeadon Mike , Adcock Ian , Kirkham Paul A
Published: January 2012

COPD is a disease of innate immunity and bacterial infections are a dominant cause of exacerbations in the later stages resulting in poor health and high mortality. The pathogen-associated molecular pattern (PAMP) lipopolysaccharide (LPS) is sensed by immune cells through activation of the toll-like receptor 4 (TLR4). This leads to the activation of NADPH oxidase (NOX) and NF-κB which together drive COPD inflammation. In this study we show in human PBMCs that LPS stimulated proinflammatory cytokine release (CXCL8 and IL6) was inhibited by approximately 50% by the broad specificity phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Our results also demonstrate that activation of PI3K following LPS stimulation is mediated by a NOX4 dependent mechanism releasing endogenous H2O2, as the NOX4 inhibitor apocynin blocked LPS induced AKT phosphorylation. Moreover, LPS-induced PI3K activation was inhibited by the anti-oxidant N-acetylcysteine in a concentration dependent manner (IC50 ~100 μM). In addition, our data demonstrated that inhibition of small G proteins, by pre-treatment with pertussis toxin, inhibited LPS-induced AKT phosphorylation. Furthermore, the G-protein inhibitors pertussis toxin and mastoparan both inhibited LPS-induced CXCL8 and IL-6 release by approximately 50%. Together, these data indicate there is a mechanism in human PBMCs where TLR4 activation by LPS leads to ROS generation through NOX4 and activation of the PI3K pathway. This effect is apparently mediated through small G proteins facilitating the release of pro-inflammatory cytokines.
SYBR Green-based Real-Time PCR targeting kinetoplast DNA can be used to discriminate between the main etiologic agents of Brazilian cutaneous and visceral leishmaniases
Authors: Pita-Pereira Daniela , Lins Rachel , Oliveira Marcia P , Lima Rosimar B , Pereira Bernardo AS , Moreira Otacilio C , Brazil Reginaldo P , Britto Constança
Published: January 2012

Background

Leishmaniases control has been hampered by the unavailability of rapid detection methods and the lack of suitable therapeutic and prophylactic measures. Accurate diagnosis, which can distinguish between Leishmania isolates, is essential for conducting appropriate prognosis, therapy and epidemiology. Molecular methods are currently being employed to detect Leishmania infection and categorize the parasites up to genus, complex or species level. Real-time PCR offers several advantages over traditional PCR, including faster processing time, higher sensitivity and decreased contamination risk.

Results

A SYBR Green real-time PCR targeting the conserved region of kinetoplast DNA minicircles was able to differentiate between Leishmania subgenera. A panel of reference strains representing subgenera Leishmania and Viannia was evaluated by the derivative dissociation curve analyses of the amplified fragment. Distinct values for the average melting temperature were observed, being 78.95°C ± 0.01 and 77.36°C ± 0.02 for Leishmania and Viannia, respectively (p < 0.05). Using the Neighbor-Joining method and Kimura 2-parameters, the alignment of 12 sequences from the amplified conserved minicircles segment grouped together L. (V.) braziliensis and L. (V.) shawii with a bootstrap value of 100%; while for L. (L.) infantum and L. (L.) amazonensis, two groups were formed with bootstrap values of 100% and 62%, respectively. The lower dissociation temperature observed for the subgenus Viannia amplicons could be due to a lower proportion of guanine/cytosine sites (43.6%) when compared to species from subgenus Leishmania (average of 48.4%). The method was validated with 30 clinical specimens from visceral or cutaneous leishmaniases patients living in Brazil and also with DNA samples from naturally infected Lutzomyia spp. captured in two Brazilian localities.

Conclusions

For all tested samples, a characteristic amplicon melting profile was evidenced for each Leishmania subgenus, corroborating the data from reference strains. Therefore, the analysis of thermal dissociation curves targeting the conserved kinetoplast DNA minicircles region is able to provide a rapid and reliable method to identify the main etiologic agents of cutaneous and visceral leishmaniases in endemic regions of Brazil.
Determination of SGK1 mRNA in non-small cell lung cancer samples underlines high expression in squamous cell carcinomas
Authors: Abbruzzese Claudia , Mattarocci Stefano , Pizzuti Laura , Mileo Anna M , Visca Paolo , Antoniani Barbara , Alessandrini Gabriele , Facciolo Francesco , Amato Rosario , D'Antona Lucia , Rinaldi Massimo , Felsani Armando , Perrotti Nicola , Paggi Marco G
Published: January 2012

Background

Lung cancer represents the most frequent cause of death for cancer. In non-small cell lung cancer (NSCLC), which accounts for the vast majority of this disease, only early detection and treatment, when possible, may significantly affect patient's prognosis. An important role in NSCLC malignancy is attributed to the signal transduction pathways involving PI3Kinase, with consequent activation of the AKT family factors. The serum and glucocorticoid kinase (SGK) factors, which share high structural and functional homologies with the AKT factors, are a family of ubiquitously expressed serine/threonine kinases under the control of cellular stress and hormones. SGK1 is the most represented SGK member.

Methods

By means of immunohistochemistry and quantitative real-time PCR, we determined SGK1 protein and mRNA expression in a cohort of 66 formalin-fixed, paraffin-embedded NSCLC surgical samples. All samples belonged to patients with a well-documented clinical history.

Results

mRNA expression was significantly higher in squamous cell carcinomas, and correlated with several clinical prognostic indicators, being elevated in high-grade tumors and in tumors with bigger size and worse clinical stage. No correlation was found between SGK1 protein expression and these clinical parameters.

Conclusions

This explorative analysis of SGK1 expression in NSCLC samples highlights the potential role of this factor in NSCLC patients' prognosis. Moreover, the higher expression in the squamous cell carcinoma subtype opens new therapeutic possibilities in this NSCLC subtype by designing specific kinase inhibitors.
Intellectual disability and other neuropsychiatric outcomes in high-risk children of mothers with schizophrenia, bipolar disorder and unipolar major depression
Authors: Morgan Vera A. , Croft Maxine L. , Valuri Giulietta M. , Zubrick Stephen R. , Bower Carol , McNeil Thomas F. , Jablensky Assen V.
Published: January 2012

Background

Recent evidence points to partially shared genetics of neuropsychiatric disorders.

Aims

We examined risk of intellectual disability and other neuropsychiatric outcomes in 3174 children of mothers with schizophrenia, bipolar disorder or unipolar major depression compared with 3129 children of unaffected mothers.

Method

We used record linkage across Western Australian population-based registers. The contribution of obstetric factors to risk of intellectual disability was assessed.

Results

Children were at significantly increased risk of intellectual disability with odds ratios (ORs) of 3.2 (95% CI 1.8–5.7), 3.1 (95% CI 1.9–4.9) and 2.9 (95% CI 1.8–4.7) in the maternal schizophrenia, bipolar disorder and unipolar depression groups respectively. Multivariate analysis suggests familial and obstetric factors may contribute independently to the risk. Although summated labour/delivery complications (OR = 1.4, 95% CI 1.0–2.0) just failed to reach significance, neonatal encephalopathy (OR = 7.7, 95% CI 3.0–20.2) and fetal distress (OR = 1.8, 95% CI 1.1–2.7) were independent significant predictors. Rates of rare syndromes in children of mothers with mental disorder were well above population rates. Risk of pervasive developmental disorders, including autism, was significantly elevated for children of mothers with bipolar disorder. Risk of epilepsy was doubled for children of mothers with unipolar depression.

Conclusions

Our findings provide epidemiological support for clustering of neuropsychiatric disorders. Further larger epidemiological studies are warranted.
Treatment-resistant and insufficiently treated depression and all-cause mortality following myocardial infarction
Authors: Scherrer Jeffrey F. , Chrusciel Timothy , Garfield Lauren D. , Freedland Kenneth E. , Carney Robert M. , Hauptman Paul J. , Bucholz Kathleen K. , Owen Richard , Lustman Patrick J.
Published: January 2012

Background

Depression is a known risk factor for mortality after an acute myocardial infarction. Patients with treatment-responsive depression may have a better prognosis than those with treatment-resistant depression.

Aims

We sought to determine whether mortality following acute myocardial infarction was associated with treatment-resistant depression.

Method

Follow-up began after myocardial infarction and continued until death or censorship. Depression was counted as present if diagnosed any time during the study period. Treatment for depression was defined as receipt of 12 or more weeks of continuous antidepressant therapy at a therapeutic dose during follow-up. Treatment-resistant depression was defined as use of two or more antidepressants plus augmentation therapy, receipt of electroconvulsive therapy or use of monoamine oxidase inhibitors. Mean duration of follow-up was 39 months.

Results

During follow-up of 4037 patients with major depressive disorder who had had a myocardial infarction, 6.9% of those with insufficiently treated depression, 2.4% of those with treated depression and 5.0% of those with treatment-resistant depression died. A multivariable survival model that adjusted for sociodemographics, anxiety disorders, beta-blocker use, mortality risk factors and health service utilisation indicated that compared with treated patients, insufficiently treated patients were 3.04 (95% CI 2.12–4.35) times more likely and patients with treatment-resistant depression were 1.71 (95% CI 1.05–2.79) times more likely to die.

Conclusions

All-cause mortality following an acute myocardial infarction is greatest in patients with depression who are insufficiently treated and is a risk in patients with treatment-resistant depression. However, the risk of mortality associated with treatment-resistant depression is partly explained by comorbid disorders. Further studies are warranted to determine whether changes in depression independently predict all-cause mortality.
The effect of near‐bed turbulence on sperm dilution and fertilization success of broadcast‐spawning bivalves
Authors: Quinn Noel P. , Ackerman Josef D.
Published: January 2012

Lay Abstract

Many marine and some freshwater bottom‐dwelling (benthic) invertebrates broadcast their gametes into the water column where fertilization occurs. The relatively slow swimming speed and rapid dilution of sperm by water currents is thought to limit fertilization, even though species that reproduce this way can be extremely successful. We examined how water velocity and bottom roughness affected the fertilization success of zebra and quagga mussels (Dreissena polymorpha and D. bugensis) in a laboratory flow chamber and in Lake Erie. Our results demonstrate that velocity gradients dilute the concentration of sperm to levels that can lead to sperm limitation. We also found that the strength and pattern of the turbulence in the water flow near the bottom had a strong effect on fertilization. Bottom roughness that led to the ejection of fluid away from the bottom—such as what occurs downstream of a patch of mussels—contributed to higher fertilization success than bottom roughness that led to skimming flows or sweeps of flow toward the bed. Bottom roughness needs to be considered in biological and other transport processes occurring near the bottom.

Biologically, dreissenid mussels are the first freshwater benthic organisms that have been shown to be sperm limited. Ecologically, the presence of their shells in the flow chamber and on the lakebed in Lake Erie created sufficient roughness to affect fertilization success. In other words, the mussels had changed the physical environment in a way that favored their reproduction. This new observation helps to explain why dreissenid mussels are successful invaders of freshwater ecosystems.