Management of myelofibrosis:a survey of current practice in the United Kingdom

To investigate the experience of clinicians in the management of patients with myelofibrosis, current treatment options and their utility.

Guideline for the diagnosis and management of myelofibrosis

The guideline group regarding the diagnosis and management of myelofibrosis was selected to be representative of UK-based medical experts, together with a contribution from a single expert from the USA. MEDLINE and EMBASE were searched systematically for publications in English from 1966 until August 2011 using a variety of key words. The writing group produced the draft guideline, which was subsequently revised by consensus of the members of the General Haematology and Haemato-oncology Task Forces of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The criteria used to state levels and grades of evidence are as outlined in the Procedure for Guidelines commissioned by the BCSH; the 'GRADE' system was used to score strength and quality of evidence. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of primary myelofibrosis, as well as post-polycythaemic myelofibrosis (post-PV MF) and post-thrombocythemic myelofibrosis (post-ET MF) in both adult and paediatric patients.

Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia

Chemoresistance is a major contributor to the aggressiveness of AML and is often due to insufficient apoptosis. The CFLAR gene is expressed as long and short splice forms encoding the anti-apoptotic proteins c-FLIP(L) and c-FLIP(S) (CFLAR(L) and CFLAR(S) , respectively) that play important roles in drug resistance. In univariate analyses of CFLAR mRNA expression in adult AML patients, those individuals with higher than median mRNA expression of the long splice form CFLAR(L) (but not the short splice form) had significantly lower 3 year overall survival (P = 0·04) compared to those with low expression. In cell line studies, simultaneous down-regulation of c-FLIP(L) and c-FLIP(S) proteins using siRNA induced apoptosis in U937 and NB-4 AML cells, but not K562 or OCI-AML3 cells. However, dual c-FLIP(L/S) downregulation sensitized all four cell lines to apoptosis induced by recombinant tumour necrosis factor-related apoptosis-inducing ligand (rTRAIL). Moreover, specific downregulation of c-FLIP(L) was found to recapitulate the phenotypic effects of dual c-FLIP(L/S) downregulation. The histone deacetylase (HDAC)1/2/3/6 inhibitor Vorinostat was found to potently down-regulate c-FLIP(L) expression by transcriptional and post-transcriptional mechanisms and to sensitize AML cells to rTRAIL. Further analyses using more selective HDAC inhibitors revealed that HDAC6 inhibition was not required for c-FLIP(L) down-regulation. These results suggest that c-FLIP(L) may have clinical relevance both as a prognostic biomarker and potential therapeutic target for HDAC inhibitors in AML although this requires further study.

Diagnosis and management of congenital and idiopathic erythrocytosis

An erythrocytosis occurs when there is an increased red-cell mass. The causes of erythrocytosis are divided into primary, when there is an intrinsic defect in the erythroid cell, and secondary, when the cause is extrinsic to the erythroid cell. An idiopathic erythrocytosis occurs when the increased red-cell mass has no identifiable cause. Primary and secondary defects can be further classified as either congenital or acquired causes. The diagnostic pathway starts with a careful history and examination followed by measurement of the erythropoietin (EPO) levels. This allows a division of those patients with a low EPO level, who can then be investigated for primary causes of erythrocytosis, and those with a normal or high EPO level, where the oxygen-sensing pathway needs to be explored further. Physiological studies in those with congenital defects in the oxygen-sensing pathway show many changes in the downstream metabolism adapting to the defect, which has a bearing on the management of the disorders. Low-dose aspirin and venesection to an achievable target are the main therapeutic options that can be considered in the management of erythrocytosis. Specific guidance on venesection options should be considered with certain causes such as high oxygen-affinity hemoglobins.

Interventions to reduce prejudice and enhance inclusion and respect for ethnic differences in early childhood: A systematic review

A systematic review was conducted of studies evaluating the effects of interventions aimed at reducing ethnic prejudice and discrimination in young children. Articles published between 1980 and 2010 and including children of 8 years and under were identified, harvested, and assessed for quality, both for the exposure/program as well as for the evaluation. In total, 32 studies (14 contact and 18 media or instruction) yielded 62 effects on attitudes and 59 effects on peer relations. An overall count of the positive (40%), non-significant (50%), and negative effects (10%) indicate a mixed picture. Overall, more attitude effects (55%) than peer relations effects (25%) were positive, and media/instruction (47%) was more successful than contact (36%). Most of the effects were observed with children from a majority ethnicity: 67% of the attitude effects were positive, and media/instruction and contact were equally effective at delivering these. Few differences were found as a function of the quality of the exposure and evaluation, but differences were found depending on the context of exposure (naturally occurring or experimental manipulation) and research design (random assignment or self-selection). In conclusion, the findings were more mixed than expected, though sufficiently strong studies exist to provide lessons for future research.


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A Superfamily of Actin-Binding Proteins at the Actin-Membrane Nexus of Higher Plants

Complex animals use a wide variety of adaptor proteins to produce specialized sites of interaction between actin and membranes. Plants do not have these protein families, yet actin-membrane interactions within plant cells are critical for the positioning of subcellular compartments, for coordinating intercellular communication, and for membrane deformation [1]. Novel factors are therefore likely to provide interfaces at actin-membrane contacts in plants, but their identity has remained obscure. Here we identify the plantspecific Networked (NET) superfamily of actin-binding proteins, members of which localize to the actin cytoskeleton and specify different membrane compartments. The founding member of the NET superfamily, NET1A, is anchored at the plasma membrane and predominates at cell junctions, the plasmodesmata. NET1A binds directly to actin filaments via a novel actin-binding domain that defines a superfamily of thirteen Arabidopsis proteins divided into four distinct phylogenetic clades. Members of other clades identify interactions at the tonoplast, nuclear membrane, and pollen tube plasma membrane, emphasizing the role of this superfamily in mediating actin-membrane interactions.

Differences in Mucosal Gene Expression in the Colon of Two Inbred Mouse Strains after Colonization with Commensal Gut Bacteria

The host genotype has been proposed to contribute to individually composed bacterial communities in the gut. To provide deeper insight into interactions between gut bacteria and host, we associated germ-free C3H and C57BL/10 mice with intestinal bacteria from a C57BL/10 donor mouse. Analysis of microbiota similarity between the animals with denaturing gradient gel electrophoresis revealed the development of a mouse strain-specific microbiota. Microarray-based gene expression analysis in the colonic mucosa identified 202 genes whose expression differed significantly by a factor of more than 2. Application of bioinformatics tools demonstrated that functional terms including signaling/secretion, lipid degradation/catabolism, guanine nucleotide/guanylate binding and immune response were significantly enriched in differentially expressed genes. We had a closer look at the 56 genes with expression differences of more than 4 and observed a higher expression in C57BL/10 mice of the genes coding for Tlr1 and Ang4 which are involved in the recognition and response to gut bacteria. A higher expression of Pla2g2a was detected in C3H mice. In addition, a number of interferon-inducible genes were higher expressed in C3H than in C57BL/10 mice including Gbp1, Mal, Oasl2, Ifi202b, Rtp4, Ly6g6c, Ifi27l2a, Usp18, Ifit1, Ifi44, and Ly6g indicating that interferons may play an essential role in microbiota regulation. However, genes coding for interferons, their receptors, factors involved in interferon expression regulation or signaling pathways were not differentially expressed between the two mouse strains. Taken together, our study confirms that the host genotype is involved in the establishment of host-specific bacterial communities in the gut. Based on expression differences after colonization with the same bacterial inoculum, we propose that Pla2g2a and interferon-dependent genes may contribute to this phenomenon.

Erythrocytosis in children and adolescents-classification, characterization, and consensus recommendations for the diagnostic approach

During recent years, the increasing knowledge of genetic and physiological changes in polycythemia vera (PV) and of different types of congenital erythrocytosis has led to fundamental changes in recommendations for the diagnostic approach to patients with erythrocytosis. Although widely accepted for adult patients this approach may not be appropriate with regard to children and adolescents affected by erythrocytosis. The "congenital erythrocytosis" working group established within the framework of the MPN&MPNr-EuroNet (COST action BM0902) addressed this question in a consensus finding process and developed a specific algorithm for the diagnosis of erythrocytosis in childhood and adolescence which is presented here. Pediatr Blood Cancer 2013;9999:XX-XX. © 2013 Wiley Periodicals, Inc.

Realist evaluation - promise, problems and practicalities

Realist evaluation is an innovative, multi-method approach to evaluating the effectiveness of complex health care interventions that is having an increasing impact on the research community. Drawing on their experience doing four realist evaluations in diverse areas of healthcare, the authors offer a comprehensive overview and critique of essential theory and practice. The first paper (Realist review and realist evaluation: an introduction) introduces the main components of the approach and shows how realist review can support realist evaluation. The second paper (Concepts and methodology for realist evaluation: help or hindrance?) provides further detail on the key concepts, shows how they can be operationalised, and discusses the advantages and difficulties of using these ideas. Following these two papers introducing and illustrating the major concepts, the third paper (Realist Evaluation: a critical realist critique) takes a step back to re-consider realist evaluation in relation to its critical realist roots, asking whether it leads to evaluators abandoning the attempt to understand (and if necessary challenge) the underlying values of health care interventions and contenting themselves merely with explicating the factors that help or hinder implementation. The fourth and final paper (Data analysis and theory development in realist evaluation) plunges back into the tangled undergrowth of multiple-method data collection and shows how disparate forms of data can be synthesised for theory development, and the results presented in a form that is useful to practitioners and policy-makers.