bluuebunny/crossref_metadata_2025 huggingface dataset:
The use of costing information in Egypt: a research note
Authors: van Triest Sander , Fathy Elshahat Mohamed
Published: September 2007

Purpose

This paper aims to investigate the use of costing information in Egypt.

Design/methodology/approach

A survey was carried out of 40 Egyptian privately held firms in four sectors (pharmaceutical, foodstuff, chemical, and packing and wrapping industries).

Findings

The paper finds that the use and sophistication of costing information in Egypt is limited. No advanced accounting techniques seem to be applied, activity‐based costing concepts are largely unknown, and the main purpose of costing information is pricing decisions, rather than performance measurement, process improvement or cost reductions.

Research limitations/implications

Considerable problems were encountered in obtaining responses to the questionnaire. The results suggest that not all questions were understood by the respondents, which could be caused by the use of Western management (accounting) terms and concepts in the questionnaire with which the respondents were unfamiliar.

Originality/value

The paper is one of few surveys of management accounting practices in Africa, and (to the best of one's knowledge) the first in Egypt.
High animal‐fat intake changes the bile‐acid composition of bile juice and enhances the development of Barrett's esophagus and esophageal adenocarcinoma in a rat duodenal‐contents reflux model
Authors: Chen Kuan‐Hao , Mukaisho Ken‐ichi , Sugihara Hiroyuki , Araki Yoshio , Yamamoto Gaku , Hattori Takanori
Published: September 2007

The dietary components responsible for the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remain unclear. Wistar rats were divided into four groups based on their diet: a low soybean‐oil diet, a low cow‐fat diet, a high soybean‐oil diet, and a high cow‐fat diet. First, we evaluated the bile acid composition of the bile juice in each group without operation, using high‐performance liquid chromatography. Because only high cow‐fat intake induced changes in the composition of bile acids in bile juice, we then selected animals fed with a low soybean‐oil diet and those with a high cow‐fat diet to carry out esophago‐jejunostomy for reflux of the duodenal contents, and compared sequential morphological changes between these groups up to 30 weeks after surgery. At 30 weeks after surgery, the reflux animals in the high cow‐fat group showed a significantly higher incidence of BE and Barrett's dysplasia than those in the low soybean‐oil group, and the incidence of EAC in the high cow‐fat group was also slightly higher than that in the low soybean‐oil group. High dietary animal fat changed the bile‐acid composition and increased the concentration of taurine conjugates in the bile juice. These increased bile acids promoted the development of BE and Barrett's dysplasia leading to EAC. (Cancer Sci 2007; 98: 1683–1688)
Identifying health disparities across the tobacco continuum
Authors: Fagan Pebbles , Moolchan Eric T. , Lawrence Deirdre , Fernander Anita , Ponder Paris K.
Published: September 2007

Aims Few frameworks have addressed work‐force diversity, inequities and inequalities as part of a comprehensive approach to eliminating tobacco‐related health disparities. This paper summarizes the literature and describes the known disparities that exist along the tobacco disease continuum for minority racial and ethnic groups, those living in poverty, those with low education and blue‐collar and service workers. The paper also discusses how work‐force diversity, inequities in research practice and knowledge allocation and inequalities in access to and quality of health care are fundamental to addressing disparities in health.

Methods We examined the available scientific literature and existing public health reports to identify disparities across the tobacco disease continuum by minority racial/ethnic group, poverty status, education level and occupation.

Findings Results indicate that differences in risk indicators along the tobacco disease continuum do not explain fully tobacco‐related cancer consequences among some minority racial/ethnic groups, particularly among the aggregate groups, blacks/African Americans and American Indians/Alaska Natives. The lack of within‐race/ethnic group data and its interactions with socio‐economic factors across the life‐span contribute to the inconsistency we observe in the disease causal paradigm.

Conclusions More comprehensive models are needed to understand the relationships among disparities, social context, diversity, inequalities and inequities. A systematic approach will also help researchers, practitioners, advocates and policy makers determine critical points for interventions, the types of studies and programs needed and integrative approaches needed to eliminate tobacco‐related disparities.
Addressing tobacco‐related health disparities
Authors: Moolchan Eric T. , Fagan Pebbles , Fernander Anita F. , Velicer Wayne F. , Hayward Mark D. , King Gary , Clayton Richard R.
Published: September 2007

Aims The aim of this review is to outline a transdisciplinary research framework for identifying, explaining and intervening to address tobacco‐related health disparities (TRHD). We will show the importance of an approach that integrates the human life‐cycle (developmental) and tobacco addiction cycle (behavioral) for interventions that address group‐specific vulnerabilities.

Methods The existing empirical knowledge base on tobacco‐related health disparities is mapped onto a conceptual framework built around life‐cycle and addiction cycle trajectories for disparate population groups.

Findings Current knowledge about developmental trajectories of tobacco use is based on general population studies with minimal information on group differences. At the national level, early onset of tobacco use is associated with a high level of tobacco dependence, low number of quit attempts, long‐term smoking history and tobacco‐related health harm. These relationships cannot be assumed for all population groups: African Americans and Asian Americans typically have a later age of tobacco use onset compared to European Americans, yet health consequences of smoking are higher among African Americans but not Asian Americans. Even less is known about group differences in the temporal progression from smoking onset to daily smoking. Determining the time‐frame from initial to regular smoking seems crucial for targeted secondary prevention, before the establishment of addictive tobacco use patterns. Group‐specific data characterizing the duration from daily tobacco use to a quit attempt or request for cessation treatment are also scant.

Conclusions A comprehensive, integrated, transdisciplinary framework is needed to guide efforts to understand tobacco‐related health disparities and to increase the effectiveness of evidence‐based interventions delivered in culturally appropriate and economically practicable ways, while optimizing the balance between demand for and access to services.
A biopsychosocial approach to examining tobacco‐related health disparities among racially classified social groups
Authors: Fernander Anita F. , Shavers Vickie L. , Hammons George J.
Published: September 2007

Aims To articulate a broader, multi‐causal model that incorporates psychosocial and environmental factors that can differ systematically across racially classified social groups (RCSGs) and impact biological pathways related to the development of tobacco‐related diseases.

Methods This paper is built upon a review of the existing scientific literature on selected biopsychosocial factors (diet/nutrition, obesity, alcoholic intake, psychosocial stress, occupational/environmental exposures and exposure to other diseases and illnesses) and tobacco use in examining the biological contributions to differences in tobacco‐related health outcomes among RCSGs.

Findings Recent work has focused on RCSG genetic variations as a possible explanation for differences in tobacco‐related health disparities. It is argued in this paper that, given the genetic heterogeneity ‘within’ RCSGs, it is unlikely that across RCSG genetic variations are likely to be the major source of differences impacting biological pathways in tobacco‐related health outcomes. The evidence shows that results, even at the level of within‐population genetic variations, have been limited and often inconsistent. A conceptual framework is proposed to account for biological pathways related to the development of tobacco‐related diseases.

Conclusions Determinants of tobacco‐related health disparities are not understood clearly. The contribution of biological factors may be important. Current efforts to determine biological differences in tobacco use and related diseases among RCSGs have focused primarily on genetic variations. However, this approach has limitations. An alternative biopsychosocial framework that examines the potential biological mechanisms through which life experiences and behavior might affect tobacco use and health outcomes in these population groups is needed, including those of life‐style (e.g. diet/nutrition, obesity, physical exercise, alcohol consumption), psychosocial (e.g. stress and coping), occupational/environmental exposures and the presence of other diseases/illnesses.
Racially classified social group tobacco‐related health disparities: what is the role of genetics?
Authors: FERNANDER ANITA F.
Published: September 2007

Certain racially classified social groups suffer disproportionately from tobacco‐caused morbidity and mortality. Recent advances in genetics are leading researchers to examine variables that may account for this. However, it is critical that investigators proceed with caution and utilize transdisciplinary approaches. A number of fundamental questions might be used to stimulate consensus building in this area of science. What is race and how should its complexity be operationalized? Is it possible/likely that pharmacogenetics will allow us to match smokers with cessation strategies based on a gene‐psychological profile? What are the most important conceptual and methodological issues for a research agenda in this area?
Overcoming confounding of race with socio‐economic status and segregation to explore race disparities in smoking
Authors: LaVeist Thomas A. , Thorpe Roland J. , Mance GiShawn A. , Jackson John
Published: September 2007

Aims  We examined the nature of racial disparities in smoking status within a sample that accounts for two major confounding factors in health disparities research—racial segregation and socio‐economic status. Also, we sought to determine the generalizability of our sample.

Design and setting  Cross‐sectional study based on data from the Exploring Health Disparities in Integrated Communities Study in south‐west Baltimore, MD (EHDIC‐SWB) and a subsample of respondents in the 2002 National Health Interview Survey (NHIS) that was matched to EHIDC‐SWB. The final matched data set sample size was 2948 adults (1474 EHDIC‐SWB; 1474 matched NHIS).

Measurements  Our outcome variables were life‐time and current smoking status and number of cigarettes smoked daily. Independent variables include race, age gender, educational attainment and income.

Findings  In the adjusted models, whites had greater odds than blacks of current smoking and reported smoking more cigarettes in the EHDIC‐SWB sample, but there were no race differences in current smoking status or in the number of cigarettes smoked per day in the NHIS. The prevalence rates for both life‐time and current smoking were substantially greater in the EHDIC‐SWB sample, but in comparisons of blacks and whites across samples we found that the magnitude of the difference between the samples was greatest for whites.

Conclusions  Unadjusted national estimates of race disparities as reported in national reports may be biased because of differential risk exposure among people of different race groups. Race differences in social and environmental contexts account partially for racial differences in smoking patterns.
How reliable and valid is the Brief Sensation Seeking Scale (BSSS‐4) for youth of various racial/ethnic groups?
Authors: Vallone Donna , Allen Jane A. , Clayton Richard R. , Xiao Haijun
Published: September 2007

Aims  To assess the reliability and validity of the Brief Sensation Seeking Scale BSSS‐4 by race/ethnicity.

Design  Six waves of nationally representative, cross‐sectional, Legacy Media Tracking Survey (LMTS) data. Analyses are based on a sample size of 24 328 individuals. Response rates for the individual survey administrations range from 60% to 30%.

Setting  Data were collected by telephone, from April 2001 to January 2004.

Participants  Youth, aged 12–17 years, who completed the LMTS.

Measurements  Sensation seeking was measured using the four‐item scale, BSSS‐4, published by Stephenson et al. in 2003. A series of items from the LMTS was used to measure youth intention to smoke and smoking behavior.

Findings  Mean sensation seeking scores increased as the risk for established smoking increased. African American youth who are open to smoking or have experimented with cigarettes had lower mean sensation seeking scores than their white and Hispanic counterparts. Coefficient alpha and average corrected item‐total correlations suggest that the BSSS‐4 is a less reliable measure of sensation seeking for African American youth compared to white and Hispanic youth.

Conclusions  The BSSS‐4 is a useful tool for identifying youth at risk for smoking; however, it is less reliable and valid for African American youth compared with other youth. Future research should investigate whether other existing sensation seeking scales are equally reliable and valid across race/ethnicity, and whether an alternative scale could or should be developed that would measure sensation seeking more effectively among African American youth.
The reliability and validity of the Brief Sensation Seeking Scale (BSSS‐8) with young adult Latino workers: implications for tobacco and alcohol disparity research
Authors: Stephenson Michael T. , Velez Luis F. , Chalela Patricia , Ramirez Amelie , Hoyle Rick H.
Published: September 2007

Aim  This study investigated the reliability and validity of the Brief Sensation Seeking Scale (BSSS‐8) in both English and Spanish with Latinos, the fastest‐growing minority group in the United States, and the correlation between sensation seeking and tobacco and alcohol use.

Design  Cross‐sectional survey, computer‐assisted telephone interviews (CATI).

Setting  Dallas and Houston, Texas.

Participants  A total of 789 Latinos participated in this study. Participants were currently in the work‐force, not enrolled in college, and between the ages of 18 and 30 years.

Measurements  Participants completed a self‐report questionnaire (in either English or Spanish) consisting of items measuring tobacco and alcohol use as well as the eight‐item Brief Sensation Seeking Scale.

Findings and conclusions  For English‐speaking Latino participants, the BSSS factor structure was second‐order unidimensional and correlated positively with life‐time cigarette use, intention to smoke in the future and amount and frequency of alcohol consumption. For Spanish‐speaking Latino participants, a four‐subfactor solution for the BSSS provided the best fit to the data although correlations between the four subscales and cigarette use were small.
Sensation seeking: a commentary
Authors: CLAYTON RICHARD R. , SEGRESS MELISSA J. H. , CAUDILL CRYSTAL A.
Published: September 2007

Aims  To discuss some of the conceptual and methodological issues about race/ethnicity and sensation seeking not discussed fully in the two empirical papers in this issue.

Methods  The authors of this commentary examined critically the papers in this issue by Vallone et al. and Stephenson et al. and asked if there were underlying or foundational issues that were ignored or not discussed adequately regarding the sensation seeking construct. After reviewing an initial list of those issues, a decision was made to discuss four of them.

Findings  There is inadequate attention paid to: (i) the developmental aspects of sensation seeking and the almost exclusive focus on youth; (ii) the possibility that sensation seeking is relevant primarily for initial events and not continuation, progression within and across drug classes, progression to dependence, regression, cessation and relapse; (iii) the putative multi‐dimensionality of sensation seeking and the pervasive tendency of researchers to ignore the dimensions; and (iv) possible lack of validity of the construct within and across racial and ethnic groups.

Conclusions  The two papers in this issue by Vallone et al. and Stephenson et al., each of which is focused on racial/ethnic differences in the relationship of sensation seeking to tobacco attitudes, intentions and tobacco use, suggest that it is time for more foundational research on the relevance of the multi‐dimensional definition of the construct. The relationship of the putative dimensions to each other and to other variables, and the utility of the construct for segmenting audiences and predicting public health outcomes, is an area where more foundational research is needed.
Differential impact of state tobacco control policies among race and ethnic groups
Authors: Tauras John A.
Published: September 2007

Aims  This paper describes patterns of racial and ethnic cigarette use in the United States and discusses changes in state‐level tobacco control policies. Moreover, this paper reviews the existing econometric literature on racial and ethnic smoking and discusses the limitations of that research. Finally, this paper outlines an agenda for future research.

Methods  Patterns of racial and ethnic smoking and changes in state‐level tobacco control policies in the United States were obtained from a variety of sources, including surveys and government and private documents and databases. After an extensive literature search was completed, the existing research was scrutinized and recommendations for much‐needed future research were put forth.

Findings  Despite the fact that certain racial and ethnic minorities bear a disproportionate share of the overall health burden of tobacco, less than a handful of econometric studies have examined the effects of state‐level public policies on racial and ethnic smoking. The existing literature finds Hispanics and African Americans to be more responsive to changes in cigarette prices than whites. Only one study examined other state‐level tobacco policies. The findings from that study implied that adolescent white male smoking was responsive to changes in smoke‐free air laws, while adolescent black smoking was responsive to changes in youth access laws.

Conclusions  While much has been learned from prior econometric studies on racial and ethnic smoking in the United States, the existing literature suffers from numerous limitations that should be addressed in future research. Additional research that focuses on races and ethnicities other than white, black and Hispanic is warranted. Furthermore, future studies should use more recent data, hold sentiment toward tobacco constant and control for a comprehensive set of tobacco policies that take into account not only the presence of the laws, but also the level of restrictiveness of each policy.
Most Latino smokers in California are low‐frequency smokers
Authors: Zhu Shu‐Hong , Pulvers Kim , Zhuang Yuerong , Báezconde‐Garbanati Lourdes
Published: September 2007

Aims  We examine the phenomenon of low‐frequency smoking (non‐daily smoking or smoking ≤ 5 cigarettes daily) among California Latinos and address its implications for addiction theory and population tobacco control.

Design, setting and participants  Data gathered in 2001 and 2003 through the California Health Interview Survey (CHIS), the largest general health survey in California. The present study focused on Latino current smokers (n = 1254 for CHIS 2001; n = 946 for CHIS 2003).

Measurement  Latino smokers reporting either non‐daily smoking or smoking ≤5 cigarettes daily were identified and grouped into one category: low‐frequency smokers.

Findings  Weighted by population parameters, more than 70% of Latino smokers in California were found to be low‐frequency smokers [70.7% (CI = 67.2%, 73.9%) in 2001 and 70.8% (CI = 67.1%−74.2%) in 2003]. This high proportion cut across all demographic dimensions in both surveys, suggesting pervasiveness and reliability of this phenomenon. Proportions for non‐daily smokers and low‐rate daily smokers were 48.6% and 22.1% in 2001 and 54.9% and 15.9% in 2003. In both surveys, more than 80% of non‐daily smokers consumed ≤ 5 cigarettes on their smoking days.

Conclusions  The fact that most Latino smokers are low‐frequency smokers calls for a new theoretical framework—beyond withdrawal‐based theories—to account for the prevalence of this behavior on the population level. It also calls into question the harm‐reduction approach as a tobacco control strategy for California Latino populations. Strategies emphasizing that every cigarette can hurt, and encouraging complete cessation, seem more fitting for this group of smokers.
Building capacity to address tobacco‐related disparities among American Indian and Hispanic/Latino communities: conceptual and systemic considerations
Authors: Báezconde‐Garbanati Lourdes , Beebe Laura A. , Pérez‐Stable Eliseo J.
Published: September 2007

Aim  To discuss systemic and conceptual issues that surround capacity building for tobacco control in traditionally underserved communities, by presenting two case studies, one in an American Indian community and another in a Hispanic/Latino community.

Design  Key informant interviews, cross‐sectional surveys and case study methods were used to create community‐specific conceptual frameworks for building capacity for tobacco control. These models of capacity building serve as the backdrop for the development of the two case studies.

Setting, participants, measurements  Interview and survey participants were identified through convenience and snowball sampling, using a community‐based participatory process in an American Indian community in Oklahoma and among the Hispanic/Latino Tobacco Education Partnership (H/LTEP) organizations in California. Using qualitative and quantitative methods, two case studies were created based on the results of interviews with key informants in each of the respective communities, outcomes of efforts to build capacity in tobacco control are presented.

Findings  The extent to which American Indian and Hispanic/Latino communities have the capacity to address effectively the disproportionate burden of tobacco abuse is contingent upon the presence of leadership, collaboration, programs, distribution of funds and resources, development of policies and an underlying understanding of community strengths, history, values and participation. Common characteristics emerge from the case studies that help bridge differences in definition and measurement across both populations and programs.

Conclusion  The conceptual frameworks for capacity building presented provide insight that enhances the ability of priority populations to engage in tobacco control strategies using culturally and language appropriate interventions.
Connective tissue growth factor is an indicator of bone involvement in multiple myeloma, but matrix metalloproteinase‐9 is not
Authors: Munemasa Shoso , Sakai Akira , Kuroda Yoshiaki , Okikawa Yoshiko , Katayama Yuta , Asaoku Hideki , Kubo Tadahiko , Miyakawa Yoshitaka , Serikawa Masahiro , Sasaki Tamito , Kimura Akiro
Published: September 2007

Bone disease (BD) in multiple myeloma (MM) is because of the activation of osteoclasts and impairment of osteoblast differentiation. Connective tissue growth factor (CTGF) is known to participate in the differentiation of mesenchymal stem cells to committed osteoprogenitor cells. We analysed the concentration of circulating CTGF in 35 MM patients and 22 malignant lymphoma (ML) patients and 14 normal individuals. CTGF is protease‐sensitive and thus is found as both an N‐terminal half fragment (N‐half CTGF) and whole (W‐CTGF). Serum levels of W‐CTGF and N‐half CTGF + W‐CTGF were determined by separate sandwich enzyme‐linked immunosorbent assays. The level of W‐CTGF was significantly lower (P < 0·005) in MM patients compared with ML patients and normal individuals, while N‐half + W‐CTGF was similar in all groups. Furthermore, W‐CTGF was significantly lower in MM patients with BD compared with those without BD (P < 0·005) and this was independent of previous treatment. Matrix metalloproteinase (MMP)‐9 is produced by myeloma cells and is thought to be related to BD in MM. However, MMP‐9 does not cleave CTGF and serum MMP‐9 level was not related to BD in MM. Thus, CTGF is an indicator of BD in MM; its metabolism and function in MM should be clarified.
Different regulatory elements are required for response of hepcidin to interleukin‐6 and bone morphogenetic proteins 4 and 9
Authors: Truksa Jaroslav , Peng Hongfan , Lee Pauline , Beutler Ernest
Published: September 2007

Hepcidin is a major regulator of iron homeostasis. Hepcidin expression is upregulated by inflammatory cytokines, particularly interleukin (IL)‐6 and even more potently by the bone morphogenetic proteins 2, 4 and 9 (BMP‐2, BMP‐4 and BMP‐9). This study showed that the regulation of hepcidin expression by IL‐6 and BMPs occurs through distinct regulatory elements. The induction of hepcidin by BMPs requires at least two regions of the Hamp1 promoter, one between 140–260 bp and the other between 1·6–2·0 kb upstream of the start of translation. Reporter constructs including 1·6–2·0 kb of the Hamp1 promoter were induced >16‐fold by BMPs whereas a 260 bp reporter Hamp1 promoter construct was induced only two‐ to threefold. The distal 1·6–2·0 kb region appeared to contain several different BMP‐responsive elements, as incremental lengthening of the promoter construct in this region produced gradual escalation of BMP‐responsiveness. In contrast, the IL‐6 response required only the proximal 260 bp Hamp1 promoter region. Furthermore, there were no regulatory elements located in the non‐coding or coding regions of Hamp1 and activation of the Hamp1 promoter was absent or markedly reduced in cells of non‐hepatic origin.
Thrombin generation: a comparison of assays using platelet‐poor and ‐rich plasma and whole blood samples from healthy controls and patients with a history of venous thromboembolism
Authors: Tappenden Kerry A. , Gallimore Michael J. , Evans Gillian , Mackie Ian J. , Jones David W.
Published: September 2007

We have developed a whole blood thrombin generation (TG) assay whereby TG is initiated with a low‐tissue factor concentration and monitored using a fluorogenic thrombin substrate. Significantly higher values were found in blood samples from 50 patients with a history of venous thromboembolism (VTE) compared with 31 healthy controls (HC), for peak height (P = 0·0034) and endogenous thrombin potential (ETP) (P = 0·0027). Results from 31 VTE patients and the 31 controls in the absence of corn trypsin inhibitor (CTI) showed significantly higher values in the VTE group for peak height (P = 0·0013) and ETP (P = 0·002). In the presence of CTI, significantly higher values were only seen in ETP (P = 0·024). No significant increases in TG were found using platelet poor (PPP) or ‐rich (PRP) plasma with or without CTI. The whole blood TG assay in the absence or presence of CTI showed a higher proportion (25/50 and 12/31, respectively) of raised peak height and/or ETP values than plasma assays (PPP 9/50 and 5/31 respectively and PRP 13/50 and 6/31, respectively). Our results show the whole blood TG assay is more sensitive for determining the increases in TG in patients with a history of VTE than PPP and PRP TG assays.
β‐Thalassaemia and sickle cell anaemia as paradigms of hypercoagulability
Authors: Ataga Kenneth I. , Cappellini Maria D. , Rachmilewitz Eliezer A.
Published: September 2007

Thalassaemia and sickle cell disease (SCD) represent the most common forms of hereditary haemolytic anaemia and result from a partial or complete lack of synthesis of one of the major α‐ or β‐globin chains of haemoglobin A or from a single amino acid mutation (β6Glu→Val) of the β‐globin chain respectively. Although they have different pathophysiologies, patients with these conditions manifest both biochemical and clinical evidence of hypercoagulability. While the frequency of various thrombotic complications may vary in β‐thalassaemia and homozygous SCD [sickle cell anaemia (SCA)], patients with both diseases manifest decreased levels of natural anticoagulant proteins, as well as increased markers of thrombin generation and platelet activation. The abnormal phospholipid membrane assymetry present in the red blood cells of β‐thalassaemia and SCA patients, with resultant phosphatidylserine exposure appears to play a significant role in the aetiology of the observed hypercoagulable state. This review presents the available data on the aetiology and clinical manifestations of the coagulation and platelet activation that exist in both β‐thalassaemia and SCA, as well as the potential therapeutic implications resulting from this hypercoagulability.
WASP localizes to the membrane skeleton of platelets
Authors: Lutskiy Maxim I. , Shcherbina Anna , Bachli Eric T. , Cooley Jessica , Remold‐O'Donnell Eileen
Published: September 2007

Patients with Wiskott‐Aldrich syndrome (WAS), an X‐linked blood cell disease, suffer from severe thrombocytopenia due to accelerated loss of defective platelets. The affected gene encodes WASP, an actin regulatory protein thought to reside in the cytoplasm of resting leucocytes. In contrast, this study showed that, for platelets, one‐quarter of WASP molecules fractionate in the detergent‐insoluble high speed pellet characterized as the membrane skeleton, the scaffold structure that underlies the lipid bilayer and stabilizes the surface membrane. Following treatment of platelets with thrombin and stirring, which induces cytoarchitectural remodelling, WASP and other membrane skeletal components sedimented at lower g force and partitioned in the low‐speed pellet. Thrombin and stirring also induced WASP tyrosine phosphorylation, a rapid activating reaction, and proteolytic inactivation by cysteine protease calpain. Both the alteration of the sedimentation profile and the proteolytic inactivation were specific for the membrane skeletal pool of WASP and were abrogated in αIIbβ3 integrin‐deficient platelets and in normal platelets treated with an integrin antagonist. The findings demonstrate that WASP is a component of the resting platelet membrane skeleton and participates in membrane skeletal rearrangements downstream of integrin outside‐in signalling. The possible implications for the platelet defect in WAS are discussed.
Low‐dose oral fludarabine plus cyclophosphamide as first‐line treatment in elderly patients with indolent non‐Hodgkin lymphoma
Authors: Fabbri Alberto , Lenoci Mariapia , Gozzetti Alessandro , Chitarrelli Ida , Olcese Francesca , Raspadori Donatella , Gobbi Marco , Lauria Francesco
Published: September 2007

Twenty‐five elderly patients with untreated indolent non‐Hodgkin lymphoma were treated with oral fludarabine 25 mg/m2/d (40 mg total dose) and cyclophosphamide 150 mg/m2/d, both for four consecutive days, repeated every 28 d for four cycles. In all, 21 (84%) patients were responsive: 10 patients achieved complete remission while partial response was obtained in 11. During an observation period of 37 months, there was an overall survival rate of 70% and a median event‐free survival of 20 months. Haematological and extra‐haematological toxicity were mild. This reduced‐dose Flu‐based oral regimen showed good efficacy and was simple to administer on an outpatient basis.
Targeting MEK1/2 blocks osteoclast differentiation, function and cytokine secretion in multiple myeloma
Authors: Breitkreutz Iris , Raab Marc S. , Vallet Sonia , Hideshima Teru , Raje Noopur , Chauhan Dharminder , Munshi Nikhil C. , Richardson Paul G. , Anderson Kenneth C.
Published: September 2007

Osteolytic bone disease in multiple myeloma (MM) is associated with upregulation of osteoclast (OCL) activity and constitutive inhibition of osteoblast function. The extracellular signal‐regulated kinase 1/2 (ERK1/2) pathway mediates OCL differentiation and maturation. We hypothesized that inhibition of ERK1/2 could prevent OCL differentiation and downregulate OCL function. It was found that AZD6244, a mitogen‐activated or extracellular signal‐regulated protein kinase (MEK) inhibitor, blocked OCL differentiation and formation in a dose‐dependent manner, evidenced by decreasedαVβ3‐integrin expression and tartrate‐resistant acid phosphatase positive (TRAP+) cells. Functional dentine disc cultures showed inhibition of OCL‐induced bone resorption by AZD6244. Major MM growth and survival factors produced by OCLs including B‐cell activation factor (BAFF) and a proliferation‐inducing ligand (APRIL), as well as macrophage inflammatory protein (MIP‐1α), which mediates OCL differentiation and MM, were also significantly inhibited by AZD6244. In addition to ERK inhibition, NFATc1 (nuclear factor of activated T‐cells, cytoplasmic, calcineurin‐dependent 1) and c‐fos were both downregulated, suggesting that AZD6244 targets a later stage of OCL differentiation. These results indicate that AZD6244 inhibits OCL differentiation, formation and bone resorption, thereby abrogating paracrine MM cell survival in the bone marrow microenvironment. The present study therefore provides a preclinical rationale for the evaluation of AZD6244 as a potential new therapy for patients with MM.
Trepanning or trephines: a history of bone marrow biopsy
Authors: Parapia Liakat A.
Published: September 2007

Trepanning of bone is the oldest known procedure carried out by man and yet it is only in the last 100 years that we have made use of the technique to diagnose and treat haematological disorders. These advances have been made possible by improvements in instruments, techniques, anaesthesia, laboratory processing and the expertise of haematologists to report the specimens. With the advent of immunological markers and molecular biology, the need for quality bone marrow specimens, if anything, has increased. It will be many years before the bone marrow aspiration/trephine procedure is relegated to the annals of history.
Chromosome 1p21 deletion is a novel prognostic marker in patients with multiple myeloma
Authors: Chang Hong , Ning Yi , Qi Xiaoying , Yeung Joanna , Xu Wei
Published: September 2007

The combination of fluorescence in situ hybridization with cytoplasmic light chain detection identified chromosome 1p21 deletion in 18 (20%) of 87 patients with multiple myeloma. 1p21 deletion was associated with higher serum calcium level, 13q deletion, and t(4;14). Patients with 1p21 deletions had a significantly shorter progression‐free survival (PFS) (median 10·5 vs. 22·3 months, P = 0·0002) and shorter overall survival (OS) (median 33·9 months vs. not reached, P = 0·002) than those without 1p21 deletions. On multivariate analysis, which included deletions of 13q, TP53, t(4;14) and CKS1B amplification, 1p21 deletion remained as an independent risk factor for PFS (P = 0·01) and OS (P = 0·04).
Antiphospholipid antibody syndrome: the flow cytometric annexin A5 competition assay as a diagnostic tool
Authors: Tomer A. , Bar‐Lev S. , Fleisher S. , Shenkman B. , Friger M. , Abu‐Shakra M.
Published: September 2007

The mechanism underlying hypercoagulability in antiphospholipid antibody syndrome (APS) is uncertain. Here, we present a flow‐cytometric assay (FCA) based on the hypothesis that anti‐platelet‐anionic‐phospholipid autoantibodies (aPL) interfere with the activity of the natural anticoagulant protein annexin A5, thereby accelerating platelet procoagulant activity. This study assessed the clinical utility of the feasible FCA, which demonstrates the competition of the patient's aPL with the binding of annexin A5 to the platelet‐anionic‐phospholipids, in the diagnosis of APS. Sixty‐two (94%) of 66 APS patients, 20 (51%) of 39 patients with systemic lupus erythematosus and two (4%) of 49 healthy individuals were positive by FCA. Compared with the anticardiolipin (aCL) assay, the relative sensitivity was 82% and the specificity 73·3%. However, 19 (25%) aCL‐negative patients were positive by FCA; 12 were positive for lupus‐anticoagulant (LA). Compared with LA assay, the relative sensitivity was 85% and the specificity 72·2%. However, 21 (26%) LA‐negative patients were FCA‐positive, 12 were positive for aCL. The FCA was particularly sensitive for APS patients with arterial (97·0%) and gestational vascular complications (100%) with overall sensitivity of 95% and specificity of 97%. Our findings suggest that the FCA is practical, sensitive and specific for the detection of clinically relevant aPL in the diagnosis of APS.
JAK2‐V617F mutation analysis of granulocytes and platelets from patients with chronic myeloproliferative disorders: advantage of studying platelets
Authors: Toyama Kohtaro , Karasawa Masamitsu , Yamane Arito , Irisawa Hiroyuki , Yokohama Akihiko , Saitoh Takayuki , Handa Hiroshi , Matsushima Takafumi , Sawamura Morio , Miyawaki Shuichi , Murakami Hirokazu , Nojima Yoshihisa , Tsukamoto Norifumi
Published: September 2007

There have been conflicting reports over the JAK2‐V617F mutation status of platelets in chronic myeloproliferative diseases (CMPDs). The aim of this study was to analyse JAK2‐V617F status, not only in granulocytes but also in platelets. The JAK2‐V617F mutation was analysed in both granulocytes and platelets in 115 patients with CMPDs using direct sequencing. JAK2‐V617F was detected in granulocytes from 71 of those patients, all 71 of whom also had platelet JAK2‐V617F expression. The remaining 44 patients showed negative JAK2‐V617F expression on granulocytes, but positive JAK2‐V617F expression was detected on the platelets from nine of the 33 essential thrombocythaemia (ET) patients, one of the eight polycythaemia vera patients, and two of the three primary myelofibrosis patients. When ET patients were divided into three groups according to granulocyte and platelet JAK2‐V617F status (both‐positive, platelets‐only positive and both‐negative), the both‐positive and platelets‐only positive groups shared the clinical features of higher white blood cell count and frequent thrombosis. These results suggest that analysis of platelets is a more sensitive approach for detecting JAK2‐V617F in CMPD patients than analysis of granulocytes. They also suggest that previous reports of the incidence of JAK2‐V617F in CMPD patients, obtained using only analysis of granulocytes, could be underestimations.
FUS expression alters the differentiation response to all‐trans retinoic acid in NB4 and NB4R2 cells
Authors: Walsby Elisabeth J. , Gilkes Amanda F. , Tonks Alex , Darley Richard L. , Mills Kenneth I.
Published: September 2007

The FUS gene is overexpressed in acute myeloid leukaemia (AML) patients and has roles in transcription and mRNA processing. We used ectopic expression of FUS and FUS antisense sequences to assess the effect of modulation of FUS expression in all‐trans retinoic acid (ATRA)‐sensitive (NB4) and insensitive (NB4R2) human acute promyelocytic (APL) cell lines which express the t(15:17) translocation. Growth, viability and differentiation patterns were maintained, but the expression of the FUS antisense construct in both the cell lines altered the response to ATRA: the previously ATRA‐sensitive NB4 cells exhibited resistance; whilst the previously resistant NB4R2 cells showed a differentiation response to treatment.
Pseudo‐exon activation caused by a deep‐intronic mutation in the fibrinogen γ‐chain gene as a novel mechanism for congenital afibrinogenaemia
Authors: Spena Silvia , Asselta Rosanna , Platé Manuela , Castaman Giancarlo , Duga Stefano , Tenchini Maria Luisa
Published: September 2007

Congenital afibrinogenaemia, characterized by severe fibrinogen deficiency, is caused by mutations within FGA, FGB or FGG. Conventional sequencing of coding regions and splice signals of these three genes did not reveal any mutation in an afibrinogenaemic proband. After confirming disease co‐segregation with the fibrinogen cluster, full intron sequencing was tackled leading to the identification of a novel transvertion within FGG intron 6 (IVS6−320A→T). Its effect on mRNA processing was evaluated in‐vitro: the in‐frame inclusion of a 75‐bp pseudo‐exon carrying a premature stop was found, representing the first report of pseudo‐exon activation as a mechanism leading to afibrinogenaemia.
Reduced‐intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long‐term outcomes
Authors: Peggs Karl S. , Sureda Anna , Qian Wendi , Caballero Dolores , Hunter Ann , Urbano‐Ispizua Alvaro , Cavet James , Ribera Josep M. , Parker Anne , Canales Miguel , Mahendra Premini , Garcia‐Conde Javier , Milligan Donald , Sanz Guillermo , Thomson Kirsty , Arranz Reyes , Goldstone Anthony H. , Alvarez Ivan , Linch David C. , Sierra Jorge , Mackinnon Stephen ,   On behalf of the UK and Spanish Collaborative Groups
Published: September 2007

The introduction of reduced‐intensity conditioning (RIC) has enabled the role of allogeneic transplantation to be re‐evaluated in Hodgkin lymphoma (HL). While T‐cell depletion reduces graft‐versus‐host disease (GvHD), it potentially abrogates graft‐versus‐tumour activity and increases infective complications. We compared the results in 67 sibling donor transplantations following RIC in multiply relapsed patients from two national phase II studies conditioned with fludarabine/melphalan. One used cyclosporine/alemtuzumab (MF‐A, n = 31), the other used cyclosporine/methotrexate (MF, n = 36) as GvHD prophylaxis. There was a small excess of chemorefractory cases in the MF cohort (P = NS). MF‐A resulted in significantly lower incidences of non‐relapse mortality, acute and chronic GvHD, but no significant excess of relapse/progression. Post donor lymphocyte infusion (DLI) disease responses occurred in 8/14 (57%) and 6/11 (55%) patients in the MF‐A and MF groups, respectively. Current progression‐free survival (CPFS) was superior with MF‐A (univariate analysis), with durable responses to DLI contributing to the favourable outcome (43% vs. 25%, P = 0·0356). Disease status at transplantation significantly influenced overall survival (P = 0·0038) and CPFS (P = 0·0014), retaining significance in multivariate analyses, which demonstrated a trend towards improved CPFS with T‐cell depletion (P = 0·0939). These data suggest that alemtuzumab significantly reduced GvHD without resulting in a deleterious impact on survival outcomes following RIC in HL, and that durable responses to DLI may be more common following the inclusion of alemtuzumab in the conditioning protocol.
Genetic alterations determine chemotherapy resistance in childhood T‐ALL: modelling in stage‐specific cell lines and correlation with diagnostic patient samples
Authors: Estes David A. , Lovato Debbie M. , Khawaja Hadya M. , Winter Stuart S. , Larson Richard S.
Published: September 2007

Acquired drug resistance eventually leads to treatment failure in T‐cell acute lymphoblastic leukaemia (T‐ALL). Immunophenotypic and cytogenetic heterogeneities within T‐ALL influence susceptibility to cytotoxic therapy, and little is known about the mechanisms of drug resistance at specific stages of T‐cell ontogeny. We developed tolerance to therapeutic concentrations of daunorubicin (DNR) and l‐asparaginase (l‐asp) in Jurkat (CD1a−, sCD3+) and Sup T1 (CD1a+, sCD3−) cell lines, having respective ‘mature’ and ‘cortical’ stages of developmental arrest. DNR resistant cells acquired multidrug resistance: 310‐fold increased resistance to vincristine (VCR) and a 120‐fold increased resistance to prednisolone (PRED). Microarray analysis identified upregulation of asparagine synthetase (ASNS) and argininosuccinate synthase 1 (ASS1) to cell lines with acquired resistance to l‐asp, and in the case of DNR, upregulation of ATP‐binding cassette B1 (ABCB1). Suppression of ABCB1, ASNS and ASS1 by RNA interference revealed their functional relevance to acquired drug resistance. Expression profiling of these genes in 80 T‐ALL patients showed correlation with treatment response. This study expands the pool of available drug resistant cell lines having cortical and mature stages of developmental arrest, introduces three new drug resistant T‐ALL cell lines, and identifies gene interactions leading to l‐asp and DNR resistance.
CD4+ T‐cell responses to Epstein–Barr virus (EBV) latent membrane protein 1 in infectious mononucleosis and EBV‐associated non‐Hodgkin lymphoma: Th1 in active disease but Tr1 in remission
Authors: Marshall Neil A. , Culligan Dominic J. , Johnston Peter W. , Millar Colin , Barker Robert N. , Vickers Mark A.
Published: September 2007

Primary infection with Epstein–Barr virus (EBV) in childhood is usually asymptomatic, whereas infection in adolescence may result in infectious mononucleosis (IM) often followed by a fatigue syndrome. EBV latent membrane protein 1 (LMP1) is expressed in latency and in many EBV‐associated tumours, including non‐Hodgkin lymphoma (NHL). Given the regulatory nature of the CD4+ T‐cell response against LMP1 previously reported in healthy donors, we investigated whether patients with active EBV‐driven disease can nevertheless mount effector [T‐helper cell, type 1 (Th1)] anti‐LMP1 responses. We therefore performed a longitudinal study of the nature of CD4+ T‐cell responses to LMP1 in four patients with IM, and five patients with NHL. In both groups, responses changed with time. During symptomatic infection or active tumour growth, responses were dominated by a Th1 effector phenotype, but switched to a regulatory interleukin‐10 response upon recovery. In addition, the fine specificities of the T cells driving these responses evolved. This study showed the dynamic nature of CD4+ T‐cell responses to LMP1, and demonstrated that, although patients can mount Th1 effector responses, recovery from IM and NHL is associated with regulatory responses.
Risk of thromboembolism in 14 000 individuals with coeliac disease
Authors: Ludvigsson Jonas F. , Welander Adina , Lassila Riitta , Ekbom Anders , Montgomery Scott M.
Published: September 2007

The risk of venous thromboembolism (VTE) was examined in individuals with coeliac disease (CD). The Swedish national inpatient register was used to identify 14 207 individuals with a diagnosis of CD (1964–2003). These individuals were matched for age, sex, calendar year and county with 69 048 reference individuals. Cox regression was used to estimate hazard ratios (HRs) for subsequent thromboembolism in individuals with more than 1 year of follow‐up and no prior VTE. CD was associated with an increased risk of subsequent VTE (HR = 1·86; 95% confidence interval (CI) 1·54–2·24). The risk increase was restricted to individuals with CD diagnosed in adulthood. Risk estimates were not affected by the presence of diabetes mellitus or concomitant surgery. Compared with inpatients as reference individuals, CD individuals remained at increased risk of subsequent VTE (adjusted HR = 1·27; 95% CI = 1·06–1·52). In conclusion, this study found a statistically significantly positive association between CD and VTE. This modest association might be explained by a combination of surveillance bias and chronic inflammation.