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The degree of HLA concordance with the patient has long been known to be the major donor-related prediction factor for the success of hematopoietic stem cell transplantations and, with the progress of HLA typing technology, selection criteria became more stringent with regard to the recommended loci and resolution. A late refinement was HLA-C matching, which gained broader acceptance only after the turn of the millennium. The enormous HLA polymorphism has always necessitated registries with a large number of donors in order to be able to provide well-matched donors to a substantial fraction of patients. Using a biostatistical approach, we investigated the impact of adding HLA-C at low or high resolution as a supplementary matching criterion on some key parameters in donor provision for a European-Caucasian population. Starting point is donor selection based on allele level matching for HLA-A, -B, -DRB1, and, optionally, HLA-DQB1.Without typing for HLA-C, 68% of the donors selected based on matching for HLA-A, -B, -DRB1, and -DQB1 at high resolution will also match for HLA-C, 29% will have a single and only 3% will have two HLA-C alleles different from the patient. In order to provide the same fraction of patients with a fully matched donor, a registrywould have to be about twice the size if HLA-C is considered in addition to the four other loci, with the exact factor increasing with the registry's size. If the provision of donors with up to a single allele mismatch is considered, this factor doubles due to the strong linkage between HLA-B and -C.These figures only change slightly when HLA-DQB1 is completely ignored or HLA-C matching is only considered at low resolution. Our results contribute to quantifying the medical and economic impact of the progress in donor selection algorithms. [ABSTRACT FROM AUTHOR]

Allocation of donors with regard to human leukocyte antigen ( HLA) is controversial in heart transplantation. This paper is a systematic review and meta-analysis of the available evidence. PubMed, Embase, and the Cochrane Library were searched systematically for studies that addressed the effects of HLA matching on outcome after heart transplantation. Fifty-seven studies met the eligibility criteria. 34 studies had graft rejection as outcome, with 26 of the studies reporting a significant reduction in graft rejection with increasing degree of HLA matching. Thirteen of 18 articles that reported on graft failure found that it decreased significantly with increasing HLA match. Two multicenter studies and nine single-center studies provided sufficient data to provide summary estimates at 12 months. Pooled comparisons showed that graft survival increased with fewer HLA- DR mismatches [0-1 vs. 2 mismatches: risk ratio ( RR) = 1.09 (95% confidence interval ( CI): 1.01-1.19; P = 0.04)]. Having fewer HLA- DR mismatches (0-1 vs. 2) reduced the incidence of acute rejection [( RR = 0.81 (0.66-0.99; P = 0.04)]. Despite the considerable heterogeneity between studies, the short observation time, and older data, HLA matching improves graft survival in heart transplantation. Prospective HLA- DR matching is clinically feasible and should be considered as a major selection criterion. [ABSTRACT FROM AUTHOR]

Infection, graft-versus-host disease (GVHD), and to a lesser extent sinusoidal obstructive syndrome (SOS) represent the major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). During the last decade, progress in prevention and treatment of these complications led to improvement in the outcome of these patients. Despite the fact that nonmyeloablative regimens have been increasingly used in elderly patients and in patients with co-morbidities, the nonrelapse related mortality remains a challenge and long-term follow-up is required. The objective of this manuscript is to provide an updated concise review of the complications of AHSCT and of the available treatment interventions. [ABSTRACT FROM AUTHOR]

The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation by sequencing at a level that should allow the genome-wide detection of most variants with frequencies as low as 1%. However, in the major histocompatibility complex (MHC), only the top 10 most frequent haplotypes are in the 1% frequency range whereas thousands of haplotypes are present at lower frequencies. Given the limitation of both the coverage and the read length of the sequences generated by the 1000 Genomes Project, the highly variable positions that define HLA alleles may be difficult to identify. We used classical Sanger sequencing techniques to type the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 genes in the available 1000 Genomes samples and combined the results with the 103,310 variants in the MHC region genotyped by the 1000 Genomes Project. Using pairwise identity-by-descent distances between individuals and principal component analysis, we established the relationship between ancestry and genetic diversity in the MHC region. As expected, both the MHC variants and the HLA phenotype can identify the major ancestry lineage, informed mainly by the most frequent HLA haplotypes. To some extent, regions of the genome with similar genetic or similar recombination rate have similar properties. An MHC-centric analysis underlines departures between the ancestral background of the MHC and the genome-wide picture. Our analysis of linkage disequilibrium (LD) decay in these samples suggests that overestimation of pairwise LD occurs due to a limited sampling of the MHC diversity. This collection of HLA-specific MHC variants, available on the dbMHC portal, is a valuable resource for future analyses of the role of MHC in population and disease studies. [ABSTRACT FROM AUTHOR]

Objectives: HLA genes are highly polymorphic in human populations as a result of diversifying selection related to their immune function. However, HLA geographic variation worldwide suggests that demographic factors also shaped their evolution. We here analyzed in detail HLA genetic variation in Europe in order to identify signatures of migration history and/or natural selection. Methods: Relationships between HLA diversity and geography were analyzed at 7 loci through several approaches including linear regression on gene diversity and haplotype frequencies. Regional variation was also assessed on HLA multi-locus phenotypes through structure analysis. Deviation from neutrality was tested by resampling. Results: Geographic distance was a strong predictor of HLA variation at 5 loci (A, B, C, DRB1 and DPB1) in Europe, and latitude significantly shaped HLA gene diversity and haplotype frequencies. Whereas the main level of genetic diversity was found within populations, both HLA gene frequencies and phenotypic profiles revealed regional variation, Southeast Europe, Great Britain and Finland being the most distinctive. Effects of natural selection were suggested at the DQ loci. Conclusions: HLA regional variation was observed in Europe and can be related to population history, locus HLA-A providing by far the strongest signals. This new HLA map of Europe represents an invaluable reference for disease-association studies and tissue transplantation. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Umbilical cord blood (UCB) stem cells allow the transplantation of partially human leukocyte antigen (HLA)-matched grafts and are a valuable resource for the treatment of hematologic malignancies and heritable hematologic, immunologic and metabolic diseases, especially when a compatible bone marrow donor is unavailable. The aim of this study was to determine how many ethnic groups in Iran are covered by the available UCB units based on HLA diversity. Methods: From 2009 until mid-2013, 4,981 (30.3%) of the 16,437 UCB samples collected met the storage criteria and were cryopreserved at a public cord blood bank (CBB) in Tehran, Iran. HLA-A, -B and -DRB1 were typed in 1,793 samples. Results: The mean volume of the cryopreserved samples was 81.25 ± 20.3 ml. The range of total nucleated cells per unit was 51 × 107-107 × 107. The most common HLA alleles were HLA-A*2 (17%) and HLA-A*24 (15.6%), HLA-B*35 (16.8%) and HLA-B*51 (13.9%), and HLA-DRB1*11 (20%) and HLA-DRB1*15 (14%). The predominant haplotypes were HLA-A*24-B*35-DRB1*11 (2%), HLA-A*02-B*50-DR*07 (1.8%), and HLA-A*02-B*51-DRB1*11 (1.5%). Conclusions: Based on the HLA-DRB1 profiles, the UCB units available at the Royan public UCB bank are a potentially adequate resource for hematopoietic stem cell transplantation for Iranian recipients belonging to particular ethnic groups. Regular educational programs to improve the public knowledge of UCB for transplantation can enhance the public CBB stocks for all Iranian ethnic groups in the future. © 2014 S. Karger GmbH, Freiburg [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies (GWAS) identify disease-associations for single-nucleotide-polymorphisms (SNPs) from scattered genomic-locations. However, SNPs frequently reside on several different SNP-haplotypes, only some of which may be disease-associated. This circumstance lowers the observed odds-ratio for disease-association. Methodology/Principal Findings: Here we develop a method to identify the two SNP-haplotypes, which combine to produce each person’s SNP-genotype over specified chromosomal segments. Two multiple sclerosis (MS)-associated genetic regions were modeled; DRB1 (a Class II molecule of the major histocompatibility complex) and MMEL1 (an endopeptidase that degrades both neuropeptides and β-amyloid). For each locus, we considered sets of eleven adjacent SNPs, surrounding the putative disease-associated gene and spanning ∼200 kb of DNA. The SNP-information was converted into an ordered-set of eleven-numbers (subject-vectors) based on whether a person had zero, one, or two copies of particular SNP-variant at each sequential SNP-location. SNP-strings were defined as those ordered-combinations of eleven-numbers (0 or 1), representing a haplotype, two of which combined to form the observed subject-vector. Subject-vectors were resolved using probabilistic methods. In both regions, only a small number of SNP-strings were present. We compared our method to the SHAPEIT-2 phasing-algorithm. When the SNP-information spanning 200 kb was used, SHAPEIT-2 was inaccurate. When the SHAPEIT-2 window was increased to 2,000 kb, the concordance between the two methods, in both of these eleven-SNP regions, was over 99%, suggesting that, in these regions, both methods were quite accurate. Nevertheless, correspondence was not uniformly high over the entire DNA-span but, rather, was characterized by alternating peaks and valleys of concordance. Moreover, in the valleys of poor-correspondence, SHAPEIT-2 was also inconsistent with itself, suggesting that the SNP-string method is more accurate across the entire region. Conclusions/Significance: Accurate haplotype identification will enhance the detection of genetic-associations. The SNP-string method provides a simple means to accomplish this and can be extended to cover larger genomic regions, thereby improving a GWAS’s power, even for those published previously. [ABSTRACT FROM AUTHOR]

Cutaneous manifestations are common in primary immune deficiency diseases, affecting between 40 % and 70 % of patients with diagnosed primary immune deficiency. Skin infections characterize many primary immune deficiencies, but there are also frequent noninfectious cutaneous manifestations seen in many of these disorders, including eczematous lesions, erythroderma, cutaneous granulomas, dysplasia of skin, hair, and nails, autoimmune conditions, and frank vasculitis. For the patient with suspected primary immunodeficiency, much can be inferred by evaluating the presenting cutaneous findings, including various infectious susceptibilities, presence of atopy, and evidence of impaired or overactive inflammatory response. The skin manifestations of primary immune deficiency diseases are often early or heralding findings of the underlying immunologic disease. Therefore, awareness of associations between skin findings and immune deficiency may aide in the early detection and treatment of serious or life-threatening immunologic defects. This review summarizes the common skin manifestations of primary immune deficiency diseases and provides the reader with a differential diagnosis of primary immune defects to consider for the most common skin manifestations. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-α (PML-RARA) fusion protein, which interferes with nuclear receptor signaling and PML nuclear body (NB) assembly. APL is the only malignancy definitively cured by targeted therapies: retinoic acid (RA) and/or arsenic trioxide, which both trigger PML-RARA degradation through nonoverlapping pathways. Yet, the cellular and molecular determinants of treatment efficacy remain disputed. We demonstrate that a functional Pml-transformation-related protein 53 (Trp53) axis is required to eradicate leukemia-initiating cells in a mouse model of APL. Upon RA-induced PML-RARA degradation, normal Pml elicits NB reformation and induces a Trp53 response exhibiting features of senescence but not apoptosis, ultimately abrogating APL-initiating activity. Apart from triggering PML-RARA degradation, arsenic trioxide also targets normal PML to enhance NB reformation, which may explain its clinical potency, alone or with RA. This Pml-Trp53 checkpoint initiated by therapy-triggered NB restoration is specific for PML-RARA-driven APL, but not the RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARA variant. Yet, as NB biogenesis is druggable, it could be therapeutically exploited in non-APL malignancies. [ABSTRACT FROM AUTHOR]

GVHD remains the major impediment to broader application of allogeneic haematopoietic SCT. It can be prevented completely, but at the expense of other complications, rejection, relapse or delayed immune reconstitution. No optimal prevention or treatment method has been defined. This is reflected by enormous heterogeneity in approaches in Europe. Retrospective comparisons between different policies, although warranted, do not give definite answers. In order to improve the present situation, an European Group for Blood and Marrow Transplantation and the European LeukemiaNet working group has developed in a Delphi-like approach recommendations for prophylaxis and treatment of GVHD in the most common allogeneic transplant setting, transplantation from an HLA-identical sibling or unrelated donor for standard risk malignant disease. The working group proposes these guidelines to be adopted as routine standard in transplantation centres and to be used as comparator in systematic studies evaluating the advantages and disadvantages of practices differing from these recommendations. [ABSTRACT FROM AUTHOR]

Population-specific matching probabilities (MP) are a key parameter to assess the benefits of unrelated stem cell donor registries and the need for further donor recruitment efforts. In this study, we describe a general framework for MP estimations of specific and mixed patient populations under consideration of international stem cell donor exchange. Calculations were based on population-specific 4-locus (HLA-A, -B, -C, -DRB1) high-resolution haplotype frequencies (HF) of up to 21 populations. In various scenarios, we calculated several quantities of high practical relevance, including the maximal MP that can be reached by recruiting a fixed number of donors, the corresponding optimal composition by population of new registrants, and the minimal number of donors who need to be recruited to reach a defined MP. Starting at current donor numbers, the largest MP increases due to n = 500,000 additional same-population donors were observed for patients from Bosnia-Herzegovina (+0.25), Greece (+0.21) and Romania (+0.20). Especially small MP increases occurred for European Americans (+0.004), Germans (+0.01) and Hispanic Americans (+0.01). Due to the large Chinese population, the optimal distribution of n = 5,000,000 new donors worldwide included 3.9 million Chinese donors. As a general result of our calculations, we observed a need for same-population donor recruitment in order to increase population-specific MP efficiently. This result was robust despite limitations of our input data, including the use of HF derived from relatively small samples ranging from n = 1028 (Bosnia-Herzegovina) to n = 33,083 (Turkey) individuals. National strategies that neglect domestic donor recruitment should therefore be critically re-assessed, especially if only few donors have been recruited so far. [ABSTRACT FROM AUTHOR]

In order to study the impact of human leucocyte antigen ( HLA) polymorphism distribution in identifying a matched haematopoietic stem cells unrelated donor (UD), we performed a multi-centric retrospective analysis with the aim of comparing the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 phenotypes of 2126 patients (772 patients for whom a donor search failed to identify a matched UD, and 1354 patients who received a 10/10 allele level matched UD). Our results showed that rare HLA-C is often responsible for difficulty in identifying a donor. This locus may add a degree of complexity to a supposed 'frequent' HLA-A HLA-B and HLA-DRB1 phenotype, turning this phenotype into a less frequent one. For example, 32.5% of the phenotypes in the non-transplanted patients could not be explained by any of the pairs of known HLA-A, HLA-B, HLA-C and HLA-DRB1 haplotypes while this percentage dropped to less than 2% if combinations of only HLA-A, HLA-B and HLA-DRB1 haplotypes were considered. Such situations can be anticipated by computing an index, based on HLA haplotype frequency, the average registry sample size ( ARS). ARS is defined as the inverse of the phenotype frequency computed using all corresponding pairs of haplotype frequencies. ARS confirmed that the most significant difference between transplanted and non-transplanted patients was correlated with the introduction of the locus HLA-C in the analysis (median: 8.3e + 4 vs 3.1e + 6, P < 0.0001). The higher the ARS the lower the likelihood of finding a 10/10 match UD reflecting the rareness of the patient's HLA. The area under receiver operator characteristics ( AUROC) values of the ARS computation for HLA-A, HLA-B and HLA-DRB1 was 0.82 (0.80; 0.84) at a low-resolution level (two digits). Overall, our study promotes the use of haplotype frequency-based computations to develop computer-assisted donor search. [ABSTRACT FROM AUTHOR]

In this study, we investigated the factors affecting cell dose harvest and the role of cell dose on outcome. We analysed data from a cohort of 703 patients who underwent unrelated bone marrow transplantation facilitated by IBMDR in GITMO centers between 2002 and 2008. The median-infused cell doses is 3.7 × 108/kg, the correlation between the nucleated cells requested from transplant centers and those harvested by collection centers was adequate. A harvested/requested cells ratio lower than 0.5 was observed only in 3% of harvests. A volume of harvested marrow higher than the median value of 1270 ml was related to a significant lower infused cell dose ( χ2: 44.4; P < 0.001). No patient- or donor-related variables significantly influenced the cell dose except for the recipient younger age ( χ2: 95.7; P < 0.001) and non-malignant diseases ( χ2: 33.8; P < 0.001). The cell dose resulted an independent predictor factor for a better outcome in patients affected by non-malignant disease ( P = 0.05) while early disease malignant patients receiving a lower cell dose showed a higher risk of relapse ( P = 0.05). [ABSTRACT FROM AUTHOR]

There have been rare comparative studies of hematopoietic stem cell transplantation from matched sibling donors (MSDs) and unrelated donors (URDs) with regard to peripheral blood stem cell transplantation (PBSCT). We performed a retrospective study of 104 consecutive acute myeloid leukemia (AML) patients who had received an allogeneic PBSCT from an MSD or a URD in order to compare transplant outcomes and posttransplant complications between the 2 groups of patients. The cumulative incidence of grade 2-4 acute graft-versus-host disease (aGVHD) at 100 days (22.6% with MSD vs. 35.3% with URD; p = 0.107) and that of chronic GVHD (cGVHD) at 2 years (72.9% with MSD vs. 56.1% with URD; p = 0.153) was not significantly different between the 2 groups. Multivariate analysis also indicated that a URD was not an independent predictor of grade 2-4 aGVHD or cGVHD. No statistically significant differences were observed in terms of relapse incidence (p = 0.371), nonrelapse mortality (p = 0.473), disease-free survival (p = 0.925) or overall survival (p = 0.534) at 2 years. URDs are comparable with MSDs as a donor type for PBSCT in AML patients if risk-stratified GVHD prophylaxis is adopted. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

For patients lacking a human leucocyte antigen-matched donor, umbilical cord blood (UCB) is an ideal, alternative source of haematopoietic stem cells (HSCs) for transplantation purposes. UCB has many advantages over bone marrow or peripheral blood taken from volunteer donors. UCB is also an important source of other stem cells, including endothelial progenitors, mesenchymal stem cells, very small embryonic/epiblast-like (VSEL) stem cells, and unrestricted somatic stem cells, which are potentially suitable for regenerative medicine. However, a significant clinical problem is that the number of HSCs in one cord-blood unit is not enough for an adult transplantation. The development of new approaches including use of multiple donors, ex vivo expansion, increasing efficiency of homing and engraftment, retrieving more cells from the placenta and cord blood is of crucial importance for the delayed engraftment after UCB transplantation. In the future, UCB will emerge as a source of cells for cellular therapies associated with tissue repair and regeneration. [ABSTRACT FROM AUTHOR]

Estimation of human leukocyte antigen ( HLA) haplotype frequencies from unrelated stem cell donor registries presents a challenge because of large sample sizes and heterogeneity of HLA typing data. For the 14th International HLA and Immunogenetics Workshop, five bioinformatics groups initiated the 'Registry Diversity Component' aiming to cross-validate and improve current haplotype estimation tools. Five datasets were derived from different donor registries and then used as input for five different computer programs for haplotype frequency estimation. Because of issues related to heterogeneity and complexity of HLA typing data identified in the initial phase, the same five implementations, and two new ones, were used on simulated datasets in a controlled experiment where the correct results were known a priori. These datasets contained various fractions of missing HLA-DR modeled after European haplotype frequencies. We measured the contribution of sampling fluctuation and estimation error to the deviation of the frequencies from their true values, finding equivalent contributions of each for the chosen samples. Because of patient-directed activities, selective prospective typing strategies and the variety and evolution of typing technology, some donors have more complete and better HLA data. In this setting, we show that restricting estimation to fully typed individuals introduces biases that could be overcome by including all donors in frequency estimation. Our study underlines the importance of critical review and validation of tools in registry-related activity and provides a sustainable framework for validating the computational tools used. Accurate frequencies are essential for match prediction to improve registry operations and to help more patients identify suitably matched donors. [ABSTRACT FROM AUTHOR]

Objective To determine whether there is a systemic predisposition to chondrocalcinosis (CC) and to examine the association between CC and osteoarthritis (OA) at distant joints. Methods We performed a cross-sectional study embedded in the Genetics of Osteoarthritis and Lifestyle (GOAL) database (n = 3,170). All GOAL participants have had radiographs of the knees, hands, and pelvis performed. These were scored for OA at the knee, hip, wrist, and metacarpophalangeal (MCP) joints and for CC at the knee, hip, wrist, and symphysis pubis joints and for MCP joint calcification. Systemic predisposition to CC was established using cluster analysis. Odds ratios (95% confidence intervals) were used to examine the association between CC at the index and distant joints, CC and OA at the same joint, and index joint OA and distant joint CC. We adjusted for age, sex, and body mass index, and for distant joint OA, if required. Results Joints with CC clustered together. This was also observed when participants with OA were excluded from the analysis. CC at each joint was associated with CC at distant joints. Knee and wrist OA but not hip OA was associated with CC at the same joint. MCP joint OA was associated with MCP joint calcification. Knee OA was associated with CC at other joints, and this was independent of OA at the distant joint. There was no association between hip OA and distant joint CC. Conclusion There is a systemic predisposition to the apparently sporadic CC. OA is associated with CC at the same joint and at distant joints, except hip OA, which is not associated with hip CC or with CC at distant joints. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies with specificity for human leukocyte antigen ( HLA) class I determinants of HLA were originally characterized using serological assays in which the targets were cells expressing three to six HLA class I variants. Because of this complexity, the specificities of the antibodies were defined indirectly by correlation. Here we use a direct binding assay, in which the targets are synthetic beads coated with 1 of 111 HLA class I variants, representing the full range of HLA-A, -B and -C variation. We studied one monoclonal antibody with monomorphic specificity ( W6/32) and four with polymorphic specificity ( MA2.1, PA2.1, BB7.2 and BB7.1) and compared the results with those obtained previously. W6/32 reacted with all HLA class I variants. MA2.1 not only exhibits high specificity for HLA-A*02, - B*57 and - B*58, but also exhibited cross-reactivity with HLA-A*11 and - B*15:16. At low concentration (1 µg/ml), PA2.1 and BB7.2 were both specific for HLA-A*02 and - A*69, and at high concentration (50 µg/ml) exhibited significant cross-reactions with HLA-A*68, - A*23 and - A*24. BB7.1 exhibits specificity for HLA-B*07 and - B*42, as previously described, but reacts equally well with HLA-B*81, a rare allotype defined some 16 years after the description of BB7.1. The results obtained with cell-based and bead-based assays are consistent and, in combination with amino acid sequence comparison, increase understanding of the polymorphic epitopes recognized by the MA2.1, PA2.1, BB7.2 and BB7.1 antibodies. Comparison of two overlapping but distinctive bead sets from two sources gave similar results, but the overall levels of binding were significantly different. Several weaker reactions were observed with only one of the bead sets. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease ( GVHD) is a leading cause of non-relapse mortality following allogeneic haematopoietic cell transplantation. Attempts to improve treatment response in clinically-established GVHD have not improved overall survival, often due to the increased risk of infectious complications. Alternative approaches to decrease GVHD-related morbidity and mortality have focused on the ability to predict GVHD prior to clinical manifestation in an effort to provide an opportunity to abort GVHD development, and to gain new insights into GVHD pathophysiology. This review outlines the research efforts to date that have identified clinical and laboratory-based factors that are predictive of acute GVHD and describes future directions in developing algorithms that will improve the ability to predict the development of clinically relevant GVHD. [ABSTRACT FROM AUTHOR]

This report describes the project to identify the global distribution of extended HLA haplotypes, a component of 16th International HLA and Immunogenetics Workshop ( IHIW), and summarizes the initial analyses of data collected. The project aims to investigate extended HLA haplotypes, compare their distribution among different populations, assess their frequency in hematopoietic stem cell unrelated donor registries and initiate an international family studies database and DNA repository to be made publicly available. HLA haplotypes compiled in immunogenetics laboratories during the evaluation of transplant candidates and related potential donors were analysed. Haplotypes were determined using the pedigree analysis tool publicly available from the National Marrow Donor Program ( NMDP) website. Nineteen laboratories from 10 countries (11 laboratories from North America, five from Asia, two from Latin America and one from Australia) contributed data on a total of 1719 families comprised of 7474 individuals. We identified 10 393 HLA haplotypes, of which 1682 haplotypes included high-resolution typing at HLA- A, B, C, DRB1 and DQB1 loci. We also present haplotypes containing MICA and other HLA loci and haplotypes containing rare alleles seen in these families. The project will be extended through the 17th IHIW, and investigators interested in joining the project may communicate with the first author. [ABSTRACT FROM AUTHOR]

The number of allogeneic hematopoietic SCTs performed globally each year continues to increase, paralleled by an increased demand for donors of therapeutic cells. Donor characteristics and collection procedures have undergone major changes during recent decades, and further changes are foreseen. Information on short- and long-term donor outcomes is of crucial importance to ensure maximal donor safety and availability. Current data, predominantly from unrelated donors, give reliable information on the frequent early events associated with donation-most of them of mild-to-moderate intensity. Information on the type and relative risk of serious adverse reactions is more limited. Moreover, only few data exist on long-term donor outcome. On the basis of this need, recommendations for a minimum data set for prospective donor follow-up were developed in a workshop with the participation of an international group of investigators actively involved in allogeneic stem cell donation under the auspices of and approved by the Worldwide Network for Blood and Marrow Transplantation. Establishment of a standardized global follow-up for both, related and unrelated, donors will enable monitoring of the short- and long-term safety profiles of hematopoietic cell donation and form a solid basis for future donor selection and counseling. [ABSTRACT FROM AUTHOR]

BACKGROUND: Relatives donating peripheral blood stem cells (PBSCs) may be accepted for donation on less strict criteria than unrelated donors. We evaluated the occurrence of adverse events during procedure and follow-up, with a special focus on donors who would have been deferred as unrelated donors. STUDY DESIGN AND METHODS: All 268 related PBSC donors at our center (1996-2006) were included. Data were retrospectively collected from medical reports and standard follow-up. Health questionnaires were sent from 2007. Medical outcomes of donors, deferrable or eligible according to international criteria for unrelated donation, were compared. RESULTS: Forty donors (15%) would have been deferred for unrelated donation. Short-term adverse events occurred in 2% of procedures. Questionnaires were returned by 162 (60%) donors on average 7.5 years after donation, bringing total person-years of follow-up to 1278 (177 in deferrable donors). Nine malignancies and 14 cardiovascular events were reported. The incidence rate of cardiovascular events in eligible donors was 6.5 (95% confidence interval [CI], 2.5-12.3) per 1000 person-years compared to 44.9 (95% CI, 17.4-85.2) in deferrable donors; incidence rates of malignancies were 4.6 (1.4-9.6) and 24.0 (6.0-53.9) per 1000 person-years, respectively, in eligible and deferrable donors. All incidence rates were within the range of age- and sex-matched general population. No autoimmune disorders were reported. CONCLUSION: In both the eligible and the deferrable related donors treated with granulocyte-colony-stimulating factor there are few short-term and long-term problems. The occurrence of post-PBSC cardiovascular events and malignant disease in related donors appears to be within the range of the general population. [ABSTRACT FROM AUTHOR]

HLA-A, -B, -C, - DRB1, - DQB1 assignments were obtained for 374 pairs of African American mothers and their umbilical cord blood units ( CBU) by DNA sequencing. An algorithm developed by the National Marrow Donor Program was used to assign 1122 haplotypes by segregation. Seventy percent of the haplotypes carried assignments at all five loci. In the remainder, alleles at various loci, most often DQB1 in 48% of the haplotypes with a missing assignment, could not be assigned due to sharing of both alleles by mother and CBU. There were 652 haplotypes carrying a unique combination of alleles at the five loci; the majority (74%) were singletons. Novel B∼C and DRB1∼ DQB1 associations were observed. The results show the genetic diversity in this population and provide validation for a publically available tool for pedigree analysis. Our observations underscore the need for procurement of increased numbers of units in the national cord blood inventory in order to identify matching donors for all patients requiring hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

In the majority of countries, surnames represent a ubiquitous cultural attribute inherited from an individual's ancestors and predominantly only altered through marriage. This paper utilises an innovative method, taken from economics, to offer unprecedented insights into the "surname space" of the Czech Republic. We construct this space as a network based on the pairwise probabilities of co-occurrence of surnames and find that the network representation has clear parallels with various ethno-cultural boundaries in the country. Our inductive approach therefore formalizes a simple assumption that the more frequently the bearers of two surnames concentrate in the same locations the higher the probability that these two surnames can be related (considering ethno-cultural relatedness, common co-ancestry or genetic relatedness, or some other type of relatedness). Using the Czech Republic as a case study this paper offers a fresh perspective on surnames as a quantitative data source and provides a methodology that can be easily incorporated within wider cultural, ethnic, geographic and population genetics studies already utilizing surnames. [ABSTRACT FROM AUTHOR]

Different RIC regimens were evaluated prior to allo-HSCT in different hematological malignancies. We conducted this prospective study in adult patients with various hematological malignancies in order to evaluate the toxicity and efficacy of treosulfan-based conditioning, followed by allo-HSCT from 10/10 HLA-identical unrelated donors. Conditioning included treosulfan 12 g/m/day i.v. (day −6 to day −4), fludarabine 30 mg/m/day i.v. (day −6 to day −2), and ATG 2.5 mg/kg/day (day −2 to day −1). PBSC were used as HSC source. We included 56 patients (29 AML, 9 MM, 8 MDS, 6 CLL, 3 ALL, and 1 CML) with a median age of 57 years (18-65.5). Fifty-four (96%) patients engrafted; the cumulative incidence of aGVHD grade ≥II at 3 months reached 31%. The cumulative incidence of cGVHD at 18 months was 34% limited and 8% extensive. The median overall survival (OS) was not reached with a 3-year probability of 52%. The cumulative incidence of relapse at 3 years was 25%, and the cumulative incidence of transplant-related mortality (TRM) at 12 and 24 months was 20% and 23%, respectively. Treosulfan appears to be a good alternative for conditioning of MUD transplant patients with promising results in terms of OS, relapse, and TRM. [ABSTRACT FROM AUTHOR]

In hematopoietic stem cell transplantation, donor selection is based primarily on matching donor and patient HLA genes. These genes are highly polymorphic and their typing can result in exact allele assignment at each gene (the resolution at which patients and donors are matched), but it can also result in a set of ambiguous assignments, depending on the typing methodology used. To facilitate rapid identification of matched donors, registries employ statistical algorithms to infer HLA alleles from ambiguous genotypes. Linkage disequilibrium information encapsulated in haplotype frequencies is used to facilitate prediction of the most likely haplotype assignment. An HLA typing with less ambiguity produces fewer highprobability haplotypes and a more reliable prediction. We estimated ambiguity for several HLA typing methods across four continental populations using an information theory-based measure, Shannon's entropy. We used allele and haplotype frequencies to calculate entropy for different sets of 1,000 subjects with simulated HLA typing. Using allele frequencies we calculated an average entropy in Caucasians of 1.65 for serology, 1.06 for allele family level, 0.49 for a 2002-era SSO kit, and 0.076 for single- pass SBT. When using haplotype frequencies in entropy calculations, we found average entropies of 0.72 for serology, 0.73 for allele family level, 0.05 for SSO, and 0.002 for single-pass SBT. Application of haplotype frequencies further reduces HLA typing ambiguity. We also estimated expected confirmatory typing mismatch rates for simulated subjects. In a hypothetical registry with all donors typed using the same method, the entropy values based on haplotype frequencies correspond to confirmatory typing mismatch rates of 1.31% for SSO versus only 0.08% for SBT. Intermediate-resolution single-pass SBT contains the least ambiguity of the methods we evaluated and therefore the most certainty in allele prediction. The presented measure objectively evaluates HLA typing methods and can help define acceptable HLA typing for donor recruitment. [ABSTRACT FROM AUTHOR]

Background:Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) up-regulates the human leukocyte antigen (HLA) class I antigen presentation machinery (APM). This appears counterintuitive with immune evasion in EBV-associated tumours like nasopharyngeal carcinoma (NPC).Methods:Latent membrane protein 1-transfected epithelial cell lines were used as a model system to study the impact of LMP1 and c-Myc on HLA class I components. The expression of components of the HLA class I APM, c-Myc and Ki-67 was analysed in LMP1+ and LMP1− NPC by immunohistochemistry.Results:In epithelial cells, LMP1 up-regulated HLA class I APM. This effect could be counteracted by c-Myc, which itself was up-regulated by LMP1 apparently through IL6 induction and Jak3/STAT3 activation. Studies of NPC biopsies revealed down-regulation of HLA class I APM expression. No difference was observed between LMP1+ and LMP1− NPC. However, expression of Ki-67 and c-Myc were up-regulated in LMP1+ tumours.Conclusion:These findings raise the possibility that c-Myc activation in NPC might antagonise the effect of LMP1 on HLA class I expression thus contributing to immune escape of tumour cells. [ABSTRACT FROM AUTHOR]

Background: Drug-induced liver injury (DILI) is one of the most common adverse reactions leading to product withdrawal post-marketing. Recently, genome-wide association studies have identified a number of human leukocyte antigen (HLA) alleles associated with DILI; however, the cellular and chemical mechanisms are not fully understood. Methods: To study these mechanisms, we established an HLA-typed cell archive from 400 healthy volunteers. In addition, we utilized HLA genotype data from more than four million individuals from publicly accessible repositories such as the Allele Frequency Net Database, Major Histocompatibility Complex Database and Immune Epitope Database to study the HLA alleles associated with DILI. We utilized novel in silico strategies to examine HLA haplotype relationships among the alleles associated with DILI by using bioinformatics tools such as NetMHCpan, PyPop, GraphViz, PHYLIP and TreeView. Results: We demonstrated that many of the alleles that have been associated with liver injury induced by structurally diverse drugs (flucloxacillin, co-amoxiclav, ximelagatran, lapatinib, lumiracoxib) reside on common HLA haplotypes, which were present in populations of diverse ethnicity. Conclusions: Our bioinformatic analysis indicates that there may be a connection between the different HLA alleles associated with DILI caused by therapeutically and structurally different drugs, possibly through peptide binding of one of the HLA alleles that defines the causal haplotype. Further functional work, together with nextgeneration sequencing techniques, will be needed to define the causal alleles associated with DILI. [ABSTRACT FROM AUTHOR]

Summary Autologous and allogeneic haematopoietic stem cell transplantation ( HSCT) is an option for the treatment of malignant and non-malignant diseases, including the severe autoimmune diseases. Intriguingly, the 'new' autoimmunity developing after transplantation is a constantly recognized phenomenon, which has to be differentiated from original disease relapse, toxicity, infection and graft- versus-host disease. The reported autoimmune diseases occurring in this setting are mainly antibody-associated and organ-specific, with scarce evidence in support for specific treatment options. This review focuses on current concepts on the pathogenesis, the available data on incidence, risk factors, manifestations and treatment of post- HSCT autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: Umbilical cord blood (UCB) has successfully used for transplantation to treat hematologic malignancies and genetic diseases. Herein, we describe the experience generated in a single public UCB bank at Zhejiang Province in China. Methods: Good manufacturing practice and standard operating procedures were used to address donor selection as well as UCB collection, processing, and cryopreservation. Total nucleated cells (TNCs), cellular viability, CD34+ cells, and colony-forming units were determined, and infectious diseases screening test, sterility test, and HLA typing for UCB units were done. Results: Only 18.51% of all collected UCB units met storage criteria, and 7,056 UCB units were cryopreserved in 10 years. The volume of UCB units was 95.0 ± 22.0 ml. The number of TNCs before and after processing was 13.32 ± 3.63 × 108 and 10.63 ± 2.80 × 108, respectively, and the recovery rate was 80.71 ± 11.26%. 0.4344 ± 0.1874% of the TNCs were CD34+ cells. The CFU-GM was 32.1 ± 28.0 colonies per 1 × 105 nucleated cells. Based mainly on HLA and nucleated cell content, 26 UCB units were released for transplantation. Conclusions A public UCB bank was successfully established in China; collection and processing of UCB units should be optimized in order to gain maximum volume and cell count. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Between 1988 and 2007, international searches for matched unrelated donors (MUDs) were performed for 1586 Austrian patients. Between 2004 and 2007, a MUD was identified for 76.7% of the patients. Between 1996 and 2003, a donor was identified for 71.3% of the patients, and between 1988 and 1995, only for 53.4% of the patients. Search times of successful searches decreased from 7.7 months in the first period to 1.7 months in the period from 2004 to 2007. However, transplants were not performed in all cases in which a donor was found: only in 61.6% of the patients between 2004 and 2007, in 53.4% between 1996 and 2003 and in 29.6% between 1988 and 1995. Multivariate analysis determined that having a common HLA type was the most important variable impacting on finding a MUD for a patient. Factors that most strongly influence a patient's access to transplant were the patient's European origin and a short time between diagnosis and start of donor search. The strongest factor for both finding a donor and being transplanted was a search being performed during more recent years: patients' chances increased from year to year. [ABSTRACT FROM AUTHOR]

Idiopathic dilated cardiomyopathy (IDC) has been hypothesized as a multifactorial disorder initiated by an environment trigger in individuals with predisposing human leukocyte antigen (HLA) alleles. Published data on the association between HLA-DR polymorphism and IDC risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 19 case-control studies including 1,378 cases and 10,383 controls provided data on the association between HLA-DR polymorphism and genetic susceptibility to IDC. Overall, statistically elevated frequencies of HLA-DR4 (OR 1.58; 95% CI 1.21-2.07; P = 0.0009) and HLA-DR5 (OR 1.35; 95% CI 1.05-1.73; P = 0.02) alleles were found in patients with IDC compared with controls. Individuals with HLA-DR3 antigen have a protective effect against IDC (OR 0.72; 95% CI 0.58-0.90; P = 0.004). In summary, this meta-analysis indicated that certain HLA-DR alleles may be genetic markers for susceptibility and resistance to IDC. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of present paper is to review and critically address the recent advances on the aetiopathogenesis of the Sjögren's syndrome, taking into account the attained clinical features, with particular relevance given to the oral involvement.Material and Methods: A comprehensive review of the available literature between 1970 and 2012, regarding to the aetiopathogenesis and clinical findings related to Sjögren's syndrome was conducted. Eligible studies were identified by searching the electronic literature PubMed, Medline, Embase, and ScienceDirect databases for relevant reports (last search update January 2012), combining the MESH heading term "Sjögren's syndrome", with the words "salivary glands, xerostomia, xerophtalmia, aetiology". The authors checked the references of the selected articles to identify additional eligible publications and contacted the authors, if necessary.Results: This article addresses a large number of the recent advances in the aetiopathogenesis of the disease, taking into account the attained clinical features of both local and systemic nature. Detailed mechanisms of the hypothesized influence of viral infections, genetic and hormonal factors, and the relevance of the altered glandular homeostasis are critically discussed with particular relevance given to the local and systemic involvement of Sjögren's syndrome. Conclusions: The increasing number of data published recently on the aetiophatogenesis of Sjögren's syndrome strengthens the hypothesis that this condition, as all autoimmune diseases, is a multifactor disorder. Genetic predisposition, hormonal and environmental factors are thought to be implicated. [ABSTRACT FROM AUTHOR]

Summary The frequencies of human leucocyte antigen (HLA)-A, -B and -DRB1 alleles and haplotypes were statistically analysed among 3238 donors from Chinese Marrow Donor Program (CMDP) Jiangsu Branch. All donors were typed using polymerase chain reaction-sequence-based typing (PCR-SBT) method or polymerase chain reaction-reverse sequence-specific oligonucleotide probe (PCR-rSSOP) method. As a result, a total of 46 A, 85 B and 51 DRB1 alleles were found in Jiangsu population. The first three frequent alleles in HLA-A, -B and -DRB1 loci respectively were A*11:01(16.52%), A*24:02(15.10%) and A*02:01(13.02%); B*13:02(11.60%), B*46:01(8.89%) and B*58:01(7.12%); and DRB1*07:01(15.78%), DRB1*09:01(15.26%) and DRB1*15:01(9.76%). The top two frequent A-B-DRB1 haplotypes were A*30:01-B*13:02-DRB1*07:01(8.87%) and A*02:07-B*46:01-DRB1*09:01(2.79%); the top three A-B haplotypes were A*33:03-B*58:01-DRB1*03:01(2.59%), A*30:01-B*13:02(9.92%) and A*33:03-B*58:01(5.48%); the top two B-DRB1 haplotypes were B*13:02-DRB1*07:01(10.23%) and B*46:01-DRB1*09:01(4.61%); the top two A-DRB1 haplotypes were A*30:01-DRB1*07:01(8.96%) and A*33:03-DRB1*13:02(3.95%). These findings provided useful information in the study of genetics and anthropology in Chinese Han population. It also served as a basic guide for selection of future donors in CMDP Jiangsu Branch. [ABSTRACT FROM AUTHOR]

Summary In order to describe the isonymic structure of Paraguay, the distribution of 4,843,868 surnames of 2,882,163 persons was studied in the 18 departments and 237 districts of the nation. The correlations between isonymic and geographic distances for departments were r = 0.713 ± 0.052 for Euclidean distance, 0.597 ± 0.074 for Nei's and 0.582 ± 0.076 for Lasker's, and for districts r = 0.320 ± 0.007, 0.235 ± 0.009 and 0.422 ± 0.008, respectively. Average α was 151 for the entire country, 140.6 ± 6.5 for departments and 108.2 ± 2.7 for districts. The geographical distribution of districts'α is compatible with the settlement of subsequent groups of migrants moving from South towards the Centre and North of Paraguay. The geographical analysis of the first three components of Lasker's isonymy distance matrix is in agreement with such a process. The prevalence of Spanish-Amerindian ethnic groups and the relative absence of indigenous surnames (absence due mainly to the forced surname change of 1848) is in agreement with the diffusion of Spanish speaking males over a low-density area populated by indigenous groups. The present distribution of Y-markers and mt-markers in the available studies in most Latin American populations is compatible with this process. [ABSTRACT FROM AUTHOR]

Background: The Austrian Bone Marrow Donor Registry is the central search coordinating unit in charge of national and international donor searches in Austria. Patients and Methods: Between 1988 and 2010, a worldwide search for an unrelated donor of blood stem cells (URD) was initiated for 2,166 Austrian patients with haematological disorders, 1,671 adults and 495 children, by the Austrian Bone Marrow Donor Registry. Results: An URD was identified for 78.3% of the patients between 2008 and 2010, for 76.7% of the patients between 2004 and 2007, for 71.3% between 1996 and 2003, but only for 53.4% of the patients in the initial period of 1988-1995. Thus, results of international donor searches improve over time. In contrast, search duration decreases steadily: Search times of successful searches decreased from about 8 months in the first period between 1988 and 1996 to 1.84 months in 2010. Overall, 1,558 of the 2,166 patients (71.9%) could be provided with a matching donor. However, not every patient provided with a URD was transplanted. Overall, only 1,141 of 2,166 patients (52.7%) proceeded to transplant. Conclusion: Figures have significantly improved for the latest period of donor searches between 2008 and 2010. In this period, a donor could be found for 78.3%, and 58.5% of the patients received a transplant. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is an autoimmune disorder caused, in most cases, by autoantibodies against components of the neuromuscular junction, frequently the acetylcholine receptor (AChR), and less often the muscle-specific kinase receptor. The thymus plays a major role in the pathogenesis of MG with anti-AChR antibodies: it shows marked pathologic alterations (hyperplastic or tumoral) in most AChR-positive patients and contains the elements required to initiate and sustain an autoimmune reaction (AChR autoantigen, AChR-specific T cells, and autoantibody-secreting plasma cells). In this study we review early and more recent findings implicating the thymus as site of AChR autosensitization in MG and briefly discuss the therapeutic role of thymectomy. We also summarize data showing that the MG thymus is in a state of chronic inflammation, and we review emerging evidence of a viral contribution to the onset and maintenance of the thymic autoimmune response. Muscle Nerve, 2011 [ABSTRACT FROM AUTHOR]

Crosstalk exists between the nervous, endocrine, and immune systems, and perturbations in these interactions have been associated with disease. This includes production of neuroendocrine factors that alter immune system activity and increase susceptibility to or severity of immune-related conditions, such as myasthenia gravis (MG) - a T-cell-dependent, B-cell-mediated autoimmune disorder. MG results from impairment of transmission to the neuromuscular junction and involves the thymus - especially in early-onset disease, but the exact mechanism by which the thymus impacts disease is unclear. MG afflicts millions of individuals worldwide each year, and both men and women can develop symptoms. However, prevalence and age of onset differs between men and women. Women exhibit higher incidence and earlier age of onset compared to men, and disease fluctuates during pregnancy. This suggests that sex hormones play a role in influencing disease outcome. In this review, we will consider what is known about the manifestation of MG, theories on how different forms of MG are influenced or alleviated by steroid hormones, current treatment options, and what measures could be important to consider in the future. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the association of HLA-A, B and HLA-DR gene expression and to assess an association of additional HLA antigens besides HLA-B27 in south Tunisian patients with spondyloarthritis (SpA). Eighty-five patients diagnosed with ankylosing spondylitis (AS, n = 68) and reactive arthrithis (ReA, n = 17) were selected and compared with 100 healthy controls (HC). HLA class I antigens were typed serologically using microlymphocytotoxicity technique. HLA-DRB1* alleles were studied by polymerase chain reaction amplification with sequence-specific primers. The significance of differences between patients and controls was tested by chi-square analysis. We found significantly increased frequencies of HLA-A3 (30.6%; pC = 0.04; OR = 2.95), HLA-B27 (62.35%; pC = 4.10, OR = 53.55), and HLA-DRB1*15 (17.2%; pC = 0.026; RR = 2.58) alleles in SpA patients compared to HC. The most frequent and strongest association was observed for HLA-B27 in AS (pC = 6.6 × 10, OR = 52.23). When AS and ReA patients were analysed separately, HLA-DRB1*15 and HLA-A3 were increased only in AS (pC = 0.01, OR = 2.99 and pC = 0.03, OR = 3.14, respectively). In ReA patients, HLA-DRB1*04 ( p = 0.033, pC = NS, OR = 2.89) was found to be the most common allele. By analysing the HLA-B27-negative subgroup, HLA-A3 and HLA-DRB1*15 expression was found to be dependent on the presence of HLA-B27. HLA-B27 expression was higher in male (45/53; 85%) as compared to female (8/53; 15%) patients ( p = 0.03). Apart from HLA-B27, HLA-A3 and HLA-DRB1*15 are the MHC class I and II alleles found most frequent in Tunisian patients with AS, whereas HLA-DRB1*04 was found most frequent in ReA patients. HLA-B27 is more frequent in male than in female patients. [ABSTRACT FROM AUTHOR]

A major goal of the World Marrow Donor Association (WMDA) is to foster international transplants of hematopoietic stem cells through the establishment of guidelines and recommendations in this field. In this tradition, this study defines a comprehensive framework for HLA matching programs, which use intricate algorithms to rapidly select potential donors for a patient from a database and to present these donors in a prioritized list. Starting with the comparison of single HLA markers of the donor and the patient possibly obtained using different testing methodologies at different resolutions, the more complex matching of loci and phenotypes is inductively built up. The consensus of this international collaborative group describes the state of the art in the field and points out many important design options compatible with the best practice. This should help existing registries to review and validate the most critical part of their IT systems and newly created donor registries around the world to tackle one of their real challenges. [ABSTRACT FROM AUTHOR]

In this study we investigated the human leucocyte antigen-A (HLA-A), -B and DRB1 polymorphism of Native American population of Paraguay, the Guarani Indians. We found that the HLA variability consisted of 5 HLA-A, 7 HLA-B and 6 HLA-DRB1 groups of alleles and of several specific alleles B*1504, B*3505, B*3912, B*4004, B*5104, DRB1*0411, DRB1*1413) common in other Native American populations. The comparison of the HLA polymorphism of the Guaranis from Paraguay with the «Mestizos» of Paraguay and the Spaniards showed that the «Mestizos» of Paraguay are genetically very distant from the Guarani Indians of Paraguay but much more close to the Spaniards. This can be explained, at least in part, by the history of the country. Our results are of importance in transplantation, in particular in the search for an unrelated donor for a Paraguayan patient requiring hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Idiopathic dilated cardiomyopathy (IDC) has been hypothesized as a multifactorial disorder initiated by an environment trigger in individuals with predisposing human leukocyte antigen (HLA) alleles. Published data on the association between HLA-DR4 antigen and IDC risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Studies in English-language articles were identified by a search of PubMed and Embase database (inception to June 2010). A total of 19 case-control studies including 1378 cases and 10,383 controls provided data on the association between HLA-DR4 antigen and genetic susceptibility to IDC. Overall, statistically elevated frequency of HLA-DR4 allele [OR (odds ratio), 1.58; 95% CI (confidence interval), 1.21-2.07; P = 0.0009] was found in patients with IDC compared with controls. When stratified by myocardial biopsy or non-biopsy cases, statistically increased risks were found for IDC in both subgroups. In the subgroup analysis by ethnicity, significantly increased risk was found among Europeans from 12 case-control studies (OR, 1.54; 95% CI, 1.11-2.12; P = 0.009). In conclusion, our results suggest that HLA-DR4 antigen is a low-penetrant risk factor for developing IDC in Europeans. [ABSTRACT FROM AUTHOR]

Requests for participation of unrelated stem cell donors in research transplant protocols are becoming more frequent. World Marrow Donor Association calls on donor registries to participate in research activities. Here, we discuss various implications of research participation and make some recommendations as how to make this possible. [ABSTRACT FROM AUTHOR]