bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of acute promyelocytic leukaemia with
all-trans
retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy
Authors: Zhou Guang-Biao , Zhang Ji , Wang Zhen-Yi , Chen Sai-Juan , Chen Zhu
Published: April 2007

To turn a disease from highly fatal to highly curable is extremely difficult, especially when the disease is a type of cancer. However, we can gain some insight into how this can be done by looking back over the 50-year history of taming acute promyelocytic leukaemia (APL). APL is the M3 type of acute myeloid leukaemia characterized by an accumulation of abnormal promyelocytes in bone marrow, a severe bleeding tendency and the presence of the chromosomal translocation t(15;17) or variants. APL was considered the most fatal type of acute leukaemia five decades ago and the treatment of APL was a nightmare for physicians. Great efforts have been made by scientists worldwide to conquer this disease. The first use of chemotherapy (CT) was unsuccessful due to lack of supportive care and cytotoxic-agent-related exacerbated coagulopathy. The first breakthrough came from the use of anthracyclines which improved the complete remission (CR) rate, though the 5-year overall survival could only be attained in a small proportion of patients. A rational and intriguing hypothesis, to induce differentiation of APL cells rather than killing them, was raised in the 1970s. Laudably, the use of
all-trans
retinoic acid (ATRA) in treating APL resulted in terminal differentiation of APL cells and a 90–95% CR rate of patients, turning differentiation therapy in cancer treatment from hypothesis to practice. The combination of ATRA with CT further improved the 5-year overall survival. When arsenic trioxide (ATO) was used to treat relapsed APL not only the patients but also the ancient drug were revived. ATO exerts dose-dependent dual effects on APL cells: at low concentration, ATO induces partial differentiation, while at relatively high concentration, it triggers apoptosis. Of note, both ATRA and ATO trigger catabolism of the PML–RARα fusion protein which is the key player in APL leukaemogenesis generated from t(15;17), targeting the RARα (retinoic acid receptor α) or promyelocytic leukaemia (PML) moieties, respectively. Hence, in treating APL both ATRA and ATO represent paradigms for molecularly targeted therapy. At molecular level, ATRA and ATO synergistically modulate multiple downstream pathways/cascades. Strikingly, a clearance of PML–RARα transcript in an earlier and more thorough manner, and a higher quality remission and survival in newly diagnosed APL are achieved when ATRA is combined with ATO, as compared to either monotherapy, making APL a curable disease. Thus, the story of APL can serve as a model for the development of curative approaches for disease; it suggests that molecularly synergistic targeted therapies are powerful tools in cancer, and dissection of disease pathogenesis or anatomy of the cancer genome is critical in developing molecular target-based therapies.
Molecular evolution study in China: progress and future promise
Authors: Zhang Ya-ping , Ge Song
Published: April 2007

China has a large land area with highly diverse topography, climate and vegetation, and animal resources and is ranked eighth in the world and first in the Northern Hemisphere on richness of biodiversity. Even though little work on molecular evolution had been reported a decade ago, studies on both the evolution of macromolecules and the molecular phylogeny have become active in China in recent years. This review highlights some of the interesting and important developments in molecular evolution study in China. Chinese scientists have made significant contribution on the methods inferring phylogeny and biogeography of animals and plants in East Asia using molecular data. Studies on population and conservation genetics of animals and plants, such as Golden monkey and Chinese sturgeon, provided useful information for conserving the endangered species. East and South Asia has been demonstrated to be one of the centres of domestication. Origin and evolution of genes and gene families have been explored, which shed new insight on the genetic mechanism of adaptation. In the genomic era, Chinese researchers also made a transition from single-gene to a genomic investigation approach. Considering the fact that amazing progress has been made in the past few years, and more and more talented young scientists are entering field, the future of molecular evolution study in China holds much promise.
Grassland ecosystems in China: review of current knowledge and research advancement
Authors: Kang Le , Han Xingguo , Zhang Zhibin , Sun Osbert Jianxin
Published: April 2007

Grasslands are the dominant landscape in China, accounting for 40% of the national land area. Research concerning China's grassland ecosystems can be chronologically summarized into four periods: (i) pre-1950s, preliminary research and survey of grassland vegetation and plant species by Russians, Japanese and Western Europeans, (ii) 1950–1975, exploration and survey of vegetation, soils and topography as part of natural resource inventory programmes by regional and national institutions mainly led by the Chinese Academy of Sciences, (iii) 1976–1995, establishment of field stations for long-term ecological monitoring and studies of ecosystem processes, (iv) 1996–present, comprehensive studies of community dynamics and ecosystem function integrating multi-scale and multidisciplinary approaches and experimental manipulations.

Major findings of scientific significance in China's grassland ecosystem research include: (i) improved knowledge on succession and biogeochemistry of the semi-arid and temperate grassland ecosystems, (ii) elucidation of life-history strategies and diapause characteristics of the native grasshopper species as one of the key grassland pests, and (iii) development of effective management strategies for controlling rodent pests in grassland ecosystems. Opportunities exist for using the natural grasslands in northern China as a model system to test ecosystem theories that so far have proven a challenge to ecologists worldwide.
Identification of single nucleotide polymorphisms in the bovine CCL2, IL8, CCR2 and IL8RA genes and their association with health and production in Canadian Holsteins
Authors: Leyva‐Baca I. , Schenkel F. , Sharma B. S. , Jansen G. B. , Karrow N. A.
Published: April 2007

The aim of this study was to identify the presence of SNPs in the chemokine genes CCL2 and IL8 and the chemokine receptor genes IL8RA and CCR2, and assess their potential contribution to variation in estimated breeding values (EBVs) for somatic cell score (SCS) and four other traits in Canadian Holstein bulls. Pools of DNA for bulls with high (H) and low (L) EBVs for SCS were used for identification of 11 SNPs. Two unreported SNPs were found in the CCL2 gene and one SNP was found in the CCR2 gene. Previously reported SNPs (three in the IL8 gene and five in the IL8RA chemokine receptor) were also identified. Two SNPs in CCL2, three in IL8, one in IL8RA and one in CCR2 were genotyped in Canadian Holstein bulls (n = 338) using tetra primer ARMS‐PCR. We investigated associations of these seven polymorphisms with three production traits (milk yield, fat yield and protein yield) and one conformation trait related to mastitis (udder depth). The allele substitution effect for the CCL2 rs41255713:T>C SNP was significant at an experimental‐wise level for milk yield (247.5 ± 79.9 kg) and protein yield (7.4 ± 2.3 kg) EBVs (P ≤ 0.05). The associations of the SNPs with SCS EBVs were not significant at an experimental‐wise level. However, the allele substitution effect of the CCR2 rs41257559:C>T SNP on SCS was significant at the comparison‐wise level (−0.04 ± 0.02, P = 0.05), which might indicate a possible association in support of other published studies. Lastly, we assigned CCR2 to BTA22q24, where a previously QTL for SCS was identified.
The locus for bovine dilated cardiomyopathy maps to chromosome 18
Authors: Guziewicz K. E. , Owczarek‐Lipska M. , Küffer J. , Schelling C. , Tontis A. , Denis C. , Eggen A. , Leeb T. , Dolf G. , Braunschweig M. H.
Published: April 2007

Bovine dilated cardiomyopathy (BDCMP) is a severe and terminal disease of the heart muscle observed in Holstein–Friesian cattle over the last 30 years. There is strong evidence for an autosomal recessive mode of inheritance for BDCMP. The objective of this study was to genetically map BDCMP, with the ultimate goal of identifying the causative mutation. A whole‐genome scan using 199 microsatellite markers and one SNP revealed an assignment of BDCMP to BTA18. Fine‐mapping on BTA18 refined the candidate region to the MSBDCMP06–BMS2785 interval. The interval containing the BDCMP locus was confirmed by multipoint linkage analysis using the software loki. The interval is about 6.7 Mb on the bovine genome sequence (Btau 3.1). The corresponding region of HSA19 is very gene‐rich and contains roughly 200 genes. Although telomeric of the marker interval, TNNI3 is a possible positional and a functional candidate for BDCMP given its involvement in a human form of dilated cardiomyopathy. Sequence analysis of TNNI3 in cattle revealed no mutation in the coding sequence, but there was a G‐to‐A transition in intron 6 (AJ842179:c.378+315G>A). The analysis of this SNP using the study's BDCMP pedigree did not conclusively exclude TNNI3 as a candidate gene for BDCMP. Considering the high density of genes on the homologous region of HSA19, further refinement of the interval on BTA18 containing the BDCMP locus is needed.
The stress dependent elastic properties of thermally induced microfractures in aeolian Rotliegend sandstone
Authors: MacBeth Colin , Schuett Hartmut
Published: April 2007

The impact of thermally induced microfractures on the stress‐sensitive elastic wave properties of aeolian Rotliegend sandstone samples is analysed. It is found that to identify the effects of the microfracture contribution accurately, a correction must first be made to account for water loss (representing a mass loss of 4–6%) from the pore throats and clays due to the heating process, despite care being taken to ensure that the thermally fractured samples re‐adsorb room moisture. Both the original and thermally fractured rocks are stress‐sensitive at the ultrasonic wave frequencies of the laboratory. However, a distinct shift in the estimated distribution of internal rock compliance indicates that the population of thermal microfractures differs in nature from that caused solely by core‐plug extraction damage. In particular, the ratio of normal to tangential compliance is observed to be higher for the thermally generated microfractures than for the broken grain‐grain contacts created by extraction unloading. This can be explained by the intragranular thermal‐fracture surfaces being smoother when compared to the intergranular boundaries. Mechanical hysteresis is observed between the up‐ and downgoing test cycles for both the original and, to a greater extent, the thermally fractured rock. This indicates that there is compaction‐induced movement of the fractures in the samples during application of stress in the laboratory.
Converted‐wave imaging in anisotropic media: theory and case studies
Authors: Li Xiang‐Yang , Dai Hengchang , Mancini Fabio
Published: April 2007

Common‐conversion‐point binning associated with converted‐wave (C‐wave) processing complicates the task of parameter estimation, especially in anisotropic media. To overcome this problem, we derive new expressions for converted‐wave prestack time migration (PSTM) in anisotropic media and illustrate their applications using both 2D and 3D data examples.

The converted‐wave kinematic response in inhomogeneous media with vertical transverse isotropy is separated into two parts: the response in horizontally layered vertical transverse isotrophy media and the response from a point‐scatterer. The former controls the stacking process and the latter controls the process of PSTM. The C‐wave traveltime in horizontally layered vertical transverse isotrophy media is determined by four parameters: the C‐wave stacking velocity VC2, the vertical and effective velocity ratios γ0 and γeff, and the C‐wave anisotropic parameter χeff. These four parameters are referred to as the C‐wave stacking velocity model. In contrast, the C‐wave diffraction time from a point‐scatterer is determined by five parameters: γ0, VP2, VS2, ηeff and ζeff, where ηeff and ζeff are, respectively, the P‐ and S‐wave anisotropic parameters, and VP2 and VS2 are the corresponding stacking velocities. VP2, VS2, ηeff and ζeff are referred to as the C‐wave PSTM velocity model. There is a one‐to‐one analytical link between the stacking velocity model and the PSTM velocity model. There is also a simple analytical link between the C‐wave stacking velocities VC2 and the migration velocity VCmig, which is in turn linked to VP2 and VS2.

Based on the above, we have developed an interactive processing scheme to build the stacking and PSTM velocity models and to perform 2D and 3D C‐wave anisotropic PSTM. Real data applications show that the PSTM scheme substantially improves the quality of C‐wave imaging compared with the dip‐moveout scheme, and these improvements have been confirmed by drilling.
CD59 or C3 are not requred for angiotensin II‐dependent hypertension or hypertrophy in mice
Authors: Coles Barbara , Lewis Ruth , Anning Peter B. , Morton Jonathan , Baalasubramanian Sivasankar , Morgan B. Paul , O'Donnell Valerie B.
Published: April 2007

Summary Complement is a major pro‐inflammatory innate immune system whose serum activity correlates with systolic blood pressure in humans. To date, no studies using in vivo models have directly examined the role of individual complement components in regulating vessel function, hypertension and cardiac hypertrophy. Herein, in vivo responses to angiotensin (ang) II were characterized in mice deficient in CD59a or C3. CD59a–/– mice had slightly but significantly elevated systolic blood pressure (107·2 ± 1·7 mmHg versus 113·8 ± 1·31 mmHg, P < 0·01, for wild‐type and CD59a–/–, respectively). Aortic rings from CD59a–/– mice showed significantly less platelet endothelial cell adhesion molecule‐1 (PECAM‐1) expression, with elevated deposition of membrane attack complex. However, acetylcholine‐ and sodium nitroprusside‐dependent dilatation, plasma nitrate/nitrite and aortic cyclic guanosine monophosphate levels were unchanged from wild‐type. Also, in vivo infusion with either ang II or noradrenaline caused similar hypertension and vascular hypertrophy to wild‐type. Mice deficient in C3 had similar basal blood pressure to wild type and showed no differences in hypertension or hypertrophy responses to in vivo infusion with ang II. These data indicate that CD59a deficiency is associated with some vascular alterations that may represent early damage occurring as a result of increased complement attack. However, a direct role for CD59a or C3 in modulating development of ang II‐dependent hypertension or hypertrophy in vivo is excluded and we suggest caution in development of complement intervention strategies for hypertension and heart failure.
The evaluation of direct composite restorations for the worn mandibular anterior dentition – clinical performance and patient satisfaction
Authors: POYSER N. J. , BRIGGS P. F. A. , CHANA H. S. , KELLEHER M. G. D. , PORTER R. W. J. , PATEL M. M.
Published: April 2007

summary  This prospective split‐mouth clinical trial evaluated the performance and patient satisfaction of 168 Herculite XRV direct composite restorations bonded to the worn anterior dentition of 18 patients with localized anterior tooth surface loss. One hundred and six of these restorations were placed on the mandibular anterior teeth. The restorations increased the anterior occlusal vertical dimension between 0·5 and 5 mm and the posterior occlusal contacts were restored after a mean duration of 6·2 months (range: 3–13 months) in 14 out of the 15 ‘Dahl’ sub‐group patients. The restorations were evaluated after 2·5 years of service by five examiners. Four patients and 23 mandibular restorations were lost to follow‐up. Multiple clinical and restorative variables were assessed to determine their influence on restoration performance. Complete failure occurred in 6% of the restorations. Circumferential preparation and height of the restorative addition did not influence the performance of the restorations. A Visual Analogue Scale (VAS) was used to assess the patient's opinion regarding sensitivity, aesthetics, longevity and function of the worn mandibular anterior teeth. A statistically significant difference (95% CI) was found between the pre‐operative and 1‐month review VAS responses for aesthetics and longevity and this was maintained at the 2·5‐year review. Direct composite restorations placed at an increased occlusal vertical dimension are a simple and time‐efficient method of managing the worn mandibular anterior dentition. Patient's acceptance and adaptation to the technique is good and the results are accompanied with a high level of patient satisfaction that is maintained for the medium‐term.
Mitochondrial phylogeography of New Zealand freshwater crayfishes, Paranephrops spp.
Authors: APTE S. , SMITH P. J. , WALLIS G. P.
Published: April 2007

Tectonic movement at the boundary of the Indo‐Australian and Pacific Plates during the Miocene and Pliocene is recognized as a driving force for invertebrate speciation in New Zealand. Two endemic freshwater crayfish (koura) species, Paranephrops planifrons White 1842 and Paranephrops zealandicus White 1842, represent good model taxa to test geological hypotheses because, due to their low dispersal capacity and life history, geographical restriction of populations may be caused by vicariant processes. Analysis of a mitochondrial DNA marker (cytochrome oxidase subunit I) reveals not two, but three major koura lineages. Contrary to expectation, the cryptic West Coast group appears to be more closely related to P. zealandicus than to P. planifrons and has diverged earlier than the final development (Late Pleistocene) of Cook Strait. Our date estimates suggest that koura lineage diversification probably coincided with early to mid‐Alpine orogeny in the mid‐Pliocene. Estimates of node ages and the phylogenies are inconsistent with both ancient Oligocene and recent postglacial Pleistocene range expansion, but suggest central to north colonization of North Island and west to east movement in South Island during mid‐ to late Pliocene. Crypsis and paraphyly of the West Coast group suggest that morphological characters presently used to classify koura species could be misleading.
Finding the relevant scale: clonality and genetic structure in a marine invertebrate (Crambe crambe, Porifera)
Authors: CALDERÓN ISABEL , ORTEGA NATALIA , DURAN SANDRA , BECERRO MIKEL , PASCUAL MARTA , TURON XAVIER
Published: April 2007

Important changes in genetic relatedness may occur at extremely small scales in benthic invertebrates, providing key information about structuring processes in populations of these organisms. We performed a small‐scale study of the population structure of the sponge Crambe crambe, in which 177 individuals from the same rocky wall (interindividual distances from 0 to 7 m) were genotyped using six microsatellite markers. 101 sponges had unique genotypes and the remaining 76 individuals formed 24 groups of sponges sharing genotypes (clones). Mean intraclone distances were found to be c. 20 cm. Spatial autocorrelation analyses showed a drastic decrease in genetic relatedness over the first 100 cm of distance. If the contribution of clonality to this pattern was eliminated, the trend was attenuated, but remained a marked one and was still significant within the first distance classes (30–40 cm). Estimated mean dispersal distances per generation were c. 35 cm, and neighbourhood sizes were estimated at c. 33 sponges. Genetic similarities with sponges of the same locality, or from other Mediterranean localities, were within the same range as those found in sponges 2–7 m apart. It is concluded that asexual reproduction plays an important role in structuring populations in this species. However, over and above the effects of clonality, a strong fine‐scale genetic structure was present at distances in the range of tens of centimetres, probably as a result of short dispersal of larvae. This fine‐scale genetic structure may be common in invertebrates with lecitotrophic larvae.
Limitation of nocturnal import of ATP into Arabidopsis chloroplasts leads to photooxidative damage†
Authors: Reinhold Thomas , Alawady Ali , Grimm Bernhard , Beran Karl Christian , Jahns Peter , Conrath Uwe , Bauer Jenny , Reiser Jens , Melzer Michael , Jeblick Wolfgang , Neuhaus H. Ekkehard
Published: April 2007

When grown in short day conditions and at low light, leaves of Arabidopsis plants with mutations in the genes encoding two plastidial ATP/ADP transporters (so‐called null mutants) spontaneously develop necrotic lesions. Under these conditions, the mutants also display light‐induced accumulation of H2O2 and constitutive expression of genes for copper/zinc superoxide dismutase 2 and ascorbate peroxidase 1. In the light phase, null mutants accumulate high levels of phototoxic protoporphyrin IX but have only slightly reduced levels of Mg protoporphyrin IX. The physiological changes are associated with reduced magnesium–chelatase activity. Since the expression of genes encoding any of the three subunits of magnesium–chelatase is similar in wild type and null mutants, decreased enzyme activity is probably due to post‐translational modification which might be due to limited availability of ATP in plastids during the night. Surprisingly, the formation of necrotic lesions was absent when null mutants were grown either in long days and low light intensity or in short days and high light intensity. We ascribe the lack of lesion phenotype to increased nocturnal ATP supply due to glycolytic degradation of starch which may lead to additional substrate‐level phosphorylation in the stroma. Thus, nocturnal import of ATP into chloroplasts represents a crucial, previously unknown process that is required for controlled chlorophyll biosynthesis and for preventing photooxidative damage.
Elevated calcium phosphate product after renal transplantation is a risk factor for graft failure
Authors: Egbuna Ogo I. , Taylor Jeremy G. , Bushinsky David A. , Zand Martin S.
Published: April 2007

Abstract:  Background:  Abnormal mineral metabolism is not uncommon after renal transplant (TXP). In dialysis patients, elevated serum phosphorous (P), calcium (Ca), CaP product, and parathyroid hormone (PTH) are associated with increased morbidity and mortality. The effect of these abnormalities on recipient and graft survival after renal transplantation is unknown.

Methods:  We retrospectively analyzed 422 kidney‐only transplants performed between June 1996 and June 2003. Cases with graft or recipient survival less than three months, pre‐TXP parathyroidectomy (PTX), cinacalcet therapy and incomplete records were excluded, leaving 303 cases for analysis using Cox models that included post‐TXP PTX, levels of albumin‐adjusted Ca(Caadj), P, CaadjP product and PTH.

Results:  There was an 11–25% prevalence of abnormal serum Caadj, P or CaadjP product within the first year post‐TXP. At least 24% of recipients not undergoing PTX with an equation estimated GFR of 40–60 mL/min had PTH levels >130 pg/mL at one yr post‐TXP. This is above levels recommended by the U.S National Kidney Foundation kidney disease quality initiative for patients with stages I–IV chronic kidney disease. Adjusted Ca > 10.5 mg/dL at three months post‐TXP was an independent risk for recipient death (OR 3.0; 95% CI: 1.2–7.4). A CaadjP product >35 mg2/dL2 at six months (OR 4.0; 95% CI: 1.2–13.1), and Ca >10.5 mg/dL at 12 months post‐TXP (OR 4.0; 95% CI: 1.2–14) were independent risks for death‐censored graft loss. Twenty‐two recipients underwent PTX for severe hyperparathyroidism.

Conclusion:  Abnormalities of mineral metabolism are common early after renal TXP. An elevated serum Caadj at three months post‐TXP increases the risk for recipient death, while an elevated CaadjP and Caadj later in the first post‐TXP year increases the risk of long‐term death‐censored graft loss.
Population samples and genotyping technology
Authors: Mack S. J. , Sanchez‐Mazas A. , Single R. M. , Meyer D. , Hill J. , Dron H. A. , Jani A. J. , Thomson G. , Erlich H. A.
Published: April 2007

The 14th International HLA (human leukocyte antigen) Immunogenetics Workshop (14th‐IHIWS) Biostatistics and Anthropology/Human Genetic Diversity project continues the population sampling, genotype data generation, and biostatistic analyses of the 13th International Histocompatibility Workshop Anthropology/Human Genetic Diversity Component, with the overall goal of further characterizing global HLA allele and haplotype diversity and better describing the relationships between major histocompatibility complex diversity, geography, linguistics, and population history. Since the 13th Workshop, new investigators have and continue to be recruited to the project and new high‐resolution class I and class II genotype data are being generated for 112 population samples from around the world.
Nomenclature for HLA microsatellites
Authors: Gourraud P. A. , Cambon‐Thomsen A. , Dauber E. M. , Feolo M. , Hansen J. , Mickelson E. , Single R. M. , Thomsen M. , Mayr W. R.
Published: April 2007

A proposal for a standardized nomenclature for human leukocyte antigen (HLA) microsatellites is presented. It provides recommendations for Microsatellites as regards to locus name, primer names, and denominations for alleles.
14th International HLA and Immunogenetics Workshop: Report on the immunogenetics of aging
Authors: Naumova E. , Pawelec G. , Ivanova M. , Constantinescu I. , Bogunia‐Kubik K. , Lange A. , Qguz F. , Carin M.
Published: April 2007

The ‘Immunogenetics of Aging’ is a newly included component within the 14th International HLA and Immunogenetics Workshop. The aim of this component was to determine the contribution of human leukocyte antigen (HLA), cytokine genes and other major histocompatibility complex‐encoded loci to successful aging and to determine an increased capacity to reach the extreme limits of life span. Two main data sets from four European populations were included in this study: unrelated healthy elderly individuals and ethnically matched young controls, and families with longevity members. Analysis was focused on HLA class I and II and cytokine gene polymorphisms. Preliminary results showed increased frequencies of DRB1*11‐ and DRB*16‐associated haplotypes that were found to be protective for autoimmune diseases in some populations. Additionally, in families with longevity members, alleles and haplotypes positively associated with autoimmunity were not observed. Analysis of cytokine gene polymorphisms showed prevalence of anti‐inflammatory profiles in healthy elderly individuals. Inheritance of extended haplotypes in families with longevity members allowed the identification of immunogenetic profiles that could be predictive for longevity. These preliminary studies indicate the relevance of genes regulating immune functions in human longevity and the importance of clarifying further their impact in successful aging.
Overview of registries, HLA typing and diversity, and search algorithms
Authors: Hurley C. K. , Maiers M. , Marsh S. G. E. , Oudshoorn M.
Published: April 2007

Over 10 million volunteer donors and cord blood units are typed for human leukocyte antigen (HLA) within hematopoietic stem cell registries and cord blood banks. Identification of matched donors in countries different from that of the searching patient is facilitated by Bone Marrow Donors Worldwide and the World Marrow Donor Association (WMDA). A survey of new volunteer donor typing among WMDA member registries has identified the methods and resolution of HLA testing and the level of quality control used to evaluate the accuracy of typing results. The diversity of HLA assignments within registries has generated a number of informatics challenges. Registries are using population genetics to enhance registry diversity and to facilitate the identification of matched donors.
Strategies for typing new volunteer donors
Authors: Setterholm M. , Morishima Y. , Pepperall J. , Schmidt A.
Published: April 2007

Unrelated donor registries use a variety of strategies for human leukocyte antigen typing newly recruited volunteers and for prospective typing and file maintenance projects. The approaches change over time with respect to the level of resolution and loci tested based on costs, advances in technologies and emerging clinical outcome data from matching studies.
14th International HLA and Immunogenetics Workshop: Report on hematopoietic cell transplantation
Authors: Petersdorf E. , Bardy P. , Cambon‐Thomsen A. , Goulmy E. , Hansen J. , Schwarer A. , Velardi A. ,   The IHWG HCT
Published: April 2007

Deciphering the role of human leukocyte antigen (HLA), killer immunoglobulin like receptor, and immune response genes in a model as complex as unrelated donor hematopoietic cell transplantation is a challenge. The allelic diversity of these genes is shaped by the race and ethnicity of transplant donors and recipients. Coupled with the genetic polymorphism is the complexity of clinical phenotypes of transplant populations: donor and recipient demographic characteristics and the regimens used by transplant physicians to prepare patients for transplantation and to prevent and treat graft‐vs‐host disease (GVHD). Furthermore, GVHD is itself a complex disease shaped by both genes and ‘environment’. How does one begin to deconstruct the genetic barrier to understand risk factors important to transplant outcome? To begin with, population‐based studies, particularly retrospective ones, benefit from adequate sample sizes to measure genetic effects. The more homogeneous the population for variables that influence clinical endpoints, the higher the likelihood that a real genetic effect can be uncovered. Even so, the feasibility of studies can be hampered if genotype and clinical data are not both complete and precise. For studies of HLA, diversity of alleles and antigens contributed by ethnically different transplant populations is an asset, because not only can a broader range of HLA mismatches be studied but they provide the opportunity for side‐by‐side analyses that may yield clues as to why transplant outcomes differ between populations.
Effect of HLA‐A2 allele disparity on clinical outcome in hematopoietic cell transplantation from unrelated donors
Authors: Morishima Y. , Kawase T. , Malkki M. , Petersdorf E. W. ,   International Histocompatibility Working Group in Hematopoietic Cell Transplantation Component
Published: April 2007

Population‐based differences in clinical outcome after unrelated donor hematopoietic cell transplantation suggest that the significance of human leukocyte antigen (HLA) mismatching may be related to locus‐specific and allele‐specific differences that distinguish ethnically diverse transplant donors and recipients. We studied the risks associated with HLA‐A locus mismatching in two large transplant populations from the International Histocompatibility Working Group in hematopoietic cell transplantation data set to better understand permissible and nonpermissible HLA‐A mismatches.
MHC class I, II, and III microsatellite marker matching and survival in unrelated donor hematopoietic cell transplantation
Authors: Malkki M. , Gooley T. , Horowitz M. , Petersdorf E. W. ,   on behalf of the IHWG HCT Component
Published: April 2007

Microsatellites (Msats) are effective markers for disease association mapping. The International Histocompatibility Working Group in hematopoietic cell transplantation applied Msats to determine whether potential new transplantation determinants are encoded within the major histocompatibility complex. Retrospective analysis of human leukocyte antigen‐identical unrelated donor transplants provided a homogeneous population to measure Msat‐associated risks of mortality.
The identification and characterisation of a novel null HLA‐DRB1 allele
Authors: Fidler S. J. , Smith L. K. , Christiansen F. T.
Published: April 2007

Since the introduction of DNA‐based human leukocyte antigen (HLA) typing a number of discrepancies with serological typing have been documented. At the time of submission of this abstract (July 2005 ImMunoGeneTics project (IMGT) project database release) 42 HLA class I and II null alleles had been described characterised by a lack of expression of cell surface antigen. These null alleles can be accounted for by a number of demonstrated molecular mechanisms including insertion, deletion and point mutation and may lead to a nonsense codon, splicing defect or premature stop codon.
The common marmoset as a novel preclinical transplant model: identification of new MHC class II DRB alleles and prediction of in vitro alloreactivity
Authors: Prasad S. , Humphreys I. , Kireta S. , Gilchrist R. B. , Bardy P. , Russ G. R. , Coates P. T. H.
Published: April 2007

The difficulties with using nonhuman primate species such as rhesus macaques and baboons have led us to investigate the common marmoset (Callithrix jacchus) as an alternative preclinical model for transplantation research. This requires reliable methods of detecting alloreactivity between donor and recipient pairs, particularly if colonies are inbred and share just a few common alleles for leucocyte antigens. We firstly identified marmoset major histocompatibility complex (MHC) Class II DRB genes (Caja‐DRB*W1201, Caja‐DRB1*03, Caja‐DRB*W16) using sequence‐based typing techniques. Genomic DNA (n= 49) was extracted from whole blood or spleen tissue. Exon 2 of target genes was amplified by PCR using primers specific for known marmoset alleles, and then sequenced using ABI PRISM® Big Dye Terminator technology and Assign sequence analysis software. DRB*W1201 was universally present. Eight DRB*W16 alleles and five DRB1*03 alleles were identified in this colony. We also identified two previously unreported DRB*W16 alleles, and confirmed inheritance of these alleles within several sibling groups. Subsequently, we investigated whether matching at MHC Class II DRB loci alone could predict alloreactivity, as assessed in vitro by two‐way mixed lymphocyte reactions (MLRs). Fully DRB‐matched, partially mismatched and fully mismatched animal pairs were prospectively chosen. MLR was performed using mononuclear cells (MNC) isolated from whole blood by density gradient separation. T‐cell proliferation after 5‐day culture was measured by 3H‐thymidine incorporation. Combined MNC from fully mismatched and partially mismatched animal pairs exhibited significant in vitro T‐cell proliferation above single cell controls (P < 0.01). MNC from fully DRB‐matched (but unrelated) animal pairs exhibited no proliferation compared with controls (P= 0.3). Using DRB genotyping, suitably alloreactive donor–recipient pairs may therefore be rapidly and accurately identified for use in further studies of cellular and solid organ transplantation.
Sequence‐based typing of HLA‐DQA1: comprehensive approach showed molecular heterogeneity
Authors: Voorter C. E. M. , Lee K. W. , Smillie D. , Tilanus M. G. J. , Van Den Berg‐Loonen E. M.
Published: April 2007

Within the human leukocyte antigen‐DQA1 workshop project the level of molecular heterogeneity of the DQA1 gene was investigated. An improved sequence‐based typing protocol was used, enabling analysis of the complete coding sequence, comprising exons 1–4. The participating laboratories implemented the amplification and sequencing primers in their own sequence‐based typing approach. The method proved to be sufficiently robust to handle the differences in protocols. All reference samples used for validation were correctly typed for DQA1 by all participating laboratories. Three different populations with a total of 736 individuals were investigated: a population of Korean origin (n= 467), a British Caucasian (n= 114), and a Dutch Caucasian (n= 155) population. Sixteen of the known 28 DQA1 alleles were detected and six new alleles were identified. All novel alleles showed a nucleotide substitution outside exon 2. Comparison of the calculated allele frequencies revealed major differences between the Korean and the Caucasian populations but also between Dutch and British Caucasians. A tight association between DQA1 and DRB1/DQB1 alleles was observed in all three populations.
KIR genotyping by reverse sequence‐specific oligonucleotide methodology
Authors: Nong T. , Saito K. , Blair L. , Tarsitani C. , Lee J.‐H.
Published: April 2007

Recent studies suggest that killer cell immunoglobulin‐like receptors (KIR) genotyping may be relevant to bone marrow/stem cell transplantation. The objective of this research was to develop a bead‐based reverse sequence‐specific oligonucleotide DNA hybridization assay for KIR genotyping using the Luminex® platform. The oligonucleotide probes were designed to recognize 14 currently known KIR genes and two pseudogenes, as well as null alleles. A unique probe design was used to allow detection of two cis‐polymorphic regions for typing of KIR2DS4, because the functioning alleles cannot readily be assigned by conventional probe detection systems. Assay performance was validated using DNA samples previously typed by the 13th International Histocompatibility Working Group with 100% concordant results.
Increased frequencies of activating natural killer receptors are associated with liver injury in individuals who do not eliminate hepatitis C virus
Authors: Paladino N. , Flores A. C. , Marcos C. Y. , Fainboim H. , Theiler G. , Arruvito L. , Williams F. , Middleton D. , Fainboim L.
Published: April 2007

This study was designed to investigate the role of killer immunoglobulin‐like receptor (KIR) genes in the outcome of hepatitis C virus (HCV) infection. In patients who cleared the virus (HCV RNA−) we found a decrease of 2DL2 (P= 0.04), and 2DS2 (P= 0.014) accompanied by an increase of 2DS5 (P= 0.04). Those RNA+ patients with elevated levels of hepatic transaminases (HCV RNA+ elevated alanine aminotransferase) showed an increased frequency of 2DS3 (P= 0.018). Additionally, in cirrhotic patients we found an increased frequency of individuals having two copies of 3DS1 and HLA‐Bw4 (P= 0.016). We conclude that higher natural killer cytotoxicity might be associated with a worse progression of the HCV infection.
Immunogenetics of mycobacterial infections in the North Indian population
Authors: Singh M. , Balamurugan A. , Katoch K , Sharma S. K. , Mehra N. K.
Published: April 2007

Several lines of evidence highlight the genetic basis of risk to develop mycobacterial diseases. Human leukocyte antigen (HLA)‐DR2 alleles (DRB1*1501 and DRB1*1502) have been found to be strongly associated with mycobacterial disease, especially the more severe forms such as lepromatous leprosy and multidrug‐resistant pulmonary tuberculosis. In this study, DNA‐based high‐resolution typing techniques of polymerase chain reaction–sequence‐specific oligonucleotide probe were used to determine the distribution of HLA‐DR/DQ alleles in patients with leprosy and pulmonary tuberculosis. Analysis of different DR2 subtypes based on valine/glycine dimorphism at codon β86 in pocket 1 of HLA‐DR showed an inverse relationship of DR2 alleles with V/G as the severity of disease increased both in leprosy and in pulmonary tuberculosis.
14th IHIWS MHC and Infection Study: summary and conclusions
Authors: Kaur G. , Singh M. , Mehra N. K.
Published: April 2007

International collaborative efforts through histocompatibility workshops have helped greatly in collating useful data on interpopulation differences in genetic susceptibility to mycobacterial and viral infections. These are imperative in exploring the genetic basis of disease pathogenesis and host resistance. Because infectious diseases involve multigenic complex traits, several genetic variants contribute modifying effects on the disease but disease outcome depends on the net relative hazards of individual genetic loci taken together. Further because occurrence of genetic variants varies in a population‐specific manner, it becomes even more complicated to show genetic influences across populations. For this, large study cohorts representing different ethnicities are needed. Information thus gained could lead to the development of more effective vaccine design to combat or diminish the emergence of pathogenic multidrug resistant forms.
HLA expression and cancer – 14th IHIWS immunohistochemistry quality control exercise exchange results
Authors: Chew S. F. , Kanaan C. , Tait B. D.
Published: April 2007

An immunohistochemistry (IH) quality control exercise was conducted as part of the 14th International HLA (human leukocyte antigen) and Immunogenetics Workshop (IHIWS) HLA Expression and Cancer component. Six laboratories participated and the exercises involved performing IH using three monoclonal antibodies (HC‐10, β2m and SI00) on three sequential paraffin‐embedded melanoma sections provided by one laboratory. High‐resolution digital photographs of five IH‐stained sections were also distributed for interpretation. While there was generally good agreement between laboratories, several differences in staining and interpretation of IH sections were identified and possible reasons given. Interpretation of the high‐resolution digital photographs showed a high level of concordance between laboratories. It is suggested that further exercises are conducted as part of future collaborative activities in order to further characterise areas of variability between IH performance and interpretation of results.
Corneal sensitivity and aqueous tear production in dogs undergoing evisceration with intraocular prosthesis placement
Authors: Blocker Tiffany , Hoffman Allison , Schaeffer David J. , Wallin Julia A.
Published: April 2007

Objective To determine whether there is an association between evisceration with intraocular prosthesis placement via a dorsal scleral approach and decreased corneal sensitivity or aqueous tear production in dogs.

Design Prospective study.

Procedure Twenty‐one dogs scheduled to undergo unilateral evisceration with intraocular prosthesis, and with a normal normotensive contralateral eye, based on slit‐lamp biomicroscopy, indirect ophthalmoscopy and applanation tonometry, were included in the study. Central corneal sensitivity was measured with a Cochet‐Bonnet esthesiometer prior to (week 0) and 2, 7, 14 and 28 weeks following surgery. Other pre‐ and postoperative data collected were Schirmer's tear test (STT I), Schirmer's tear test with topical anesthesia (STT II), corneal fluorescein retention, and intraocular pressure (IOP; postoperative control eye only). Axial globe length was determined for both eyes. Scleral incision length in the surgery eye was also recorded.

Results Corneal sensitivity was significantly lower in eyes undergoing evisceration with intraocular prosthesis than in control eyes both preoperatively and postoperatively at all time points. There was no significant difference between preoperative and postoperative corneal sensitivity within the two groups. There was no significant difference in STT I or STT II‐values between control eyes and surgery eyes preoperatively. There was a significant difference between preoperative and 2‐week postoperative STT I in the surgery eye. There was a significant difference between the preoperative and 28‐week postoperative STT II in the surgery eye. The 28‐week postoperative STT I‐values differed significantly between control and surgery eyes. Corneal sensitivity tended to decrease with increased degree of buphthalmos or with increased scleral incision length, although neither relationship was statistically significant.

Conclusions Eyes that have sustained chronically elevated intraocular pressure had decreased axial corneal sensitivity compared to normal eyes, which persisted even after intraocular pressure was reduced. The presence of buphthalmos appeared to be a factor in globes developing decreased corneal sensitivity. Evisceration via a dorsal scleral incision did not result in a significant further reduction in axial corneal sensitivity. A mild reduction in aqueous tear production occurred over time in globes following evisceration with intraocular prosthesis.
Circadian rhythm of intraocular pressure in cats
Authors: Del Sole María J. , Sande Pablo H. , Bernades José M. , Aba Marcelo A. , Rosenstein Ruth E.
Published: April 2007

Objective To evaluate the rhythm of intraocular pressure (IOP) in healthy domestic cats with no evidence of ocular disease and to analyze the influence of photoperiod, age, gender and ocular diseases on diurnal‐nocturnal variations of cat IOP.

Animals All animals were Domestic Short‐haired cats; 30 were without systemic or ocular diseases, classified as follows: 12 male intact adult cats, five intact adult female, five adult spayed female, and eight male cats; the latter were less than 1 year of age. In addition, five adult cats with uveitis and three adult cats with secondary glaucoma were included.

Procedure IOP was assessed with a Tono‐Pen XL at 3‐h intervals over a 24‐h period in 12 healthy adult male cats kept under a photoperiod of 12‐h light/12‐h darkness for 2 weeks. Eight animals from the same group were then kept under constant darkness for 48 h, and IOP was measured at 3‐h intervals for the following 24 h. In addition, IOP was assessed at 3 p.m. and 9 p.m. in five intact females, five spayed females, and in eight young cats, as well as in five adult cats with uveitis and three glaucomatous cats.

Results Consistent, daily variations in IOP were observed in animals exposed to a light‐dark cycle, with maximal values during the night. In cats exposed to constant darkness, maximal values of IOP were observed at subjective night. Differences of IOP values between 3 p.m. and 9 p.m. (diurnal‐nocturnal variations) persisted in intact females, spayed females, and young animals, as well as in uveitic and glaucomatous eyes.

Conclusions The present results indicate a daily rhythm of cat IOP, which appears to persist in constant darkness, suggesting some level of endogenous circadian control. In addition, daily variations of cat IOP seem to be independent of gender, age, or ocular diseases (particularly uveitis and glaucoma).
Grid keratotomy as a treatment for superficial nonhealing corneal ulcers in 10 horses
Authors: Brünott A. , Boevé M. H. , Velden M. A.
Published: April 2007

Objective  To describe the clinical symptoms of 10 cases of superficial nonhealing corneal ulcers in horses and to evaluate the results of grid keratotomy in these patients.

Design  Retrospective study.

Animals  Ten horses with superficial nonhealing corneal ulceration in one eye.

Procedure  The signalment, history and clinical symptoms are reported of 10 patients with superficial nonhealing corneal ulcers during the period from August 2003 to February 2005. Grid keratotomy was performed in all cases. In addition, the surgical procedure of grid keratotomy and response to therapy are described.

Results  Horses generally responded well to grid keratotomy (eight cases healed after one grid keratotomy and one horse healed after a second grid keratotomy; one case was not available for follow‐up). Only 2/10 had discomfort after treatment and only 2/9 had some degree of scarring after treatment. The healing time, which was known in seven cases, averaged 8.4 days (± SD 4).

Conclusions and clinical relevance  Grid keratotomy is an appropriate option for treatment of superficial nonhealing corneal ulcers in horses. The procedure is simple to perform. It generally induces a rapid and uncomplicated healing of the cornea. Only in a limited number of cases does a small amount of scarring occur.