bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of the Rákóczi Rebellion on Habsburg Strategy: Incentives and Opportunity Costs
Authors: Höbelt Lothar
Published: December 2005

The emperor’s preoccupation with the Hungarian Rákóczi rebellion close to home, rather than with fighting Louis XIV more effectively, was often cited as a reason for the break-up of the alliance between the Habsburgs and the Protestant sea-powers towards the end of the War of the Spanish Succession. Yet, with the possible exception of the one campaign in 1705, the Habsburgs never wavered in their determination to accord priority to the war with France. When they finally did send more troops into Hungary after 1708, cavalry in particular, the opportunity costs were small - mainly because there were so few opportunities to exploit elsewhere: a few thousand hussars would not have made that much of a difference in Flanders.
Changing Patterns of Thalassemia Worldwide
Authors: VICHINSKY ELLIOTT P.
Published: December 2005

Abstract: Thalassemia is a growing global public health problem with an estimated 900,000 births of clinically significant thalassemia disorders expected to occur in the next 20 years. This growth will occur in disorders previously uncommon in many parts of the world. In particular, hemoglobin (Hb) E‐β‐thalassemia and Hb H disease account for much of the projected increases in thalassemia. Worldwide, Hb E‐β‐thalassemia is one of the most frequent hemoglobinopathies. The incidence of Hb E approaches 60% of the populations in many regions of Southeast Asia. In coastal regions of North America, its prevalence is rapidly growing. The severity of Hb E‐β‐thalassemia ranges from a complete lack of symptoms to transfusion dependence. α‐Thalassemia diseases, often considered benign, are now recognized to be more severe than originally reported. Hb H, Hb H‐constant spring (CS), and homozygous α‐thalassemia affect at least a million people worldwide. California considers Hb H disease a public health problem and has initiated a neonatal screening program for Hb H and particularly Hb H‐CS. Homozygous α‐thalassemia, usually fatal, is also being more commonly detected. Several regions have initiated universal prenatal screening programs to address homozygous α‐thalassemia. In summary, the prognosis for thalassemia disorders is improving, but prenatal diagnosis and neonatal screenings are needed. Comprehensive services that address language and social barriers as well as access to Hb F‐enhancing agents and transfusions are needed.
Isolation and Characterization of Hematopoietic Transcription Factor Complexes by in Vivo Biotinylation Tagging and Mass Spectrometry
Authors: GROSVELD FRANK , RODRIGUEZ PATRICK , MEIER NATALIA , KRPIC SANJA , POURFARZAD FARZIN , PAPADOPOULOS PETROS , KOLODZIEJ KATARZYNA , PATRINOS GEORGE P. , HOSTERT ARND , STROUBOULIS JOHN
Published: December 2005

Abstract: We have described the application of a simple biotinylation tagging approach for the direct purification of tagged transcription factor complexes, based on the use of artificial short peptide tags that are specifically and efficiently biotinylated by the bacterial BirA biotin ligase, which is co‐expressed in cells with the tagged factor. We used this approach to initially characterize complexes formed by the hematopoietic transcription factor GATA‐1 in erythroid cells. GATA‐1 is essential for the erythroid differentiation, its functions encompassing upregulation of erythroid genes, repression of alternative transcription programs, and suppression of cell proliferation. However, it was not clear how all of these GATA‐1 functions are mediated. Our work describes, for the first time, distinct GATA‐1 interactions with the essential hematopoietic factor Gfi‐1b, the repressive MeCP1 complex, and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA‐1/FOG‐1 and GATA‐1/TAL‐1 complexes. We also provide evidence that distinct GATA‐1 complexes are associated with specific GATA‐1 functions in erythroid differentiation, for example, GATA‐1/Gfi‐1b with the suppression of cell proliferation and GATA‐1/FOG‐1/MeCP1 with the repression of other hematopoietic transcription programs. We next applied the biotinylation tag to Ldb‐1, a known partner of GATA‐1, and characterized a number of novel interaction partners that are essential in erythroid development, in particular, Eto‐2, Lmo4, and CdK9. Last, we are in the process of applying the same technology to characterize the factors that are bound to the suppressed γ‐globin promoter in vivo.
Germline Epimutation: A Basis for Epigenetic Disease in Humans
Authors: MARTIN DAVID I.K. , WARD ROBYN , SUTER CATHERINE M.
Published: December 2005

Abstract: Epigenetic modifications of DNA produce reversible and clonally heritable alterations in transcription state. Errors in the elaborate apparatus of epigenetic silencing possessed by higher eukaryotes can lead to “epimutation,” abnormal silencing of a gene. It was supposed that an epimutation in the germline would produce a phenotype equivalent to that resulting from an inactivating germline mutation in the same gene. In testing this hypothesis individuals were identified in whom one allele of the gene encoding the DNA mismatch repair protein MLH1 is epigenetically silenced throughout the soma (implying a germline event). These individuals fit the clinical criteria for hereditary nonpolyposis colorectal cancer, which is usually produced by germline mutation of MLH1. None of the affected individuals have any genetic abnormality that would explain the presence of the epimutation. Thus, an epimutation can phenocopy a genetic disease; this innate epigenetic defect is not necessarily the result of anything other than chance. Epigenetic phenomena tend to be stochastic, reversible, and mosaic; the occurrence and inheritance of epimutations are likely to have rules completely different from those of Mendelian genetics. The application of this principle to the thalassemias is discussed.
Role of Iron in Inducing Oxidative Stress in Thalassemia: Can It Be Prevented by Inhibition of Absorption and by Antioxidants?
Authors: RACHMILEWITZ ELIEZER A. , WEIZER‐STERN ORLY , ADAMSKY KONSTANTIN , AMARIGLIO NINETTE , RECHAVI GIDEON , BREDA LAURA , RIVELLA STEFANO , CABANTCHIK Z IOAV
Published: December 2005

Abstract: The pathophysiology of thalassemia is, to a certain extent, associated with the generation of labile iron in the pathological red blood cell (RBC). The appearance of such forms of iron at the inner and outer cell surfaces exposes the cell to conditions whereby the labile metal promotes the formation of reactive oxygen species (ROS) leading to cumulative cell damage. Another source of iron accumulation results from increased absorption due to decreased expression of hepcidin. The presence of labile plasma iron (LPI) was carried out using fluorescent probes in the FACS. RNA expression of hepcidin was measured in two models of thalassemic mice. Hepcidin expression was also measured in human hapatoma HepG2 cells following incubation with thalassemic sera. LPI was identified and could be quantitatively measured and correlated with other parameters of iron overload. Hepcidin expression was downregulated in the livers of thalassemic mice, in major more than in intermedia. Thalassemic sera down regulated hepcidin expression in HepG2 liver cells. A possible way to decrease iron absorption could be by modulating hepcidin expression pharmacologically, by gene therapy or by its administration. Treatment with combination of antioxidants such as N‐acetylcysteine for proteins and vitamin E for lipids in addition to iron chelators could neutralize the deleterious effects of ROS and monitored by quantitation of LPI.
Ferritin as an Iron Concentrator and Chelator Target
Authors: LIU XIAOFENG , THEIL ELIZABETH C.
Published: December 2005

Abstract: Ferritin has a broad role to play in new strategies for managing Cooley's anemia and the thalassemias. Serum ferritin iron content is relegated to reporting on tissue iron concentrations. Recently, a new property of ferritin was discovered: gated pores, which are highly conserved in ferritins of humans down to bacteria, and control iron flow to chelators. The pore gates can be selectively opened to increase chelator access by mutation, temperature, and physiological concentrations of urea. In another recent observation, the iron in ferritin from seeds such as soybeans has been shown to be readily available to tissues with high demand for iron, such as red blood cells, but slower to be mobilized in other tissues, compared to nonheme iron salts, presumably through a controlled iron gating mechanism. Because the iron pore gating property of ferritin is more thoroughly investigated, and the knowledge that much of the iron to be chelated in the thalassemias is from a solid iron mineral inside the ferritin protein nanocage, a new role of ferritin in regulating cellular iron homeostasis is established. Two new areas, based on recent knowledge of the molecular properties of ferritin, are (1) exploration of food ferritin as a potentially safer form of dietary nonheme iron, and (2) development of chelators targeted to ferritin protein pores that control chelator access.
The Design of Orally Active Iron Chelators
Authors: HIDER ROBERT C. , ZHOU TAO
Published: December 2005

Abstract: It is now generally accepted that it is not possible to design iron(III)‐selective hexadentate chelators with high oral bioavailability. In order to achieve suitable levels of oral activity for the treatment of systemic iron overload either tridentate or bidentate molecules need to be investigated. There are a number of such molecules in clinical practice, including hydroxypyridin‐4‐ones, desferrithiocin analogues and bis‐hydroxyphenyltriazoles. The underlying chemistry of each group is described, together with an indication of the distribution properties, redox cycling activity, and iron scavenging activity.
Combined Therapy with Deferoxamine and Deferiprone
Authors: KATTAMIS ANTONIS
Published: December 2005

Abstract: Therapy with either deferiprone (DFP) or deferoxamine (DFO) is inadequate in achieving negative iron balance in many patients with thalassemia. There are mounting theoretical, experimental, and clinical evidences of increased efficacy when therapy includes both chelating agents. DFP and DFO chelate excess iron in different ways without affecting each other's metabolism. When both chelators are administered simultaneously, they interact either in an additive or synergistic manner, probably through “shuttling” iron from DFP to DFO. Iron‐balance studies have shown that the use of both agents on the same day can induce negative iron balance in all patients. Long‐term combined therapy with DFO with DFP results in considerable reduction of both ferritin levels and liver iron concentration as well as significant improvement in cardiac siderosis and function. This therapeutic regimen is well tolerated and safe, even though it may be related to a small increase in the incidence of agranulocytosis compared with DFP monotherapy. Apart from using both agents simultaneously, sequential administration of DFP and DFO has also shown promising results. Combining the available iron chelators offers many therapeutic options that can be tailored to each patient individually. It is an exciting advance in treating hemosiderosis in thalassemic patients.
Bone Marrow Transplantation in Adults with Thalassemia: Treatment and Long‐Term Follow‐Up
Authors: GAZIEV JAVID , SODANI PIETRO , POLCHI PAOLA , ANDREANI MARCO , LUCARELLI GUIDO
Published: December 2005

Abstract: Current regular blood transfusion programs and chelation treatment have considerably improved survival of patients with thalassemia, which resulted in a larger proportion of adult patients. However, disease‐ and treatment‐related complications in these patients progress over time, causing severe morbidity and shortened life expectancy. Stem cell transplantation still remains the only cure currently available for patients with thalassemia. This study updates transplant outcomes in 107 adult patients with median age of 22 years (range, 17‐35 years) who received bone marrow transplantation (BMT) from human leukocyte antigen (HLA)‐identical related donors between 1988 and 1996 (group A) and describes the results of BMT in 15 adult patients with median age of 21 years (range, 17‐31 years) who were treated with a new treatment protocol (Protocol 26) between 1997 and 2003 (group B). The probability of survival, event‐free survival, nonrejection mortality, and rejection for group A patients were 66%, 62%, 37%, and 4%, respectively, with a median follow‐up of 12 years (range, 8.3‐16.2 years). Group B patients treated with the new protocol had some improvement in thalassemia‐free survival (67%) and lower transplant‐related mortality (27%) than that of previous protocols. However, transplant‐related mortality in these high‐risk patients remains elevated. Current myeloablative BMT in adult patients is characterized by higher transplant‐related toxicity due to an advanced phase of disease. Although this new approach to transplant adult patients with a reduced‐dose intensity‐conditioning regimen has improved thalassemia‐free survival, transplant‐related mortality in these high‐risk patients remains elevated.
Stem Cell Transplantation with S‐59 Photochemically Treated T‐Cell Add‐Backs to Establish Allochimerism in Murine Thalassemia
Authors: KUYPERS FRANS A. , WATSON GORDON , SAGE EZRA , WALTERS MARK C. , HAMRICK JAMES , HEARST JOHN E.
Published: December 2005

Abstract: Hematopoietic cell transplantation (HCT) from HLA‐identical sibling donors has curative potential for β‐thalassemia. The probability of surviving free of thalassemia under these conditions is approximately 85%. The application of this therapy is limited because many patients lack an HLA‐identical sibling donor. HLA‐mismatched stem cell transplantation for thalassemia is severely restricted by graft rejection and the risks for graft‐versus‐host disease (GVHD). Thus, the development of a novel method that facilitates immunological tolerance and improves the safety of HLA‐mismatched HCT would greatly expand the opportunity of HCT for thalassemia patients. We hypothesized that removal of T cells from the donor hematopoietic stem cell preparation and subsequent add‐back after photochemical treatment with S‐59, a psoralen, would promote and stabilize the engraftment and significantly reduce the risk of GVHD. This was tested in a MHC‐mismatched HCT model of murine thalassemia. S‐59‐treated T cells were infused simultaneously with bone marrow‐derived stem cells into mice with a heterozygous deletion of one β‐globin alleles that had been conditioned with a sublethal dose of total body irradiation. Mice that received treated T cells showed increased engraftment compared to those that did not receive T cells. T‐cell treatment improved survival without GVHD compared to recipients that received untreated T cells. We conclude that photochemical treatment of T cells facilitates engraftment and minimizes GVHD in allo‐HCT for murine thalassemia, and sets the stage for further development of such protocols for the treatment of patients with thalassemia.
Preimplantation Genetics: Improving Access to Stem Cell Therapy
Authors: KULIEV ANVER , RECHITSKY SVETLANA , TUR‐KASPA ILAN , VERLINSKY YURY
Published: December 2005

Abstract: There has been progress in the application of stem cell transplantation for treatment of an increasing number of severe congenital and acquired bone marrow disorders, currently restricted by the availability of human leukocyte antigen (HLA)‐matched related donors. Preimplantation HLA typing has recently been introduced to improve the access to stem cell therapy for inherited bone marrow failures. Preimplantation genetic diagnosis (PGD) provides an option not only for avoiding an affected pregnancy with thalassemia and other inherited disorders but also for preselection of the HLA‐compatible donors for affected siblings. Multiple short tandem repeat markers throughout the HLA region are applied for this purpose, allowing 100% accuracy of HLA typing, through picking up possible recombination in the HLA region, as well as the copy number of chromosome 6, which affect accuracy of preimplantation HLA typing. Present experience of preimplantation HLA typing includes preimplantation HLA typing in 180 cycles, 122 of which were done as part of PGD for Fanconi anemia, thalassemia, Wiscott‐Aldrich syndrome, hyper‐immunoglobulin M syndrome, hypohidrotic ectodermal dysplasia with immune deficiency, and X‐linked adrenoleukodystrophy, and 58 for the sole purpose of HLA typing for leukemias and for aplastic and Diamond‐Blackfan anemia. The applied method resulted in the accurate preselection and transfer of 100% HLA‐matched embryos, yielding already three dozen clinical pregnancies and the birth of two dozen HLA‐matched children to the siblings requiring stem cell transplantation. Successful therapy with HLA‐matched stem cells, obtained from these PGD children, has been achieved already for Diamond‐Blackfan anemia hypohidrotic ectodermal dysplasia with immune deficiency and thalassemia.
Pharmacological Induction of Fetal Hemoglobin: Why Haven't We Been More Successful in Thalassemia?
Authors: FATHALLAH HASSANA , SUTTON MILLICENT , ATWEH GEORGE F.
Published: December 2005

Abstract: The first studies of the pharmacological induction of fetal hemoglobin were conducted in patients with sickle cell disease and thalassemia. Although hydroxyurea was approved by the FDA for the treatment of sickle cell disease in 1996, no similar pharmacological agent(s) has been approved for the treatment of patients with thalassemic disorders. The small‐scale studies of the induction of fetal hemoglobin in thalassemia have been generally disappointing. The aim of this report is to provide a critical analysis of the factors that may be responsible for our failure to develop an effective fetal hemoglobin induction therapy for patients with thalassemia. We also describe several areas for future investigation that may be critically important for the development of an effective therapy for thalassemia.
Single and Combination Drug Therapy for Fetal Hemoglobin Augmentation in Hemoglobin E‐β0‐Thalassemia: Considerations for Treatment
Authors: SINGER SYLVIA T. , KUYPERS FRANS A. , OLIVIERI NANCY F. , WEATHERALL DAVID J. , MIGNACCA ROBERT , COATES THOMAS D. , DAVIES SALLY , SWEETERS NANCY , VICHINSKY ELLIOTT P. ,   THE E/β‐THALASSEMIA STUDY GROUP
Published: December 2005

Abstract: Patients with hemoglobin E (Hb E)‐β0‐thalassemia, one of the most common hemoglobinopathies worldwide, could benefit from drugs that increase fetal and total hemoglobin levels and thereby decrease the need for transfusions. The long‐term clinical outcome of such therapy, its hematologic effects, and which patients are likely to benefit from treatment are unknown. Consequently, the use of such drugs for Hb E‐β0‐thalassemia is limited, and countries where resources for safe and regular transfusion are scarce cannot benefit from them. In a multicenter trial of 42 patients treated with hydroxyurea for two years, almost half the patients demonstrated a significant increase in steady‐state hemoglobin level. Drug toxicity was minimal. Combined treatment of hydroxyurea with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate was ineffective. After 5 years of follow‐up, a subset of patients remained off transfusions. Hydroxyurea should be considered for a subset of Hb E‐β0‐thalassemia patients.
Induction of Fetal Globin in β‐Thalassemia: Cellular Obstacles and Molecular Progress
Authors: PERRINE SUSAN P. , CASTANEDA SERGUEI A. , BOOSALIS MICHAEL S. , WHITE GARY L. , JONES BRANDON M. , BOHACEK REGINE
Published: December 2005

Abstract: Accelerated apoptosis of erythroid progenitors in β‐thalassemia is a significant barrier to definitive therapy because the beneficial effects of fetal globin‐inducing agents on globin chain balance may not be inducible in cells in which programmed cell death is established early. Accordingly, our objectives have been to identify methods to decrease cellular apoptosis and to identify orally tolerable fetal globin gene inducers. A pilot clinical trial was conducted to determine whether combined use of a fetal globin gene inducer (butyrate) and rhu‐erythropoietin (EPO), the hematopoietic growth factor that prolongs erythroid cell survival and stimulates erythroid proliferation, would produce additive hematologic responses in any thalassemia subjects. Butyrate and EPO were administered in 10 patients. Novel fetal globin gene inducers that also stimulate erythroid proliferation were evaluated for pharmacokinetic profiles. Patients with β+‐thalassemia had relatively low levels of endogenous EPO (<145 mU/mL) and had additive responses to administered EPO and butyrate. Patients with at least one β0‐globin mutation had higher baseline HbF levels (>60%) and EPO levels (>160 mU/mL), and three‐fourths of these subjects responded to the fetal globin gene inducer alone. A few select fetal globin‐inducing short‐chain fatty acid derivatives that stimulated cell proliferation also had favorable pharmacokinetics. These studies identify a significant subset of thalassemia patients who appear to require exogenous EPO to respond optimally to any HbF inducer, as well as new therapeutic candidates that act on both cellular and molecular pathologies of β‐thalassemia. Both approaches now offer excellent potential for tolerable, definitive treatment of β‐thalassemia.
Quality of Life in Thalassemia
Authors: TELFER P. , CONSTANTINIDOU G. , ANDREOU P. , CHRISTOU S. , MODELL B. , ANGASTINIOTIS M.
Published: December 2005

Abstract: Morbidity and mortality related to thalassemia have been reduced significantly with modern medical treatment, and quality of life (QOL) should now be considered an important index of effective health care. An assessment of QOL differs from other forms of medical assessment in that it focuses on the individuals' own views of their well‐being and assesses other aspects of life, giving a more holistic view of well‐being. There is very little published work on evaluation of QOL in thalassemia. A suitable tool should be reproducible, sensitive to the major features of the condition that affect patients' lives, and applicable in the range of different cultural, age, and social settings. Such an instrument would be valuable in evaluating new forms of treatment and in comparing health outcomes between different clinics. Two instruments have been assessed, one derived from the WHOQOL‐100 questionnaire, and one designed specifically for thalassemia, which assesses psychosocial and clinical burden, as they affect adult patients, parents, and children. Further studies are required to develop and assess such tools for use in thalassemia. Another approach is to seek patients' own views of their routine treatment and the extent to which medical treatment affects QOL. Results from patient questionnaires in the United Kingdom and Cyprus are consistent in finding problems with organization of transfusions, insufficient options with chelation therapy, and poor communication. Practical measures could be taken to address these issues.
Eighth Cooley's Anemia Symposium: Summation and Perspective
Authors: NIENHUIS ARTHUR W.
Published: December 2005

Abstract: The Eighth Cooley's Anemia Symposium provided an outstanding summary of current knowledge about the thalassemia syndromes and their treatment. The known spectrum of disease is changing due to growing knowledge about the thalassemias in developing countries, due to immigration patterns throughout the world, and due to improved outcome for transfusion‐dependent patients based on the development of effective chelation regimens. Much progress has been made in the development of noninvasive measurement of tissue iron concentration, which has provided new insights into the effects of iron chelation. Although subcutaneous deferoxamine remains the mainstay of treatment, oral deferiprone seems particularly effective at removing cardiac iron and preventing cardiac complications. Additional oral iron chelators are in the pipeline. Growing knowledge and insights into the mechanisms of gene regulation arising from the study of the globin gene clusters have not yet resulted in a full understanding of hemoglobin switching mechanisms. Efforts continue to develop and evaluate drugs for inducing fetal hemoglobin, although progress has been slow. In contrast, there has been substantial progress in the development of vectors for gene therapy of thalassemia and the first clinical trial has been proposed. However, proto‐oncogene activation and neoplastic transformation, potential risks of vector insertional mutagenesis, have now been observed in a clinical trial for severe combined immunodeficiency, adding a note of caution. Allogenetic stem cell transplantation from a matched sibling has cured many thalassemia patients and progress is being made in the use of alternative donors for this purpose.
Measuring Chromosome Breaks in Patients with Thalassemia
Authors: OFFER TAL , BHAGAT AMRITA , LAL ASHUTOSH , ATAMNA WAFA , SINGER SYLVIA T. , VICHINSKY ELLIOTT P. , KUYPERS FRANS A. , AMES BRUCE N.
Published: December 2005

Abstract: Iron‐mediated oxidative stress plays an important role in the pathophysiology of thalassemia. Oxidative stress can cause lesions in DNA, including double‐strand breaks. DNA damage, which is a cause of cancer (although not the only one), is recognized as deleterious. Unlike cancer, DNA damage can be assayed easily and relatively inexpensively in humans. In this study, a sensitive micronucleus assay was used to measure the frequency of chromosomal breaks in patients with α‐ and β‐thalassemia. The micronucleus test is based on the observation that a secondary nucleus (micronucleus) is formed around a chromosomal fragment, outside the main nucleus of a dividing cell. Micronuclei are readily apparent in red blood cells (RBCs), which otherwise lack DNA. We combined an immunomagnetic separation technique with single‐laser flow cytometry to isolate and analyze reticulocytes in peripheral blood for the presence of micronuclei before these cells are removed by the spleen. Blood samples were obtained from patients with thalassemia and healthy volunteers. After immunomagnetic enrichment of CD71‐positive reticulocytes, the cells were stained for micronuclei using the DNA dye 7‐aminoactinomycin D (7‐AAD) and evaluated by flow cytometry. Our findings indicate that higher levels of micronuclei frequencies are present in thalassemic RBCs.
Outcomes of Preimplantation Genetic Diagnosis Therapy in Treatment of β‐Thalassemia: A Retrospective Analysis
Authors: QURESHI NAVEEN , FOOTE DRUCILLA , WALTERS MARK C. , SINGER SYLVIA T. , QUIROLO KEITH , VICHINSKY ELLIOTT P.
Published: December 2005

Abstract: Thalassemia is one of the most common single‐gene disorders that can be cured by hematopoietic stem cell transplantation (HCT) from a human leukocyte antigen (HLA)‐identical sibling donor. In families that have an affected child, preimplantation genetic diagnosis (PGD) can be used to select an unaffected, HLA‐identical embryo. In brief, this procedure requires in vitro fertilization, oocyte retrieval, fertilization, and blastomere biopsy for identification of unaffected HLA‐identical embryos. After delivery, umbilical cord blood from the sibling donor is collected for HCT. The objective of this study was to determine the outcomes of families using PGD therapy for cure of β‐thalassemia and to review the limitations of PGD therapy. Families affected with β‐thalassemia who attempted PGD therapy were retrospectively identified and reviewed for indication, attempted cycles, successful pregnancy, and transplantation outcomes. Eight identified families affected by thalassemia underwent PGD. The diagnosis of their affected children included six cases of β‐thalassemia major and two cases of transfusion‐dependent hemoglobin E‐β‐thalassemia patients. A total of 14 cycles of PGD were attempted, ranging from one to four attempts per family. Following successful identification of HLA‐identical cells, two pregnancies occurred, of which one resulted in engraftment of a β‐thalassemia child. PGD therapy offers the possibility of recruiting a suitable donor for HCT, yet is limited by financial cost due to labor‐intensive techniques, low probability of obtaining an HLA‐matched unaffected embryo, variable implantation capacity, and significant emotional impact. Improvements in PGD therapy's efficacy and cost will make this a more viable option for affected families.
Murine and Math Models for the Level of Stable Mixed Chimerism to Cure β‐Thalassemia by Nonmyeloablative Bone Marrow Transplantation
Authors: ROBERTS CARLA , KEAN LESLIE , ARCHER DAVID , BALKAN CAN , HSU LEWIS L.
Published: December 2005

Abstract: Stable mixed chimeric stem cell transplantation in hemoglobinopathies exploits shorter erythroid survival in hemolytic anemias, providing normal donor red blood cells with a competitive survival advantage. This study examined the level of stable mixed chimerism necessary for complete hematological cure of the thalassemic phenotype, using a nonmyeloablative busulfan chemotherapeutic preparation. Thalassemic mice transplanted from congenic wild‐type donors developed partial mixed chimerism. Hematologic cure required >80% donor red blood cells and only >13% donor white blood cells. Murine and human transplant results were compared with a math model for survival advantage of donor peripheral blood cells produced by steady‐state chimeric marrow.
Low Bone Mineral Density in Adolescents with β‐Thalassemia
Authors: VOGIATZI MARIA G. , AUTIO KAREN A. , MAIT JEFFREY E. , SCHNEIDER ROBERT , LESSER MARTIN , GIARDINA PATRICIA J.
Published: December 2005

Abstract: The pervasiveness of low bone mass (LBM) in β‐thalassemia (Thal) patients (pts) is escalating as the average life expectancy of these pts increases. Adolescence is a period of substantial bone accrual, which is crucial for future bone strength. Studies of LBM are prevalent among adults with Thal. However, limited information exists about bone accrual and LBM in adolescents with the disease. Thirty‐one pts with β‐Thal (26 Thal major [TM], 5 Thal intermedia [TI]), aged 9‐20 years (mean: 15.3 years), 14 males and 17 females, underwent measurement of spinal bone mineral density (BMD) by DEXA (Lunar, Prodigy). Height, weight, body mass index, and Tanner stage were assessed at the time of the BMD measurement. A total of 16.1% of the patients had normal bone mass (Z≥−1), 22.6% had reduced bone mass (Z=−1 to −2), and 61.3% had low bone mass (Z≤−2). BMD Z correlated with height and weight Z scores. Some 53.9% of subjects had normal gonadal function and 46.1% had induced puberty with gonadal steroids. BMD Z significantly worsened with age (P < .0001). However, there was no difference in the LBM prevalence between subjects with normal versus those with induced puberty: BMD Z was −2 or less in 71.4% of subjects with normal puberty versus 66.7% in those with induced puberty. Our results indicate a high prevalence of LBM among adolescents with Thal regardless of adequate transfusion and chelation regimens. Bone accrual was found to be suboptimal in adolescents with normal or induced puberty. Thus, calcium and vitamin D supplementation with antiresorptive therapies should be evaluated in the adolescent Thal pt with close monitoring of growth and sexual development.
Utility of Holter Electrocardiogram in Iron‐Overloaded Hemoglobinopathies
Authors: QURESHI NAVEEN , AVASARALA KISHOR , FOOTE DRUCILLA , VICHINSKY ELLIOTT P.
Published: December 2005

Abstract: Cardiac arrhythmias are among the leading causes of morbidity and mortality of transfusion‐dependent, iron‐overloaded β‐thalassemia patients. Routine screening with Holter electrocardiogram has been recommended; however, infrequent electrocardiographic changes limit its clinical usefulness. The purpose of this study was to determine the diagnostic yield of Holter electrocardiogram monitoring and its correlation with patient symptoms and disease status. A retrospective analysis was performed on 27 transfusion‐dependent thalassemia patients who underwent cardiac questionnaire and Holter screening yearly, in addition to echocardiogram and quantitative iron‐level determination. Four patients had clinically significant arrhythmias detected on Holter screening, while 2 patients developed severe cardiac complications secondary to arrhythmias within 1 year of follow‐up of normal Holter screening. Early detection of cardiac events among transfusion‐dependent thalassemia patients with Holter electrocardiography is not clinically effective. Other screening modalities, including the transtelephonic event recorder, should be evaluated in arrhythmia surveillance.
Therapeutic Approaches to Pulmonary Hypertension in Hemoglobinopathies: Efficacy and Safety of Sildenafil in the Treatment of Severe Pulmonary Hypertension in Patients with Hemoglobinopathy
Authors: DERCHI GIORGIO , FORNI GIAN LUCA
Published: December 2005

Abstract: New approaches to the treatment of pulmonary arterial hypertension (PH) have increased symptomatic relief and prolonged survival. PH is a common sequela of the hemoglobinopathies, but the use of standard oral treatment options is limited because of toxicity and poor effectiveness. Sildenafil citrate is a selective and potent inhibitor of cGMP‐specific phosphodiesterase‐5 (PDE5), which promotes selective smooth muscle relaxation in lung vasculature and has been used successfully in the treatment of PH. Hemoglobinopathic patients suffering from severe PH who were treated with sildenafil citrate (50 mg b.i.d.) for periods ranging from 4 to 48 months showed a significant decrease in pulmonary pressure and improvement in exercise capacity and functional class. No significant adverse events were reported. These data, described in a small group of patients, indicate that sildenafil citrate is effective in the treatment of PH in hemoglobinopathies and is well tolerated long‐term at a daily dose of 100 mg.
Allosensitization in Patients Receiving Multiple Blood Transfusions
Authors: SAKHALKAR V. S. , ROBERTS K. , HAWTHORNE L. M. , MCCASKILL D. M. , VEILLON D. M. , CALDITO G. C. , COTELINGAM J. D.
Published: December 2005

Abstract: Extended antigen (C, E, K) matching decreased the incidence of alloantibody (alloAB) and autoantibody (autoAB) formation, in addition to eliminating transfusion reactions in the multiply transfused sickle cell disease patients. AlloAB formation possibly transforms the immune system into a hyperactive state leading to further and earlier alloAB and autoAB formation. However, additional CEK matching results in marked overuse of Rh‐negative packed red blood cell (pRBC) units, 30 minutes' extra time of a skilled technologist, and $153 extra CEK reagent cost per unit to find CEK‐matched pRBCs for every transfusion for these multiply transfused patients.
Separation of Normoblasts from Whole Blood by Ultracentrifugation on Arabino‐Galactane Discontinuous Gradients: A Tool for Prenatal Diagnosis
Authors: PIOMELLI SERGIO , HIRSCH DANIEL , CORASH LAWRENCE
Published: December 2005

Abstract: Normoblasts can be separated at high resolution from whole blood by ultracentrifugation on discontinuous gradients of arabino‐galactane after the red blood cells are removed by sedimentation. With this method, isolation of fetal normoblasts from maternal blood could provide a tool for rapid prenatal diagnosis. The availability of this noninvasive technique could avoid the cost and the risks of miscarriage that are associated with the current invasive procedures.
Non‐Transferrin‐Bound Iron during Blood Transfusion Cycles in β‐Thalassemia Major
Authors: GROSSE REGINE , LUND ULRIKE , CARUSO VINCENZO , FISCHER ROLAND , JANKA GRITTA E. , MAGNANO CARMELO , ENGELHARDT RAINER , DÜRKEN MATTHIAS , NIELSEN PETER
Published: December 2005

Abstract: Serum non‐transferrin‐bound iron (NTBI) levels assessed at arbitrary time points during transfusion cycles may not be representative if NTBI is undergoing significant changes during transfusion cycles. In 15 patients with β‐thalassemia major (age: 21 ± 6 years, liver iron concentration: 2200 ± 1200 μg/g‐liver), NTBI and other hematologic parameters (transferrin saturation, transferrin receptor) were measured weekly. The largest variation of NTBI levels between individual patients was observed at midcycle. For long‐term monitoring of NTBI levels, a particular time point relative to the last blood transfusion should be selected for blood drawing.
Effects of Wetness in Steam Turbines
Authors: Hesketh J A , Walker P J
Published: December 2005

Courses in mechanical engineering usually introduce the theory of axial-flow turbo-machines in terms of simple velocity triangles representing the bulk flow of ideal compressible fluid through the blade passages. A distinctive practical difference, peculiar to steam turbines (ST), is the presence of liquid-water in the flow field.

The steam wetness in such turbines is widely known to be doubly-damaging, leading to both loss of efficiency and to mechanical damage (erosion, etc.) of the machine components. Over recent decades, a whole new field of mechanical engineering science has evolved on the subject of wetness in steam turbines, and general practices have been established within the industry. This article reviews the general effects that are of major importance to the turbine designer/engineer, power plant operator, and especially to researchers in this field.
Inertia Effect on the Thermohydrodynamic Characteristics of Journal Bearings
Authors: Nassab Gandjalikhan S. A.
Published: December 2005

In this article, the effect of lubricant inertia on the thermohydrodynamic behaviour of journal bearings is studied. Many researchers have analysed the inertia effect on lubricant flow in bearings using different simplifying assumptions. The purpose of this study is to eliminate most of those assumptions, using computational fluid dynamics (CFD) techniques to solve the exact governing equations. The bearing has a finite length and operates under incompressible laminar flow and steady conditions. Numerical solutions of the full three-dimensional Navier-Stokes equations with and without inertia terms, coupled with the energy equation in the lubricant flow and the heat conduction equations in the bearing and the shaft are obtained. Cavitation effects are also considered using an appropriate three-dimensional cavitation model. In order to study the effect fluid inertia under several different conditions, solutions are obtained for different values of the eccentricity and radial clearance and also for different values of the rotational speed of the shaft. To validate the computational results, comparison with the experimental data of other investigators is made, and reasonable agreement is obtained.
Properties of Acid Sites Generated on Sol–Gel Derived Zn2SiO4
Authors: Nakabayashi Hirotoshi , Shino Yoritsugu , Kobayashi Junya
Published: December 2005

ZnO–SiO2 binary oxides prepared by the sol–gel method were calcined at various temperatures in order to reveal the relations between the surface properties as an acid–base catalyst and the bulk structures measured by X-ray diffraction. It was found that the acid amount and strength as well as the catalytic activity increased remarkably when the Zn2SiO4 phase was formed exclusively by the reactions between ZnO and SiO2 particles at 1173 K. Changes in the bulk structures were suggested to affect the surface properties of the oxide particles.
Synthesis and Characterization of Ruthenium(II)–Nitrile Complexes with Bisamide-tpa Ligands (tpa = Tris(2-pyridylmethyl)amine)
Authors: Kojima Takahiko , Hayashi Ken-ichi , Shiota Yoshihito , Tachi Yoshimitsu , Naruta Yoshinori , Suzuki Takuya , Uezu Kazuya , Yoshizawa Kazunari
Published: December 2005

Ruthenium(II)–acetonitrile complexes having pentadentate tris(2-pyridylmethyl)amine (tpa) derivatives with coordinated amide CO groups were prepared and characterized by various spectroscopic methods, electrochemical measurements, and DFT calculations. The acetonitrile ligand was indicated to tightly bind to the ruthenium(II) center in an η1-N fashion. The Mulliken charge distribution, obtained by a calculation, indicated that the ruthenium(II)–nitrile bond is more covalent than other coordination bonds of the tpa moiety. The redox potentials of Ru centers and the chemical shifts of methyl groups of the acetonitrile ligands exhibited a linear relationship, indicating that electron density of the Ru center controls that of the acetonitrile ligand. Those complexes showed fluxional behavior in CD3CN solutions to exhibit one mode of thermal motion; it also altered the symmetry of the complexes.
Synthesis of a Molecular Tweezer Containing Pentafluorophenyl Groups and Investigation of the π–π Stacking Interaction for a Pentafluorophenyl Group in a Polar Organic Solvent
Authors: Korenaga Toshinobu , Kawauchi Yusuke , Kosaki Takahiro , Ema Tadashi , Sakai Takashi
Published: December 2005

A molecular tweezer having two bidentate pentafluorophenyl (C6F5) groups was synthesized, and the π–π stacking ability of the C6F5 groups toward benzene derivatives in a polar organic solvent was evaluated. The structure of the molecular tweezer was revealed to be dimeric in the crystalline state by X-ray analysis. Association constants (Ka) between the molecular tweezer and aromatic guests in THF were found to be roughly correlated with the quadrupole moment (Qzz) of the guests, suggesting that the quadrupole–quadrupole contribution plays a significant role in the π–π interaction even in a polar organic solvent.
Nickel-Catalyzed Dimerization of [5]Cumulenes (Hexapentaenes)
Authors: Kuwatani Yoshiyuki , Yamamoto Gaku , Oda Masaji , Iyoda Masahiko
Published: December 2005

Tetraaryl[5]cumulenes react with low-valent nickel complexes at the second double bond to produce novel [4]radialene derivatives that are head-to-head dimers of [5]cumulenes. The head-to-head dimers are also synthesized by a stepwise route. On the other hand, the nickel-catalyzed dimerization of [5]cumulenes with bulky substituents produces other types of extended [4]radialenes and [5]radialenones depending on the bulkiness of the terminal alkyl substituents. Thus, tetrakis-t-butyl[5]cumulene and 1,4-bis(2,2,6,6-tetramethylcyclohexylidene)[3]cumulene react at the central double bond to give the corresponding [4]radialene and [5]radialenone, whereas 1,4-bis(2,2,5,5-tetramethylcyclopentylidene)[3]cumulene and its benzo-annelated derivative react at the second double bond in a head-to-tail manner to afford the corresponding extended [4]radialenes. Tetrakis-t-butyl[5]radialenone was converted into [5]radialene by using a methylation–dehydration procedure. The extended [4]- and [5]radialenes and [5]radialenones have been fully characterized by spectroscopic analyses, X-ray crystallography, and/or independent chemical synthesis. The properties of these novel exocyclic π-electron systems have been investigated in detail. The aryl-substituted [4]radialenes exhibit facile bond rotation with low energy barriers. The [5]radialene and [5]radialenone form the corresponding cations easily by the addition of an acidic proton. The selectivity of the nickel-catalyzed dimerization of [5]cumulenes is discussed on the basis of theoretical calculations.
Synthesis, Characterization, and Catalytic Performance of a ZSM-5/Y Composite
Authors: Shen Baojian , Chen Honglin , Guo Jintao , Pan Huifang
Published: December 2005

A ZSM-5/Y composite zeolite was prepared from Y synthesis gel by using an in-situ two-step hydrothermal crystallization process. Optimized synthetic parameters made it practical to control the transformation of zeolite Y to P, or other undesired phases during ZSM-5/Y composite formation. It was found that the pH value range of the second phase (ZSM-5 in ZSM-5/Y composite) formation is much narrower than ordinary ZSM-5 synthesis, and a lower crystallization temperature was preferred in the second step. SEM showed that the morphology of the ZSM-5/Y composite was influenced by the different synthetic methods, such as seeds and templates. The NMR data indicated that the distribution of the Si(nAl) environments are different in ZSM-5/Y composite samples that made by different methods. The composite synthesized with seeds possessed a higher ratio of Si(0Al) to Si(1Al) than that of the composite synthesized with templates. Compared to a catalyst of a mechanical mixture of ZSM-5 and Y zeolite, the catalytic cracking performance of the ion-exchanged composite zeolite catalyst showed a better yield in gasoline formation when heavy oil was used as a feedstock in a MAT reactor, and the isomerization and aromatization abilities to the gasoline fraction were better than the physical mixture of the ZSM-5 and Y. This suggested that the composite structure of the zeolite may benefit the heavy oil transformation and related reaction steps during the course of the cracking process.
Effects of Axial Ligands on the Formation of a Layered Structure in Mono- and Di-Cationic Charged Tetraphenylporphyrinatoantimony(V)/Synthetic Clay Composites
Authors: Shiragami Tsutomu , Nabeshima Keiko , Nakashima Satoko , Matsumoto Jin , Takagi Shinsuke , Inoue Haruo , Yasuda Masahide
Published: December 2005

Novel metalloporphyrin–clay composites were prepared from a synthetic clay (Sumecton SA: SSA) and cationic tetraphenylporphyrinatoantimony(V) bromide (SbTPP, 1–4) having various axial ligands. Both the crystal structure for SbTPP–SSA composites and the adsorption behaviors of SbTPP into SSA sheets are investigated regarding the relation to the structure of an axial ligand at SbTPP by measuring the X-ray diffraction (XRD), IR, UV–vis, and fluorescence spectroscopy. The XRD analysis revealed that powdered SbTPP–SSA composites could take a layered structure for 1, and an amorphous structure for 2, respectively. The IR spectrum of naked SSA showed a broad absorption band around 3000–3600 cm−1, which can probably be assigned as some adsorbed water molecules onto SSA. The intensity of the broad absorption band became weaker with an increase of the loading level (%LL), which was defined as a ratio of the concentration of the cationic sites of 1–4 to the concentration of anionic sites of SSA. The band completely disappeared at 100%LL in both 2–SSA and 4–SSA composites with the amorphous structure, whereas the band remained even at 100%LL in both 1–SSA and 3–SSA composites with the layered structure. Information about an aggregation state of 1–4 into SSA was obtained by measuring both the UV–vis absorption spectra of 1–4 in an aqueous colloidal clay solution and the fluorescence spectra of SbTPP–SSA composites in the solid state by using a confocal laser scanning fluorescence microscope. Each spectral data indicated that the ammonium cationic part on an axial ligand of 1 only led to effective non-aggregated adsorption onto SSA sheets, while 2–4 were located with the aggregated state on SSA sheets. These results also support that an axial ligand structure can control not only the formation of the crystal structure, but also the adsorption behaviors with aggregation or non-aggregation onto SSA sheets.
A Public Safety Exception to Solicitor—Client Privilege
Authors: Mahoney Richard
Published: December 2005

There is now universal recognition that solicitor–client privilege is more than a mere rule of evidence. It prohibits disclosure by a solicitor of client confidences in all circumstances, including those where no judicial proceeding is in existence. Accordingly, if during a solicitor–client communication that is protected by privilege, the client announces his or her intention to commit a crime of violence, privilege prevents a disclosure by the solicitor to the police of the client's intention. This conflicts with the permission to disclose in such circumstances that is granted by chapter 16.02(3) of the Law Society's Guide to the Professional Conduct of Solicitors. This article explores that conflict and recommends recognition of a ‘public safety’ exception to solicitor–client privilege which would permit disclosure in this class of case. The operation of such an exception is then considered.