bluuebunny/crossref_metadata_2025 huggingface dataset:
Playing and Making Games for Learning
Authors: Kafai Yasmin B.
Published: December 2005

This article presents an overview of what we know about two perspectives, coined instructionist and constructionist, to games for learning. The instructionists, accustomed to thinking in terms of making instructional educational materials, turn naturally to the concept of designing instructional games. Far fewer people have sought to turn the tables: by making games for learning instead of playing games for learning. Rather than embedding “lessons” directly in games, constructionists have focused their efforts on providing students with greater opportunities to construct their own games—and to construct new relationships with knowledge in the process. Research has only begun to build a body of experience that willmake us believe in the value of playing and making games for learning.
Comparative Video Game Criticism
Authors: Bogost Ian
Published: December 2005

This article explores comparative criticism and video game software development through the figure of the bricoleur, the handyman who assembles units of preexisting meaning to form new structures. An intersection of these two domains—what the author calls comparative video game criticism—suggests a more intimate interrelation between criticism and production. The author offers a critique of functionalist approaches to video game analysis and argues instead for a comparative analysis of the expressive capacity of games and how they relate to other forms of human production.
Playful Identities, or the Ludification of Culture
Authors: Raessens Joost
Published: December 2005

One of the main aims of game studies is to investigate to what extent and in what ways computer games are currently transforming the understanding of and the actual construction of personal and cultural identities. Computer games and other digital technologies such as mobile phones and the Internet seem to stimulate playful goals and to facilitate the construction of playful identities. This transformation advances the ludification of today's culture in the spirit of Johan Huizinga's homo ludens.
Game Studies and Beyond
Authors: Wolf Mark J. P.
Published: December 2005

This article describes why video game studies is an important branch of media studies and suggests ways it may be linked to the study of other media.
Beyond Cyberspatial Flaneurie
Authors: Simon Bart
Published: December 2005

This article seeks to make a case for the cultural analysis of digital games as a critical location for understanding the role of digital technologies in mediating the everyday social interaction and organization of subjects in the early 21st century. Digital games are considered as exemplary objects of analysis in terms of shifts in leisure culture, the increasing prevalence of computer-mediated interaction, the proliferation and intensification of visual culture, and the form and structure of posthuman information societies. The future of game studies lies in the willingness to grapple with the specificities of the medium without losing sight of and making a case for its broader cultural significance.
Why Study New Games?
Authors: Turner Fred
Published: December 2005

This article recalls the New Games Tournament of 1966 and with it, twoways to imagine play in the period: one, military war gaming and the other, the protest-oriented play of the counterculture. It then analyzes the legacy of these cultural styles for contemporary forms of gaming.
Why Game (Culture) Studies Now?
Authors: Steinkuehler Constance A.
Published: December 2005

Games are an extremely valuable context for the study of cognition as inter(action) in the social and material world. They provide a representational trace of both individual and collective activity and how it changes over time, enabling the researcher to unpack the bidirectional influence of self and society. As both designed object and emergent culture, g/Games (a) consist of overlapping well-defined problems enveloped in ill-defined problems that render their solutions meaningful; (b) function as naturally occurring, selfsustaining, indigenous versions of online learning communities; and (c) simultaneously function as both culture and cultural object—as microcosms for studying the emergence, maintenance, transformation, and even collapse of online affinity groups and as talkaboutable objects that function as tokens in public conversations of broader societal issues within contemporary offline society. In this article, the author unpacks each of these claims in the context of the massively multiplayer online games.
The Pleasures and Dangers of the Game
Authors: Krzywinska Tanya
Published: December 2005

What are the pleasures and the dangers of theway that the study of digital games has crystallized over the past 3 years? The author argues here that a pluralistic approach is required if the full complexity of games is to be addressed and analyzed, and as such, textual approaches to the analysis games should not be dismissed no matter what the particular focus of attention. To understand a game's design, the way it seeks to shape the player's experience and to make the game meaningful, it is essential to take account of the formal features of a given game. Being up close and personal forces one to think through the specificities of a game and what it is like to play that game. The author therefore advocates a combination of a formal and phenomenological approach as a means of exploring the complex relationship between game text and player.
Finding Common Ground in New Worlds
Authors: Ondrejka Cory
Published: December 2005

As games continue to displace television as a mainstream leisure activity, there has never been a better time to study games and to create solid connections between game developers and academic researchers. Building these connections will not be easy for there exists little common ground, and games are surrounded by supposition and saddled with the contradictory presumptions of harm and triviality. Despite these challenges, it is time to study games.
Intersections of Race, Class, Gender, and Crime
Authors: Burgess-Proctor Amanda
Published: December 2005

More than 30 years after the first scholarship of its kind was produced, feminist studies of crime are more commonplace than ever before. Two recent milestone events—the 20th anniversary of the American Society of Criminology’s Division on Women and Crime and the creation of this journal, the official publication of the division—provide the perfect opportunity to reflect on what lies ahead for feminist criminology. In this article, the author argues that the future of feminist criminology lies in our willingness to embrace a theoretical framework that recognizes multiple, intersecting inequalities. Specifically, the author maintains that to advance an understanding of gender, crime, and justice that achieves universal relevance and is free from the shortcomings of past ways of thinking, feminist criminologists must examine linkages between inequality and crime using an intersectional theoretical framework that is informed by multiracial feminism.
Cysteine-rich protein 1 (CRP1) regulates actin filament bundling
Authors: Tran Thuan C , Singleton CoreyAyne , Fraley Tamara S , Greenwood Jeffrey A
Published: December 2005

Background

Cysteine-rich protein 1 (CRP1) is a LIM domain containing protein localized to the nucleus and the actin cytoskeleton. CRP1 has been demonstrated to bind the actin-bundling protein α-actinin and proposed to modulate the actin cytoskeleton; however, specific regulatory mechanisms have not been identified.

Results

CRP1 expression increased actin bundling in rat embryonic fibroblasts. Although CRP1 did not affect the bundling activity of α-actinin, CRP1 was found to stabilize the interaction of α-actinin with actin bundles and to directly bundle actin microfilaments. Using confocal and photobleaching fluorescence resonance energy transfer (FRET) microscopy, we demonstrate that there are two populations of CRP1 localized along actin stress fibers, one associated through interaction with α-actinin and one that appears to bind the actin filaments directly. Consistent with a role in regulating actin filament cross-linking, CRP1 also localized to the membrane ruffles of spreading and PDGF treated fibroblasts.

Conclusion

CRP1 regulates actin filament bundling by directly cross-linking actin filaments and stabilizing the interaction of α-actinin with actin filament bundles.
Accuracy of clinical pallor in the diagnosis of anaemia in children: a meta-analysis
Authors: Chalco Juan P , Huicho Luis , Alamo Carlos , Carreazo Nilton Y , Bada Carlos A
Published: December 2005

Background

Anaemia is highly prevalent in children of developing countries. It is associated with impaired physical growth and mental development. Palmar pallor is recommended at primary level for diagnosing it, on the basis of few studies. The objective of the study was to systematically assess the accuracy of clinical signs in the diagnosis of anaemia in children.

Methods

A systematic review on the accuracy of clinical signs of anaemia in children. We performed an Internet search in various databases and an additional reference tracking. Studies had to be on performance of clinical signs in the diagnosis of anaemia, using haemoglobin as the gold standard. We calculated pooled diagnostic likelihood ratios (LR's) and odds ratios (DOR's) for each clinical sign at different haemoglobin thresholds.

Results

Eleven articles met the inclusion criteria. Most studies were performed in Africa, in children underfive. Chi-square test for proportions and Cochran Q for DOR's and for LR's showed heterogeneity. Type of observer and haemoglobin technique influenced the results. Pooling was done using the random effects model. Pooled DOR at haemoglobin <11 g/dL was 4.3 (95% CI 2.6–7.2) for palmar pallor, 3.7 (2.3–5.9) for conjunctival pallor, and 3.4 (1.8–6.3) for nailbed pallor. DOR's and LR's were slightly better for nailbed pallor at all other haemoglobin thresholds. The accuracy did not vary substantially after excluding outliers.

Conclusion

This meta-analysis did not document a highly accurate clinical sign of anaemia. In view of poor performance of clinical signs, universal iron supplementation may be an adequate control strategy in high prevalence areas. Further well-designed studies are needed in settings other than Africa. They should assess inter-observer variation, performance of combined clinical signs, phenotypic differences, and different degrees of anaemia.
C.35delG/ GJB2 and del(GJB6-D13S1830) mutations in Croatians with prelingual non-syndromic hearing impairment
Authors: Medica Igor , Rudolf Gorazd , Balaban Manuela , Peterlin Borut
Published: December 2005

Background

C.35delG/GJB2 mutation is the most frequent genetic cause of deafness in Caucasians. Another frequent mutation in some Caucasian populations is del(GJB6-D13S1830). Both GJB2 and GJB6 genes belong to the same DFNB1 locus and when the two mutations are found in combination in a hearing-impaired person, a digenic pattern of inheritance is suggested.

Methods

We examined 63 Croatian subjects (25 familial and 38 sporadic cases) with prelingual non-syndromic hearing impairment by polymerase chain reaction for the presence of the c.35delG/GJB2 and the del(GJB6-D13S1830) mutations.

Results

Of the 63 unrelated hearing-impaired subjects, the mutation c.35delG/GJB2 was found in 21 subjects (33.3%). In 5 of them the mutation was found in the heterozygous state, all of them being compound heterozygotes, as sequencing revealed a second mutation within the coding region of the gene in 3 subjects, and a splice site mutation in 2 subjects. The del(GJB6-D13S1830) mutation was not found in the investigated hearing-impaired Croatian subjects.

Conclusion

Our results contribute to the knowledge of geographic distribution and population genetics of the GJB2 and GJB6 mutations in the Europeans.
Thalassemia: The Continued Challenge
Authors: NATHAN DAVID G.
Published: December 2005

Abstract: This overview describes the history of transfusion therapy and consequent iron overload in thalassemia. It emphasizes the importance of measurement of hepatic iron and reviews the history of chelation therapy. It briefly describes the discoveries of the genetic basis of thalassemia and the application of that knowledge in prenatal diagnosis. The review goes on to emphasize pharmaceutical efforts to induce fetal hemoglobin synthesis in thalassemic red cells and ends with a discussion of oral iron chelators, stem cell transplant, and the status of gene therapy.
Keynote Address: The Challenge of Thalassemia for the Developing Countries
Authors: WEATHERALL DAVID J.
Published: December 2005

Abstract: The thalassemias occur at some of their highest frequencies in the developing countries, particularly those of Asia. In many countries, facilities for the control of these conditions are extremely limited. Although a great deal can be done to help the situation by developing further North‐South and South‐South partnerships for disseminating better practice, the major problem for the future lies in the unwillingness of governments and international health agencies to accept that the thalassemias present a health burden comparable to that of other major diseases in the developing countries. However, preliminary analyses suggest that, at least in the case of Asia, this is not true. Further work of this nature, together with more detailed frequency and economic data, are required to provide solid evidence for the health burden posed by thalassemia in the developing world. Unless this is done, the large populations of patients with thalassemia in these countries will continue to be neglected.
A Phase I/II Clinical Trial of β‐Globin Gene Therapy for β‐Thalassemia
Authors: BANK ARTHUR , DORAZIO RONALD , LEBOULCH PHILIPPE
Published: December 2005

Abstract: Recent success in the long‐term correction of mouse models of human β‐thalassemia and sickle cell anemia by lentiviral vectors and evidence of high gene transfer and expression in transduced human hematopoietic cells have led to a first clinical trial of gene therapy for the disease. A LentiGlobin vector containing a β‐globin gene (βA‐T87Q) that produces a hemoglobin (HbβA‐T87Q) that can be distinguished from normal hemoglobin will be used. The LentiGlobin vector is self‐inactivating and contains large elements of the β‐globin locus control region as well as chromatin insulators and other features that should prevent untoward events. The study will be done in Paris with Eliane Gluckman as the principal investigator and Philippe Leboulch as scientific director.
Progress Toward the Genetic Treatment of the β‐Thalassemias
Authors: SADELAIN MICHEL , LISOWSKI LESZEK , SAMAKOGLU SELDA , RIVELLA STEFANO , MAY CHAD , RIVIERE ISABELLE
Published: December 2005

Abstract: The β‐thalassemias are congenital anemias that are caused by mutations that reduce or abolish expression of the β‐globin gene. They can be cured by allogeneic hematopoietic stem cell (HSC) transplantation, but this therapeutic option is not available to most patients. The transfer of a regulated β‐globin gene in autologous HSCs is a highly attractive alternative treatment. This strategy, which is simple in principle, raises major challenges in terms of controlling expression of the globin transgene, which ideally should be erythroid specific, differentiation‐ and stage‐restricted, elevated, position independent, and sustained over time. Using lentiviral vectors, May et al. demonstrated in 2000 that an optimized combination of proximal and distal transcriptional control elements permits lineage‐specific and elevated β‐globin expression, resulting in therapeutic hemoglobin production and correction of anemia in β‐thalassemic mice. Several groups have by now replicated and extended these findings to various mouse models of severe hemoglobinopathies, thus fueling enthusiasm for a potential treatment of β‐thalassemia based on globin gene transfer. Current investigation focuses on safety issues and the need for improved vector production methodologies. The safe implementation of stem cell‐based gene therapy requires the prevention of the formation of replication‐competent viral genomes and minimization of the risk of insertional oncogenesis. Importantly, globin vectors, in which transcriptional activity is highly restricted, have a lesser risk of activating oncogenes in hematopoietic progenitors than non‐tissue‐specific vectors, by virtue of their late‐stage erythroid specificity. As such, they provide a general paradigm for improving vector safety in stem cell‐based gene therapy.
Objectives and Mechanism of Iron Chelation Therapy
Authors: HERSHKO C.AIM , LINK GABRIELA , KONIJN ABRAHAM M. , CABANTCHIK Z IOAV
Published: December 2005

Abstract: Prevention of cardiac mortality is the most important beneficial effect of iron chelation therapy. Unfortunately, compliance with the rigorous requirements of daily subcutaneous deferoxamine (DFO) infusions is still a serious limiting factor in treatment success. The development of orally effective iron chelators such as deferiprone and ICL670 is intended to improve compliance. Although total iron excretion with deferiprone is somewhat less than with DFO, deferiprone may have a better cardioprotective effect than DFO due to deferiprone's ability to penetrate cell membranes. Recent clinical studies indicate that oral ICL670 treatment is well tolerated and is as effective as parenteral DFO used at the standard dose of 40 mg/kg of body weight/day. Thus, for the patient with transfusional iron overload in whom results of DFO treatment are unsatisfactory, several orally effective agents are now available to avoid serious organ damage. Finally, combined chelation treatment is emerging as a reasonable alternative to chelator monotherapy. Combining a weak chelator that has a better ability to penetrate cells with a stronger chelator that penetrates cells poorly but has a more efficient urinary excretion may result in improved therapeutic effect through iron shuttling between the two compounds. The efficacy of combined chelation treatment is additive and offers an increased likelihood of success in patients previously failing DFO or deferiprone monotherapy.
Recent Insights into Interactions of Deferoxamine with Cellular and Plasma Iron Pools: Implications for Clinical Use
Authors: PORTER J.B. , RAFIQUE R. , SRICHAIRATANAKOOL S. , DAVIS B. A. , SHAH F. T. , HAIR T. , EVANS P.
Published: December 2005

Abstract: Despite the availability of deferoxamine (DFO) for more than three decades, its rates of interaction with cellular iron pools in different tissues, and the effects of its pharmacokinetics on the interaction with plasma iron pools, remain incompletely understood. The positive charge of DFO, together with the negative resting potential in vertebrate cells, favors cellular uptake, whereas the low lipophilicity and high molecular weight counter this effect. The findings presented suggest a facilitated uptake of DFO into hepatocytes, being several hundred‐fold faster than into red cells. Antibodies that selectively recognize ferrioxamine (FO) show that initial hepatocellular iron chelation is cytosolic, but later transposes to lysosomal and ultimately canalicular compartments. Strong FO staining is visible in myocytes within 4‐8 h after commencing a subcutaneous DFO infusion, indicating effective chelation of myocyte iron. A methodology was developed to study the interaction of DFO and its metabolites with plasma iron pools by stabilizing DFO with aluminum ions, thereby preventing iron shuttling from non‐transferrin‐bound iron (NTBI) onto DFO after plasma collection. DFO removes only about a third of NTBI rapidly, and NTBI is rarely cleared completely. Increasing DFO dosing does not increase NTBI removal, but instead leads to a greater rebound in NTBI on cessation of intravenous infusion. Thus, intermittent infusions of high‐dose DFO are less desirable than continuous infusions at low doses, particularly in high‐risk patients. Here the benefits of continuous DFO on heart function occur before changes in T2*‐visible storage iron, consistent with early removal of a toxic labile iron pool within myocytes.
Deferiprone: New Insight
Authors: PIGA A. , ROGGERO S. , VINCIGUERRA T. , SACCHETTI L. , GALLO V. , LONGO F.
Published: December 2005

Abstract: Recent results from independent studies suggest that deferiprone is more cardioprotective than deferoxamine. Patients on long‐term treatment with deferiprone have a better myocardial magnetic resonance imaging pattern and less chance to develop a new cardiac disease or worsen an existing one. Most of these observations are retrospective and require confirmation from randomized controlled trials. Other new observations regard the effects of combining the two chelators. Most results indicate an additional effect on iron excretion and a significant reduction of the time required to mitigate severe iron overload and to reverse clinical heart disease. Again, these data require confirmation, as they were mostly obtained on individual cases or small groups of patients treated with a wide range of combinations of the two chelators, but the univocity of results is impressive. After many years of controversy, deferiprone is emerging as a useful oral iron chelator that enhances the chances for the patient to have optimal treatment. Well‐designed and ‐conducted studies will help in answering the questions still open.
Sibling Donor Cord Blood Transplantation for Thalassemia Major: Experience of the Sibling Donor Cord Blood Program
Authors: WALTERS MARK C. , QUIROLO LYNN , TRACHTENBERG ELIZABETH T. , EDWARDS SANDIE , HALE LISA , LEE JOANNA , MORTON‐WILEY JOI , QUIROLO KEITH , ROBERTSON SHANDA , SABA JULIE , LUBIN BERT
Published: December 2005

Abstract: The Sibling Donor Cord Blood (SDCB) Program was initiated in 1998 as a resource to collect, characterize, and release cord blood units (CBUs) from families affected by malignant and nonmalignant disorders for transplantation. Families in the United States were recruited by telephone after referrals by community and academic physicians. Collection kits were mailed to prospective participants and family members were instructed about CBU procurement from community hospitals and shipping to a central laboratory. Data about the infant's delivery and CBU harvest, CBU processing, prethaw characteristics, sterility, and human leukocyte antigen (HLA) typing were collected. Standard outcome data were collected after CBU release for transplantation. Descriptive analyses of CBU collections, processing, release, and transplantation outcomes were performed. Currently, 1617 CBU collections have been processed from families with thalassemia (6%), sickle cell disease (28%), malignant disorders (49%), and other rare hematological disorders (17%). Thirty‐two of 96 donor‐recipient pairs with thalassemia major were HLA identical and 14 have received cord blood transplantation, either alone or in combination with bone marrow or peripheral blood progenitor cells (N= 4) from the same donor. Eleven of the 14 survive free of thalassemia after transplantation. These preliminary results confirm the feasibility and utility of remote‐site sibling donor cord blood collection and subsequent transplantation for hematological disorders, with a very high rate of usage from a cord blood bank dedicated to performing these unique collections. It was concluded that cord blood transplantation from sibling donors represents a suitable alternative to bone marrow transplantation.
Caring for Adults with Thalassemia in a Pediatric World
Authors: COMPAGNO LAURICE M.
Published: December 2005

Abstract: Improved technology and medical advances have increased the life span for patients with thalassemia. Therefore, serious consideration must now be given to adult issues such as fertility, employment opportunities, medical insurance, and long‐term coping with chronic illness. Since thalassemia is a childhood illness, most adults are seen in pediatric hospitals—often, in centers with a specialty for thalassemia. Compared to a decade ago, many more patients in thalassemia centers are adolescents or older. Unfortunately, pediatric hospitals are not fully equipped to meet the changing and complex needs of adults. Emergency room care, hospital admissions, decentralized care, comprehensive care, and psychosocial issues are current challenges that must be addressed. In this study, six adult patients were asked to keep track of their care for one month to further examine self‐care for thalassemia, a high‐maintenance disease. From a qualitative perspective, the issues and challenges that adults face are examined and solutions for improved care are discusssed.
Thalassemia and Learning: Neurocognitive Functioning in Children
Authors: ARMSTRONG F DANIEL
Published: December 2005

Abstract: As more effective management and even cure of thalassemia become possible, attention is beginning to be directed to the potential neurologic and resulting neurocognitive effects of this illness on adults and children. Recent studies indicate that for adults with β‐thalassemia major and intermedia, and for children with sickle β‐thalassemia (Sβ‐thalassemia), there is a substantial risk for silent brain infarcts that may be associated with neurocognitive impairment similar to that reported for children with sickle cell anemia. Here the available literature in this area is reviewed and the limited outcomes are compared with those available from large, multicenter longitudinal studies of sickle cell anemia. On the basis of these comparisons, it is recommend that children with thalassemia be screened for specific neuropsychological impairments and that they be provided early intervention and special education access as available under the Individuals with Disabilities Education Act (IDEA) or the 504 Regulations of the Rehabilitation Act of 1973.
Monitoring Long‐Term Efficacy of Iron Chelation Treatment with Biomagnetic Liver Susceptometry
Authors: FISCHER ROLAND , PIGA ANTONIO , HARMATZ PAUL , NIELSEN PETER
Published: December 2005

Abstract: In patients with thalassemia, the assessment of liver iron concentration (LIC) can be used to initiate chelation treatment with desferrioxamine (DFO), deferiprone (DFP), or novel chelators (deferasirox); to adjust chelation dose according to the actual blood transfusion rate; and to monitor chelation efficacy. The results from measurements by SQUID biomagnetic liver susceptometry in the LIC range 17‐11,500 μg/g of liver in about 1000 patients were used to derive nonstandard parameters, which may be useful in the treatment monitoring of patients with thalassemia. From these measurements, including liver volumes, the documented chelation dose rates, and the blood transfusion rates, the chelator index (equivalent Therapeutical Index), the total body iron elimination rate, and the molar efficacy were calculated. Chelator indices (CIs) ranged from 0.1 to 11.7 mmol/d/g of Fe for DFO, with a threshold of CI greater than 1.2 mmol/d/g of Fe indicating DFO toxicity. For DFP, CI ranged from 0.1 to 23.2 mmol/d/g of Fe. In long‐term studies (2 and 4 years), mean molar efficacies of DFO and DFP were found to be quite stable with 17.6 ± 4.8% and 4.9 ± 1.4%, respectively. Currently, specific chelation dose is based upon body weight. Because liver iron measurements by biosusceptometry are now regularly available in Europe and America, as well as quantitative MRI worldwide, these methods may be used to adjust chelation treatment regimens to body iron stores.
Methods for Noninvasive Measurement of Tissue Iron in Cooley's Anemia
Authors: SHETH SUJIT , TANG HAIYING , JENSEN JENS H. , ALTMANN KAREN , PRAKASH ASHWIN , PRINTZ BETH F. , HORDOF ALAN J. , TOSTI CHRISTINA L. , AZABAGIC ANDJELA , SWAMINATHAN SRIRAMA , BROWN TRUMAN R. , OLIVIERI NANCY F. , BRITTENHAM GARY M.
Published: December 2005

Abstract: To examine the relationship between myocardial storage iron and body iron burden, as assessed by hepatic storage iron measurements, we studied 22 patients with transfusion‐dependent thalassemia syndromes, all being treated with subcutaneous deferoxamine, and 6 healthy subjects. Study participants were examined with a Philips 1.5‐T Intera scanner using three multiecho spin echo sequences with electrocardiographic triggering and respiratory navigator gating. Myocardial and hepatic storage iron concentrations were determined using a new magnetic resonance method that estimates total tissue iron stores by separately measuring the two principal forms of storage iron, ferritin and hemosiderin. In a subset of 10 patients with β‐thalassemia major, the hepatic storage iron concentration had been monitored repeatedly for 12‐14 years by chemical analysis of tissue obtained by liver biopsy and by magnetic susceptometry. In this subset, we examine the relationship between hepatic iron concentration over time and our current magnetic resonance estimates of myocardial iron stores. No significant relationship was found between simultaneous estimates of myocardial and hepatic storage iron concentrations. By contrast, in the subset of 10 patients with β‐thalassemia major, the correlation between the 5‐year average of hepatic iron concentration and the current myocardial storage iron was significant (R= .67, P= .03). In these patients, myocardial storage iron concentrations seem to reflect the control of body iron over a period of years. Magnetic resonance methods promise to provide more effective monitoring of iron deposition in vulnerable tissues, including the liver, heart, and endocrine organs, and could contribute to the development of iron‐chelating regimens that more effectively prevent iron toxicity.
Measurement and Mapping of Liver Iron Concentrations Using Magnetic Resonance Imaging
Authors: ST. PIERRE TIMOTHY G. , CLARK PAUL R. , CHUA‐ANUSORN WANIDA
Published: December 2005

Abstract: Measurement of liver iron concentration (LIC) is an important clinical procedure in the management of transfusional iron overload with iron chelation. LIC gives an indication of over‐ or underchelation. Although chemical assay of needle biopsy samples from the liver has been considered the “gold standard” of LIC measurement, needle biopsy sampling errors can be surprisingly large owing to the natural spatial variation of LIC throughout the liver and the small size of biopsy specimens. A magnetic resonance imaging technique has now been developed that enables safe noninvasive measurement and imaging of LIC with a known accuracy and precision. Measurements of LIC can be made over the range of LIC encountered in clinical practice. The technique is based on the measurement and imaging of proton transverse relaxation rates (R2) within the liver. The R2 imaging technique can be implemented on most clinical 1.5‐T MRI instruments, making it readily available to the clinical community.
Physiology and Pathophysiology of Iron Cardiomyopathy in Thalassemia
Authors: WOOD JOHN C. , ENRIQUEZ CATHLEEN , GHUGRE NILESH , OTTO‐DUESSEL MAYA , AGUILAR MICHELLE , NELSON MARVIN D. , MOATS REX , COATES THOMAS D.
Published: December 2005

Abstract: Iron cardiomyopathy remains the leading cause of death in patients with thalassemia major. Magnetic resonance imaging (MRI) is ideally suited for monitoring thalassemia patients because it can detect cardiac and liver iron burdens as well as accurately measure left ventricular dimensions and function. However, patients with thalassemia have unique physiology that alters their normative data. In this article, we review the physiology and pathophysiology of thalassemic heart disease as well as the use of MRI to monitor it. Despite regular transfusions, thalassemia major patients have larger ventricular volumes, higher cardiac outputs, and lower total vascular resistances than published data for healthy control subjects; these hemodynamic findings are consistent with chronic anemia. Cardiac iron overload increases the relative risk of further dilation, arrhythmias, and decreased systolic function. However, many patients are asymptomatic despite heavy cardiac burdens. We explore possible mechanisms behind cardiac iron‐function relationships and relate these mechanisms to clinical observations.
Rescued Mice with Hb E Transgene‐Developed Red Cell Changes Similar to Human β‐Thalassemia/HbE Disease
Authors: WANNASUPHAPHOL BUNDIT , KALPRAVIDH RUCHANEEKORN , PATTANAPANYASAT KOVIT , IOANNAU PANOS , KUYPERS FRANS A. , FUCHAROEN SUTHAT , WINICHAGOON PRANEE
Published: December 2005

Abstract: A novel C57BL/6 transgenic murine model of HbE has been developed, and the heterotetrameric (mα2hβE2) hemoglobin shows significant complementation of mild thalassemia phenotype in double heterozygous (βm+βm−, βhE) and homozygous knockout (βm−βm−, βhE) mice with 100% heterotetrameric hemoglobin. Lethal homozygous β‐thalassemic mice rescued by HbE transgenes mimic β‐thalassemia/HbE phenotype in human. Although anemia was not pronounced, other hematologic parameters were abnormally similar to β‐knockout mice. Flow cytometric study revealed a highly oxidative status in the red cells, but there were no marked changes in PS red cells and RBC vesicles. RBC life span and half‐time of rescued red cells were shortened, indicating a rapid RBC destruction.
Osteoporosis in β‐Thalassemia: Clinical and Genetic Aspects
Authors: ORIGA R. , FIUMANA E. , GAMBERINI M. R. , ARMARI S. , MOTTES M. , SANGALLI A. , PAGLIETTI E. , GALANELLO R. , BORGNA‐PIGNATTI C.
Published: December 2005

Abstract: Osteoporosis and osteopenia are frequent complications of thalassemia major (TM) and intermedia (TI). Osteoporosis was found in 23/25 patients with TI and in 115/239 patients with TM. In TM, no association was found with specific polymorphisms in candidate genes (vitamin D receptor, estrogen receptor, calcitonin receptor, and collagen type 1 alpha 1). Osteoporosis in female patients with TM was strongly associated with primary amenorrhea (P < .0001), while in male patients with TM, hypogonadism was not significantly related to bone mineral density (BMD) (P= .0001). Low BMD was also associated with cardiomiopathy (P= .01), diabetes mellitus (P= .0001), chronic hepatitis (P= .0029), and increased ALT (P= .01).
Prenatal Diagnosis of Hemoglobinopathies in Ontario, Canada
Authors: BASRAN RAVEEN K. , PATTERSON MARGIE , WALKER LYNDA , NAKAMURA LISA M. , ENG BARRY , CHUI DAVID H.K. , WAYE JOHN S.
Published: December 2005

Abstract: In 1989, the Province of Ontario established a molecular diagnostic laboratory for carrier detection and prenatal diagnosis of hemoglobinopathies. Over the past 15 years, the laboratory has provided prenatal diagnosis for 672 pregnancies at‐risk for severe hemoglobinopathies: 276 (41%) for homozygous β‐thalassemia or hemoglobin (Hb) E/β‐thalassemia, 211 (31%) for homozygous α0‐thalassemia (Hb Bart's hydrops fetalis), and/or Hb H disease, and 185 (28%) for various sickling disorders (Hb SS, Hb SC, Hb S/β‐thalassemia). Despite the availability of services for carrier screening, genetic counseling, and prenatal diagnosis, there has been only a modest reduction in the overall incidence of hemoglobinopathies in Ontario.
Role of Intergenic Human γ‐δ‐Globin Sequences in Human Hemoglobin Switching and Reactivation of Fetal Hemoglobin in Adult Erythroid Cells
Authors: BANK ARTHUR , O'NEILL DAVID , LOPEZ ROCIO , PULTE DIANNE , WARD MAUREEN , MANTHA SIMON , RICHARDSON CHRISTINE
Published: December 2005

Abstract: The details of the molecular events regulating normal human hemoglobin switching and reactivation of fetal hemoglobin in adult hematopoietic cells are unclear. The potential role of sequences between the human γ‐ and δ‐globin genes (intergenic γ‐δ sequences) in this process has been in question until the recent finding that two patients homozygous for the Corfu deletion, involving the loss of 7.2 kb of the intergenic γ‐δ region upstream of the δ gene, have 88% and 90% fetal hemoglobin, only mild anemia, and no transfusion requirements. These results provide the first strong evidence in humans that the γ‐δ intergenic sequences alone have a role in the reactivation of fetal hemoglobin in adult‐type cells, and perhaps are involved in normal hemoglobin switching as well. The polypyrimidine (PYR) complex is a hematopoietic cell‐specific and stage‐specific chromatin remodeling complex that binds upstream of the human δ‐globin gene within the Corfu deletion. Deletion of the PYR binding site has been shown to delay human γ‐to‐β globin switching. The PYR complex is present in adult human hematopoietic cells and absent in fetal‐embryonic cells: properties of a globin‐switching complex. Taken together, the data from patients with the Corfu deletion and the PYR complex results suggest that intergenic γ‐δ sequences are involved in human γ‐to‐β globin switching and reactivation of fetal hemoglobin in adult cells.
Quality of Life in Patients with Thalassemia Intermedia Compared to Thalassemia Major
Authors: PAKBAZ ZAHRA , TREADWELL MARSHA , YAMASHITA ROBERT , QUIROLO KEITH , FOOTE DRUCILLA , QUILL LAURA , SINGER TITI , VICHINSKY ELLIOTT P.
Published: December 2005

Abstract: The impact of thalassemia major and thalassemia intermedia and their associated complications on quality of life (QOL) is largely unknown. Determining the degree of health impairment as perceived by the patient is essential information needed to recommend suitable therapy. The objective of this study was to evaluate QOL in transfusion‐independent patients with thalassemia (non‐Tx) compared with that in transfused patients (Tx) and to identify the factors that affect QOL in thalassemia. A convenient sample of 48 thalassemia patients (29 Tx and 19 non‐Tx) with mean age of 14.6 years (SD = 7.5 years) were selected during a comprehensive visit to complete a Dartmouth Primary Care Cooperative Information Chart System (COOP) questionnaire. Patients rated QOL from excellent (1) to poor (5) on five dimensions of health status. Scores of 4 or 5 represent major limitations. These results were augmented by a brief medical history and chart review. Forty‐one percent of Tx patients and 47% of non‐Tx patients reported severe impairments in 1‐6 and 1‐2 domains, respectively. The most commonly reported affected domains were feelings such as anxiety, depression, and concern of overall health status or indications of recent deterioration in health. In contrast with previous beliefs, transfusion‐independent thalassemia patients also suffer serious impairment in QOL. Presented data suggest that all patients with thalassemia undergo QOL assessment so that interventions focused on affected domains can be implemented.
Does Heterozygous β‐Thalassemia Confer a Protection against Coronary Artery Disease?
Authors: TASSIOPOULOS STERGIOS , DEFTEREOS SPYROS , KONSTANTOPOULOS KOSTAS , FARMAKIS DIMITRIS , TSIRONI MARIA , KYRIAKIDIS MICHALIS , AESSOPOS ATHANASSIOS
Published: December 2005

Abstract: Six hundred and thirty‐eight patients who presented with clinical symptoms and/or electrocardiographic findings suggestive of stable angina pectoris were studied; they were also investigated by coronary arteriography. Hemoglobin electrophoresis was performed on all patients to detect the presence of the β‐thalassemia trait. Results were analyzed by logistic regression analysis to determine whether the latter confers any protective effect against advanced coronary artery disease (aCAD; defined as the presence of atheromas in coronary arteries, resulting in stenosis at least 70%). WeThe role of the currently accepted risk factors (smoking, hypertension, hypercholesterolemia, and diabetes) in developing aCAD were reconfirmed, while at the same time it was found that β‐thalassemia heterozygosity is associated with a reduced risk against aCAD (odds ratio 0.39, 95% confidence interval 0.16‐0.98). The lipoprotein and blood rheology profile of these individuals may be the underlying causes of this protective effect.
Exploring the Role of Hepcidin, an Antimicrobial and Iron Regulatory Peptide, in Increased Iron Absorption in β‐Thalassemia
Authors: BREDA LAURA , GARDENGHI SARA , GUY ELLA , RACHMILEWITZ ELIEZER A. , WEIZER‐STERN ORLY , ADAMSKY KONSTANTIN , AMARIGLIO NINETTE , RECHAVI GIDEON , GIARDINA PATRICIA J. , GRADY ROBERT W. , RIVELLA STEFANO
Published: December 2005

Abstract: To develop new treatments for β‐thalassemia, it is essential to identify the genes involved in the relevant pathophysiological processes. Iron metabolism in thalassemia mice being investigated, focusing on the expression of a gene called hepcidin (Hamp), which is expressed in the liver and whose product (Hamp) is secreted into the bloodstream. In mice, iron overload leads to overexpression of Hamp, while Hamp‐knockout mice suffer from hemochromatosis. The aim of this study is to investigate Hamp in the mouse model of β‐thalassemia and to address the potential gene transfer of Hamp to prevent abnormal iron absorption.
Preclinical and Clinical Development of Deferitrin, a Novel, Orally Available Iron Chelator
Authors: DONOVAN JOANNE M. , PLONE MELISSA , DAGHER RAFIF , BREE MARK , MARQUIS JUDITH
Published: December 2005

Abstract: Deferitrin, a novel, orally available iron chelator, is in the early stage of clinical development for the treatment of chronic iron overload due to transfusional therapy. Preclinical pharmacology studies demonstrate iron excretion largely by the fecal route. Initial clinical studies have shown deferitrin to be well absorbed. Further clinical studies are ongoing to determine the efficiency and safety of deferitrin.
Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways fromDrosophilato vertebrates
Authors: Huangfu Danwei , Anderson Kathryn V.
Published: December 2005

Although the framework of the Hedgehog (Hh) signaling pathway is evolutionarily conserved, recent studies indicate that fundamental differences exist between Drosophila and vertebrates in the way signals are transduced from the membrane protein Smoothened (Smo) to the Ci/Gli transcription factors. For example, Smo structure and the roles of fused and Suppressor of fused have diverged. Recently, many vertebrate-specific components have been identified that act between Smo and Gli. These include intraflagellar transport proteins, which link vertebrate Hh signaling to cilia. Because abnormal Hh signaling can cause birth defects and cancer, these vertebrate-specific components may have roles in human health.
DrosophilaKnickkopf and Retroactive are needed for epithelial tube growth and cuticle differentiation through their specific requirement for chitin filament organization
Authors: Moussian Bernard , Tång Erika , Tonning Anna , Helms Sigrun , Schwarz Heinz , Nüsslein-Volhard Christiane , Uv Anne E.
Published: December 2005

Precise epithelial tube diameters rely on coordinated cell shape changes and apical membrane enlargement during tube growth. Uniform tube expansion in the developing Drosophila trachea requires the assembly of a transient intraluminal chitin matrix, where chitin forms a broad cable that expands in accordance with lumen diameter growth. Like the chitinous procuticle, the tracheal luminal chitin cable displays a filamentous structure that presumably is important for matrix function. Here, we show that knickkopf (knk) and retroactive (rtv) are two new tube expansion mutants that fail to form filamentous chitin structures, both in the tracheal and cuticular chitin matrices. Mutations in knk and rtv are known to disrupt the embryonic cuticle, and our combined genetic analysis and chemical chitin inhibition experiments support the argument that Knk and Rtv specifically assist in chitin function. We show that Knk is an apical GPI-linked protein that acts at the plasma membrane. Subcellular mislocalization of Knk in previously identified tube expansion mutants that disrupt septate junction (SJ) proteins, further suggest that SJs promote chitinous matrix organization and uniform tube expansion by supporting polarized epithelial protein localization. We propose a model in which Knk and the predicted chitin-binding protein Rtv form membrane complexes essential for epithelial tubulogenesis and cuticle formation through their specific role in directing chitin filament assembly.
Classical Nucleation Theory and Its Application to Condensing Steam Flow Calculations
Authors: Bakhtar F , Young J B , White A J , Simpson D A
Published: December 2005

The paper discusses the classical theory of the homogeneous nucleation of water droplets from supersaturated vapour and its application in predicting condensation in steam nozzles. The first part consists of a review of classical nucleation theory, focusing on the many modifications made to the original Becker-Döring theory and providing some new insights into recent developments. It is concluded that the predictive accuracy required for engineering calculations is not yet attainable with a theory derived from first principles. The areas that require most attention relate to the properties of small molecular clusters and the energy transfer processes in the non-isothermal theory. Experiments in converging-diverging nozzles provide the best means for validation at the very high nucleation rates of interest, but measurements of pressure distribution and the Sauter mean droplet radius are insufficient to provide independent checks on the separate theories of nucleation and droplet growth. Nevertheless, a judicious choice for the nucleation rate equation, in combination with a standard droplet growth model and a suitable equation of state for steam, can provide accurate predictions over a wide range of conditions. The exception is at very low pressures where there is evidence that the droplet growth rate in the nucleation zone is underestimated.
Predicting Sliding Wear Behaviour of a Tin-Based White Metal Under Varying Pressure and Speed Conditions
Authors: Tachi Y , Ishihara S , Tamura K , Goshima T , McEvily A. J.
Published: December 2005

To determine the effects of loading on the sliding wear behaviour of a tin-based white bearing metal JIS WJ2, experiments were performed over a range of pressures and speeds. A linear relation between stress and cut-off life was obtained on the log-log plot at constant shaft speed. These relations were expressed as different straight lines on the log-log plot, which depend on the shaft speed. However, there is a unique curve in the relation, frictional stress versus cut-off life, regardless of the shaft speeds.

To establish a quantitative method of analysing the steady-state sliding wear mode, the following constitutive relation was proposed

d w/d N = A(τ – τth)2

where w is the amount of wear, N the number of shaft rotations, A the material constant, τ the interfacial shear stress, and τth the threshold level for wear damage. The aforementioned equation has been used as a basis for estimating wear life. Good agreement between the predictions and the experimental results was obtained.
On the Dynamics of Elastohydrodynamic Mixed Lubricated Ball Bearings. Part II: Non-Linear Structural Vibration
Authors: Sarangi M , Majumdar B. C. , Sekhar A. S.
Published: December 2005

Equations of motion of a ball bearing are formulated in generalized coordinates, using Lagrange's equation considering the vibrational characteristics of the individual constituents such as inner race, outer race, cage, and balls, in order to investigate the structural vibration of the bearing. This article is the second part of the present study dealing with structural vibration, whereas in the first part, elastohydrodynamic mixed lubricated contact stiffness and damping coefficients are determined. Utilizing these stiffness and damping coefficients, a non-linear load-deflection contact model is developed. This is then used in the equations of motion. The equations of motion are solved using Runge-Kutta integration technique. This work differs from the previous studies in the sense that the model simulates the vibration, considering that both the lubricated contact stiffness and damping correspond to the conservative and dissipative energies, respectively. It is observed that under undamped conditions, all the elements of the bearing actively participate in energy sharing and oscillate periodically, containing more than one frequency. The system vibration, however, died down rapidly in the presence of damping.