bluuebunny/crossref_metadata_2025 huggingface dataset:
Injuries in Team Sport Tournaments during the 2004 Olympic Games
Authors: Junge Astrid , Langevoort Gijs , Pipe Andrew , Peytavin Annie , Wong Fook , Mountjoy Margo , Beltrami Gianfranco , Terrell Robert , Holzgraefe Manfred , Charles Richard , Dvorak Jiri
Published: November 2005

Background

Several authors have analyzed the incidence of injuries in a given sport, but only a few have examined the exposure-related incidence of injuries in different types of sports using the same methodology.

Purpose

Analysis of the incidence, circumstances, and characteristics of injuries in different team sports during the 2004 Olympic Games.

Study Design

Cohort study; Level of evidence, 2.

Methods

During the 2004 Olympic Games, injuries in 14 team sport tournaments (men's and women's soccer, men's and women's handball, men's and women's basketball, men's and women's field hockey, baseball, softball, men's and women's water polo, and men's and women's volleyball) were analyzed. After each match, the physician of the participating teams or the official medical representative of the sport completed a standardized injury report form. The mean response rate was 93%.

Results

A total of 377 injuries were reported from 456 matches, an incidence of 0.8 injuries per match (95% confidence interval, 0.75-0.91) or 54 injuries per 1000 player matches (95% confidence interval, 49-60). Half of all injuries affected the lower extremity; 24% involved the head or neck. The most prevalent diagnoses were head contusion and ankle sprain. On average, 78% of injuries were caused by contact with another player. However, a significantly higher percentage of noncontact (57%) versus contact injuries (37%) was expected to prevent the player from participating in his or her sport. Significantly more injuries in male players (46%) versus female players (35%) were expected to result in absence from match or training. The incidence, diagnosis, and causes of injuries differed substantially between the team sports.

Conclusion

The risk of injury in different team sports can be compared using standardized methodology. Even if the incidence and characteristics of injuries are not identical in all sports, prevention of injury and promotion of fair play are relevant topics for almost all team sports.
Middle-Aged Children of Alzheimer Parents, A Pilot Study: Stable Neurocognitive Performance at 20-Year Follow-up
Authors: Jarvik Lissy F. , La Rue Asenath , Gokhman Izabella , Harrison Tracy , Holt Lori , Steh Bill , Harker Judith , Larson Scott , Yaralian Pauline , Matsuyama Steven , Rasgon Natalie , Geschwind Daniel , Freimer Nelson , Jimenez Elvira , Schaeffer Jeffrey
Published: November 2005

The objective of this pilot study on a convenience sample of 25 offspring of Alzheimer patients (mean age 61.5 ± 8.8 years; range, 50-82) was the early detection of neurocognitive decline. This preliminary report appears to be the first one dealing with 20-year follow-up of neurocognitive data of Alzheimer’s disease (AD) children. Digit symbol (Wechsler Adult Intelligence Scale) was the only of 11 neurocognitive measures with a significant decline. And that decline between first and last testing (mean = 19.98 ± 0.30 years) was on raw scores, not scaled scores. Neither parents’ age at onset of AD nor autopsy confirmation or offspring APOE-e4 status influenced neurocognitive results. More robust data than currently available are needed to confirm the findings of this first pilot study and to determine both the trajectory of neurocognitive decline in AD and the risks of developing AD faced by children whose parent had the disease.
Predicting Alzheimer’s Disease in the Baltimore Longitudinal Study of Aging
Authors: Zonderman Alan B.
Published: November 2005

Longitudinal studies offer opportunities for studying children whose parents have Alzheimer’s disease. The Baltimore Longitudinal Study of Aging (BLSA) has examined adult cognitive performance but has not systematically recruited participants’ children. We initiated studies of dementia in the 1980s. This work suggested that hormone replacement and use of nonsteroidal anti-inflammatory drugs reduced the risk of Alzheimer’s disease and that risk for Alzheimer’s disease could be predicted from cognitive performance as many as 20 years prior to its onset. More recently, we showed that premorbid levels of free testosterone were lower in men who developed Alzheimer’s disease and premorbid depressive symptomatology was a risk for Alzheimer’s disease in men but not women as many as 6 years before the onset of dementia. Participants in the BLSA include family members with a variety of degrees of relationship, but there is no systematic effort to collect data from relatives of participants.
Performance on Neurocognitive Tests by Co-twins to Dementia Cases Compared to Normal Control Twins
Authors: Gatz Margaret , Fiske Amy , Reynolds Chandra A. , Johansson Boo , Fratiglioni Laura , Pedersen Nancy L.
Published: November 2005

Nondemented co-twins of twins who were diagnosed as demented were compared to randomly selected members of normal control twin pairs in which both members of the pair were nondemented. Nondemented co-twins included 23 monozygotic and 62 dizygotic twins; there were 27 normal control twins. Both monozygotic and dizygotic nondemented co-twins of dementia cases scored significantly lower than normal control twins on 5 of 10 cognitive tests. Moreover, monozygotic co-twins of dementia cases had a generally lower score profile than dizygotic co-twins of dementia cases did. These findings show that being at greater genetic risk for dementia is reflected in cognitive performance even in the absence of a diagnosis of dementia.
Cognitive Decline and Literacy Among Ethnically Diverse Elders
Authors: Manly Jennifer J. , Schupf Nicole , Tang Ming-X. , Stern Yaakov
Published: November 2005

Researchers on genetic and environmental influences on risk for Alzheimer’s disease must be prepared for the growing ethnic and racial diversity of our participants. Within the investigation, years of education has typically served as a proxy for cognitive reserve, which may be one factor in influencing risk of cognitive decline among aging people. However, among ethnic minorities, years of education is a poor reflection of the value of educational experience and native ability. This study was conducted among 1002 ethnically diverse English-speaking residents of Northern Manhattan who were cognitively and functionally normal at a baseline evaluation. We found that literacy level was a better predictor of decline in memory, executive function, and language skills than was years of education. The results of this study suggest that in an ethnically diverse cohort, literacy level should be considered as a mediator of the interactions of biological and environmental factors on cognitive decline.
Very Early Detection of Alzheimer Neuropathology and the Role of Brain Reserve in Modifying Its Clinical Expression
Authors: Mortimer James A. , Borenstein Amy R. , Gosche Karen M. , Snowdon David A.
Published: November 2005

Numerous studies show that the pathology of Alzheimer’s disease is present decades before a clinical diagnosis of dementia can be made. Given the likelihood that agents will become available that reliably delay onset and/or slow progression of Alzheimer’s disease, it will be important to detect preclinical Alzheimer’s disease as early as possible for maximal treatment effect. Detection of individuals by sensitive cognitive measures provides one way to identify people who are at high risk of developing clinical Alzheimer’s disease. However, it is likely that those with considerable brain or cognitive reserve will be able to mask cognitive deficits until very close to the onset of the dementia, rendering such cognitive measures insensitive. Optimum biomarkers for Alzheimer’s disease therefore need to target the severity of underlying brain pathology independently of brain reserve. Findings are presented showing the importance of higher education and larger brain size in masking the underlying disease pathology.
Recent Clinical-Pathologic Research on the Causes of Dementia in Late Life: Update From the Honolulu-Asia Aging Study
Authors: White Lon , Small Brent J. , Petrovitch Helen , Ross G. Webster , Masaki Kamal , Abbott Robert D. , Hardman John , Davis Daron , Nelson James , Markesbery William
Published: November 2005

In this study, we compare neuropathological findings at autopsy with clinical dementia diagnoses, such as Alzheimer’s disease and vascular dementia. Participants consisted of 363 aged Japanese-American men from the Honolulu-Asia Aging Study. Results indicated that the correspondence between clinical and neuropathologic diagnosis was not great, with 56% of patients diagnosed with probable or possible Alzheimer’s disease during life but with only 19% having neuritic plaques and/or neurofibrillary tangles as the sole or dominant dementia-related lesions in the brain at autopsy. Although 16% of cases were attributed to mixed causes during life, almost 40% were found to have significant mixtures of dementia-related lesions at autopsy. Finally, both Alzheimer’s disease and non-Alzheimer’s disease neuropathologic lesions contributed independently to the explanation of variance on a test of overall cognitive performance. The results suggest that clinical diagnosis of dementia made during life may fail to reflect the pathogenic complexity of this condition in very elderly persons.
Longitudinal Models of Growth and Survival Applied to the Early Detection of Alzheimer’s Disease
Authors: McArdle John J. , Small Brent J. , Bäckman Lars , Fratiglioni Laura
Published: November 2005

This article explores new statistical methodologies for using longitudinal data in the early prediction of Alzheimer’s disease (AD). Specifically, the authors examine some new techniques that allow the joint or “shared” estimation of longitudinal components based on both duration (survival) and quantitative changes (growth curves). These new shared growth-survival parameter models may be used to characterize the declining functions that anticipate the onset of AD. The authors apply these models to data from the Kungsholmen Project, a longitudinal study of aging in Stockholm, Sweden. They examine age-based survival-frailty models for the onset of AD, latent growth-decline curve models for changes in cognition over age, and 3 alternative forms of models for the shared relationships of survival and early cognitive decline. The accuracy and reliability of this approach is considered for a better understanding of the developmental course of AD in these data, including the potential removal of biases due to subject selection.
Middle-Aged Children of Persons With Alzheimer’s Disease: APOE Genotypes and Cognitive Function in the Wisconsin Registry for Alzheimer’s Prevention
Authors: Sager Mark A. , Hermann Bruce , La Rue Asenath
Published: November 2005

Adult children of persons with Alzheimer’s disease are at increased risk of developing Alzheimer’s disease because of hereditary, environmental, and health risk factors shared with affected parents. The Wisconsin Registry for Alzheimer’s Prevention (WRAP) has completed baseline assessments on 452 middle-aged persons (mean = 53 years) who have at least 1 parent with AD. Forty-five percent had 1 or more apolipoprotein (APOE) ε4 alleles. There were few significant differences between ε4 carriers and noncarriers in demographics, health, and lifestyle measures or in neuropsychological performance. The high percentage of WRAP participants who are carriers of APOE ε4 underscores their increased risk for developing Alzheimer’s disease, but the absence of differences related to APOE status and high mean scores on cognitive tests suggests that the APOE ε4 gene has yet to have a clinical impact on cognitive functioning. The WRAP cohort may be a valuable group to follow prospectively to characterize the nature of cognitive change in relation to risk factors and to identify underlying preclinical neurobiological changes.
Genetic Risk Assessment for Adult Children of People With Alzheimer’s Disease: The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) Study
Authors: Roberts J. Scott , Cupples L. Adrienne , Relkin Norman R. , Whitehouse Peter J. , Green Robert C. ,   for the REVEAL (Risk Evaluation and Education for Alzheimer’s Disease) Study Group
Published: November 2005

As genetic risk factors continue to be identified for common, complex adult-onset diseases, it will become increasingly important to understand if, how, and when to translate these discoveries into clinical practice. This article provides an overview of and results to date from the REVEAL study, a multisite randomized clinical trial (n = 162) examining the impact of a genetic risk assessment program, including apolipoprotein E genotype disclosure, for adult children of people with Alzheimer’s disease. The study’s rationale and procedures are described, including the generation of numerical lifetime risk curves for use in the education and counseling protocol. Findings are summarized across numerous study questions, including (1) who seeks genetic risk assessment and why, (2) how apolipoprotein E results affect risk perceptions, (3) the psychological impact of genetic risk assessment, and (4) how risk information affects participants’ subsequent health and insurance behaviors.
The impact of mood stabilizers on bipolar disorder: the 1890s and 1990s compared
Authors: Harris Margaret , Chandran Summit , Chakraborty Nabonita , Healy David
Published: November 2005

This study comparing patterns of service utilization by bipolar patients in North-West Wales found a greater prevalence of service utilization in the 1990s compared with the 1890s. In the pre-lithium era, admissions for bipolar disorders occurred at a rate of 4 every 10 years; they now occur at a rate of 6.3 every 10 years. Where 100 years ago, there were 16 bipolar patients per million population resident per day in hospital, there are now 24 per million resident in acute service beds and more in non-acute beds. These data are incompatible with simple claims that mood stabilizing drugs ‘work’. An alternative is that these agents have treatment effects, and further research is needed to match treatments to patients in order to optimize outcomes.
Crack Propagation in Finite Elastodynamics
Authors: Tarantino Angelo Marcello
Published: November 2005

Within the framework of finite elastodynamics, a crack propagation analysis, for sheets of compressible hyperelastic material, is formulated. By exploiting a dynamic generalization of the Stephenson's result, general far-field loading conditions are considered. Through an asymptotic singular analysis, the motion and the stress fields around a dynamically moving crack tip are then computed. Emphasis is placed on the order of singularity in the asymptotic Piola-Kirchhoff and Cauchy stresses, on the determination of crack profile and of the vector energy flux at the moving crack tip. Moreover, the most important differences with respect to the classical predictions of linear elastodynamic theory are evidenced.
Non-Isochoric Bending and Shearing
Authors: Carroll M. M.
Published: November 2005

Two families of non-homogeneous finite deformations are treated. For each family, the governing system of second-order nonlinear partial differential equations reduces to a system of first-order non-linear ordinary differential equations for homogeneous compressible elastic solids with arbitrary isotropic or anisotropic response.
Public Views on Sentencing Juvenile Murderers
Authors: Applegate Brandon K. , Davis Robin King
Published: November 2005

Concerns about juvenile murderers were raised by increases in juvenile homicide rates between the mid-1980s and mid-1990s. Little is known, however, about what level of punishment the public desires for such youths. Using a randomly selected sample of Florida citizens and a factorial vignette survey approach, the present study assesses the impact of characteristics of the offender, aspects of the offense, and perceptions of a youth’s maturity on public preferences for the punishment of juvenile murderers. Our findings show that the public favors short sentences of incarceration or less punitive responses in most cases and that the most salient determinant of punitiveness is the type of murder committed. These results are discussed in light of prior research and current policy directions.
Other-Sex Friendship Involvement among Delinquent Adolescent Females
Authors: Solomon Brett Johnson
Published: November 2005

Ninety-two delinquent and nondelinquent African American and Hispanic adolescent females (ages 13 to 17) from Los Angeles County were interviewed to determine the likelihood of male friendship selection. Using both qualitative and quantitative measures, the group’s demographic backgrounds, friendship selection, and quality were compared. Additionally, delinquent girls completed measures examining their self-perceptions and feelings of loneliness. Results indicate that delinquent girls are significantly more likely than nondelinquent girls to identify males as their closest friends. Age of friend, perceived advantages of the friendship, and involvement in delinquent and similar activities are related to male friendship selection. The results also reveal that delinquent girls with male friends do not differ from the female-friend groups on quantitative measures of friendship quality. Finally, among the delinquent population only, no differences between friendship groups exist for feelings of loneliness, competence, and self-worth.
Aplastic Anemia: Management of Adult Patients
Authors: Maciejewski Jaroslaw P. , Risitano Antonio M.
Published: November 2005

The primary therapeutic approach to acquired aplastic anemia (AA) in older adults differs from the primary approach used in children and younger adults because in the former group, the results of allogeneic bone marrow transplantation (BMT) are less favorable. With increasing age of the patients, immunosuppressive therapy with antithymocyte globulin (ATG) and cyclosporine (CsA) constitutes the primary treatment option and may be better than BMT. There are very few clinical clues as to the selection of patients likely to respond to immunosuppression. Repeated ATG/CsA cycles are often used as salvage regimens, but in refractory patients BMT may be the best treatment option, as the prognosis for non-responders is poor without definitive treatment. Conservative therapy such as intense immunosuppression is associated with a high relapse rate but does not impact the survival and overall prognosis. The inability to eliminate autoimmune T cell clones using current therapeutic strategies suggests that prolonged immunosuppressive maintenance therapy may be needed for a substantial proportion of patients. Late clonal complications of conservatively treated patients include evolution to myelodysplasia and paroxysmal nocturnal hemoglobinuria and may develop in 20% of the patients. However, BMT also has several sequelae including an increased frequency of solid tumors. Novel immunosuppressive and immunomodulatory agents and constantly improving results of allogeneic BMT will further improve the survival rate of adult patients with AA.
Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia
Authors: Ottmann Oliver G. , Wassmann Barbara
Published: November 2005

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) includes at least one-quarter of all adults with ALL. Until recently, conventional chemotherapy programs that have been effective in other precursor B-cell ALL cases have been unable to cure patients with this diagnosis. Allogeneic stem cell transplantation early in first remission has been the recommended therapy. The availability of imatinib mesylate and other tyrosine kinase inhibitors and small molecules that affect the BCR/ABL signaling pathways may be changing the treatment paradigm and the prognosis for these patients. The results from clinical trials using imatinib in the frontline setting and in relapsed patients as well as preliminary experience treating imatinib-resistant Ph+ ALL will be described.
Acute Lymphoblastic Leukemia: Older Patients and Newer Drugs
Authors: Larson Richard A.
Published: November 2005

Although the median age for adults with acute lymphoblastic leukemia (ALL) is older than 60 years, relatively few of these patients have been enrolled on prospective clinical trials. The presence of coexisting medical disorders and unfavorable cytogenetic and biological characteristics within this population presents considerable challenges for successful treatment using conventional chemotherapy programs. Selected patients have achieved remission and long-term survival following intensive chemotherapy. Preliminary data using several new agents that have shown promise for patients with ALL are described.
New Strategies for the Treatment of Acute Myeloid Leukemia Including Antibodies and Other Novel Agents
Authors: Tallman Martin S.
Published: November 2005

The prognosis for younger adults (≤ 55–60 years) with acute myeloid leukemia (AML) has improved during the last four decades. However, there has been little progress in the treatment of older adults. This disappointing observation is important because the median age of patients with AML is about 70 years. Approximately 60%–80% of younger adults with AML achieve complete remission (CR) with the cytotoxic agents cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only 30%–40% of such patients are alive and disease-free at 5 years. Among older adults, CR is achieved in 40%–55%, but there are very few long-term survivors. Many studies have evaluated the impact of alternative doses and schedules, as well as additional cytotoxic drugs, on the prognosis for this group of patients. The outcome has not improved substantially beyond that achieved with conventional doses of an anthracycline and cytarabine followed by high-dose cytarabine consolidation.

Several factors identified at diagnosis can predict outcome. The most important of these is the karyotype of the leukemic cells. Another critical factor is the presence of transmembrane transporter proteins, which confer multidrug resistance and mutations in or overexpression of specific genes such as WT1, C/EBPα, BAX, and BCL-2/BAX ratio, BAALC, EVI1, KIT and FLT3. The development of specific agents directed at gene mutations, signal transduction pathways and unique cell surface antigens provide the foundation for new therapeutic strategies. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyltransferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, FLT3 inhibitors, apoptosis inhibitors, and nucleoside analogs. All of these agents can potentially address the heterogeneous abnormalities in AML and significantly improve the outcome for patients.
Update on Supportive Care and New Therapies: Immunomodulatory Drugs, Growth Factors and Epigenetic-Acting Agents
Authors: Hellström-Lindberg Eva
Published: November 2005

Patients with “low-risk” myelodysplastic syndrome (MDS) are mostly treated with approaches aiming to reduce the negative consequences of ineffective hematopoiesis. Transfusion therapy should be tailored to allow adequate oxygenation and optimal quality of life, and may lead to the need for iron chelation therapy. Growth factors (erythropoietin and granulocyte colony-stimulating factor [G-CSF]) may induce long-lasting improvement of hemoglobin levels and does not increase the risk for leukemic transformation. Growth factors should be offered to defined subgroups of patients. Immunosuppression with anti-thymoglobulin or cyclosporine A may be an alternative for younger patients with refractory anemia (RA). The new immunomodulating compound lenalidomide, CC5013, is very active in the 5q– syndrome and is under evaluation for other low-risk MDS subtypes. “High-risk” MDS is associated with poor survival and high risk for leukemic transformation. The DNA hypomethylating compounds azacytidine and decitabine may offer improved long-term outcomes in this group of patients, although there has so far been no effect on survival rates. The efficacy of farnesyl transferase inhibitors has been evaluated in a series of phase II trials. The overall response rate was low, but the majority of responses were CRs. Finally, a number of new drugs directed to various biological and genetic targets are entering clinical trials.
Pathobiology of Lymphoid and Myeloid Blast Crisis and Management Issues
Authors: Ilaria Robert L.
Published: November 2005

Despite recent improvements in the treatment of early-stage disease, the blastic phase of chronic myeloid leukemia (CML) remains a therapeutic challenge. For imatinib-naïve patients, imatinib provided encouraging hematologic and cytogenetic benefits; however, the vast majority of CML blast crisis cases today arise in patients already on imatinib-based therapy. Clonal evolution and duplication of the Philadelphia chromosome continue to be associated with blastic phase transformation, but recent studies have identified BCR/ABL kinase domain mutations in 30%–40% of blast crisis patients. This implies that BCR-ABL–targeted therapy might have influenced the molecular road map to blastic transformation. In this review, we will examine the effect of imatinib on primitive CML progenitors and how this might influence the pathophysiology of blast crisis. A rational framework for deciding how best to integrate stem cell transplantation, traditional chemotherapy, imatinib, and other BCR-ABL kinase inhibitors in the care of blast crisis patients will also be discussed.
Red Cell Enzymes
Authors: Prchal Josef T. , Gregg Xylina T.
Published: November 2005

Mutations leading to red cell enzyme deficiencies can be associated with diverse phenotypes that range from hemolytic anemia, methemoglobinemia, polycythemia, and neurological and developmental abnormalities. While most of these mutations occur sporadically, some such as common glucose-6-phosphate dehydrogenase (G6PD) mutants are endemic and rarely cause disease. Common G6PD mutants likely reached their prevalence because they provide some protection against severe malarial complications. In this review G6PD, pyruvate kinase, 5′ nucleotidase, and cytochrome b5 reductase deficiencies will be discussed in greater detail. Limitations of commonly used screening tests for detection of these disorders will also be emphasized, as well as emerging knowledge about non-enzymatic function of the glycolytic enzymes.
Targeting the IAP Family of Caspase Inhibitors as an Emerging Therapeutic Strategy
Authors: Schimmer Aaron D. , Dalili Shadi
Published: November 2005

The IAPs (inhibitor of apoptosis proteins) are a family of caspase inhibitors that block the execution phase of apoptosis. Overexpression of IAPs confers chemoresistance and, in some groups of patients, is associated with a poor prognosis. Given their role in the development and progression of solid tumors and hematologic malignancies, efforts are underway to develop therapeutic IAP inhibitors, with a focus on X-linked IAP (XIAP) and survivin. Antisense oligonucleotides that target XIAP and survivin have been developed and are currently in phase I clinical trial. Small-molecules that bind and inhibit XIAP have also been identified and are in the process of clinical development. This review focuses on the preclinical data that support the development of IAP-targeted therapies.
Modulating the Bcl-2 Family of Apoptosis Suppressors for Potential Therapeutic Benefit in Cancer
Authors: Shore Gordon C. , Viallet Jean
Published: November 2005

Members of the BCL-2 family of proteins regulate and execute many cell intrinsic apoptosis pathways, including those arising from dysregulated expression of cellular oncogenes. Since pro-survival members of the family are often strongly elevated in diverse cancers, with the potential to confer resistance to both endogenous cell death stimuli and many cancer treatments, there has been intense interest to develop strategies to therapeutically modulate their activity. Although encouraging genetic and pharmacological preclinical proof of concept has been obtained, the challenge for clinical development will be to devise strategies that address the fact that multiple pro-survival members are typically up-regulated in a given cancer and the family operates primarily through protein-protein interactions. Moreover, since several current therapies themselves are known to stimulate the levels of one or more family members, there will be additional challenges (and opportunities) in exploiting this target in the clinic. In this review, we describe the rationale for targeting the BCL-2 family of apoptosis suppressors in cancer and the progress that has been made in modulating the family by small molecule antagonists.
Immunobiology and Pathophysiology of Hodgkin Lymphomas
Authors: Poppema Sibrand
Published: November 2005

Classical Hodgkin lymphoma (HL) is characterized by the presence of Reed-Sternberg (RS) cells, which are transformed post-germinal center B cells destined for apoptosis since they have not undergone successful immunoglobulin gene rearrangement. Several mechanisms, including latent infection by Epstein-Barr virus (EBV), allow these cells to survive. It is remarkable that many of the signaling pathways that promote survival are shared between the EBV-induced proteins, such as EBNA1, LMP1, and LMP2, and other molecules that are upregulated in RS cells. A key role is played by the presence of constitutive nuclear factor (NF)-κB, which is induced by LMP1, as well as by CD30, CD40, tumor necrosis factor (TNF)-α, and Notch1 interactions, and results in the upregulation of at least 45 genes including chemokines, cytokines, receptors, apoptotic regulators, intracellular signaling molecules, and transcription factors. The other characteristic of classical HL is the presence of an extensive inflammatory infiltrate. Key features of this infiltrate are that it comprises Th2 and T regulatory cells and generally lacks Th1 cells, CD8 cytotoxic T cells, and natural killer (NK) cells. The RS cells appear to induce this infiltrate by the secretion of Th2 type chemokines such as TARC and MDC. The RS cells also produce cytokines that inhibit Th1 responses, as interleukin (IL)-10 and transforming growth factor (TGF)-β express CD95 ligand, which induces apoptosis of activated Th1 and CD8 T cells. Other important mechanisms that allow the RS cells to escape an effective anti-EBV immune response include the downregulation of HLA class I in EBV-negative cases or the presence of a polymorphism in HLA class I in EBV-positive cases that allow escape from CD8-mediated cytotoxicity. On the other hand, expression of HLA-G allows the escape from NK cells that would normally recognize the HLA class I-negative RS cells. Overall, the cellular infiltrate in HL appears to play a decisive role in allowing the RS cells to survive by providing an environment that suppresses cytotoxic immune responses and providing cellular interactions and cytokines that support the growth and survival of RS cells. Future therapeutic strategies could focus directly on the NF-κB activation, on various receptors to ligand interactions, on the chemokine and cytokine network, or on the induction of effective anti-EBV latent protein immune responses.
Therapies for Relapsed Hodgkin Lymphoma: Transplant and Non-Transplant Approaches Including Immunotherapy
Authors: Bartlett Nancy L.
Published: November 2005

Autologous stem cell transplant remains the standard of care for relapsed Hodgkin lymphoma (HL). Approximately 50% of patients with chemo-sensitive relapse will be cured with this approach. The optimal pretransplant salvage regimen is controversial, but less toxic combinations seem to be equivalent to more aggressive approaches. For patients with chemo-refractory disease at relapse and those failing autologous transplant, the long-term prognosis remains poor. New approaches such as reduced-intensity allogeneic transplant, monoclonal antibodies targeting the CD30 antigen, Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes, and bortezomib are under investigation, but preliminary results are disappointing. New therapies are needed for patients with relapsed HL.
Biology and Treatment of Epstein-Barr Virus–Associated Non-Hodgkin Lymphomas
Authors: Heslop Helen E.
Published: November 2005

Epstein-Barr virus (EBV) is associated with several different types of aggressive non-Hodgkin lymphoma (NHL). Individuals with primary or secondary immunodeficiency are susceptible to developing B cell lymphoproliferation due to outgrowth of EBV-infected B cells that express type III latency characterized by expression of all nine latent-cycle EBV antigens. These cells would normally be susceptible to control by EBV-specific T cells, and strategies to restore EBV-specific immune responses may be effective therapeutically. EBV-associated lymphomas occurring in individuals who do not have a known immunodeficiency include NK and T malignancies with cytotoxic phenotypes, sporadic cases of B-NHL and lymphomatoid granulomatosis. These malignancies respond poorly to standard chemoradiotherapy, and immunotherapeutic or pharmacologic strategies targeting EBV are being explored.
Salvage Therapy for CLL and the Role of Stem Cell Transplantation
Authors: Gribben John G.
Published: November 2005

Chronic lymphocytic leukaemia (CLL) remains an incurable disease and, notwithstanding the excellent remission rates now achieved with purine analogs and monoclonal antibodies, the vast majority of patients with CLL are destined to relapse after primary treatment. The management of relapsed CLL patients is then dependent upon a number of factors, most importantly age, performance status, previous therapy administered, the response and duration of response to such therapy, and time from last therapy. Although prior therapy and response to such therapy are important factors in determining next therapy, it is often difficult to determine their importance from published studies. Furthermore, the goal of therapy, whether palliative or aggressive, must also be weighed into the decision when deciding on the next line of treatment. With many potential treatments available, the sequence of treatments and the timing of procedures such as stem cell transplantation remain controversial and are the focus of ongoing clinical trials.
Hematopathology Approaches to Diagnosis and Prognosis of Indolent B-Cell Lymphomas
Authors: Gascoyne Randy D.
Published: November 2005

The advent of new technologies has contributed to improvements in the diagnosis and classification of the non-Hodgkin lymphomas (NHL). Use of a more extensive test menu of paraffin active monoclonal antibodies for immunohistochemistry, molecular cytogenetic studies including standard cytogenetics, multi-color fluorescence in-situ hybridization (FISH), polymerase chain reaction and locus-specific FISH, as well as developments in high-resolution techniques including microarray gene expression profiling and array comparative genomic hybridization (CGH) allow more accurate diagnosis and precise definition of biomarkers of value in risk stratification. The identification of disease-specific gene lists resulting from expression profiling provides a number of potential protein targets that can be validated using immunohistochemistry. We will highlight how improvements in our understanding of lymphoma biology rapidly facilitate the development of new diagnostic reagents that could be used to alter clinical practice. These changing trends allow the development of new diagnostic strategies used to render accurate sub-classification of entities within the category of indolent B-cell lymphomas, including their distinction from related but more aggressive disorders, such as mantle cell lymphoma. A comprehensive understanding of the biology of these distinct lymphoid tumors will allow us to identify novel disease-related genes and should facilitate the development of improved diagnostics, outcome prediction, and personalized approaches to treatment.
Pathophysiology of β Thalassemia—A Guide to Molecular Therapies
Authors: Thein Swee Lay
Published: November 2005

The central mechanism underlying the pathophysiology of the β thalassemias can be related to the deleterious effects of imbalanced globin chain synthesis on erythroid maturation and survival. An imbalance of the α/non-α globin chains leads to an excess of unmatched α globin which precipitates out, damaging membrane structures leading to accelerated apoptosis and premature destruction of the erythroid precursors in the bone marrow (ineffective erythropoiesis). Close observation of the genotype/phenotype relationships confirms the pathophysiological mechanism and provides clues to molecular therapies, all of which aim to reduce the α/non-α chain imbalance. They include inheritance of the milder forms of β thalassemia, co-inheritance of α thalassemia, or genetic factors (quantitative trait loci, QTLs) for increasing γ globin expression. Currently, the most promising molecular therapeutic approaches include increasing β globin gene expression by stem cell gene therapy and increasing γ globin expression using pharmacological agents or by transduction of the γ globin genes.
Multimodality Therapies and Optimal Schedule of Antibodies: Rituximab in Lymphoma as an Example
Authors: Ghielmini Michele
Published: November 2005

Rituximab was the first humanized antibody widely used on patients, so research on its optimal use was a clinical challenge. Many studies have been performed to optimize its dose and schedule, and more are ongoing. The dose of 375 mg/m2 has become standard, mainly because it shows activity and has little associated toxicity. The combination of rituximab with chemotherapy has been shown to prolong remission in all types of lymphomas, and in patients with diffuse large B-cell lymphoma it can improve survival. As a single agent, particularly when the treatment is prolonged over several months, results are similar to chemotherapy but with fewer side effects. Finally, used as maintenance therapy it can prolong the duration of chemotherapy-obtained remissions. Based on available data, the administration of 375 mg/m2 before each chemotherapy cycle can be recommended for first line treatment of patients with curable B-cell lymphomas and for patients with high-risk indolent lymphoma who are rituximab-naïve. Single-agent treatment at a prolonged schedule is recommended for cases of indolent disease not in need of urgent response and for patients who are unlikely to tolerate chemotherapy.
Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy
Authors: Friedberg Jonathan W.
Published: November 2005

Anti-CD20 therapy has had a truly dramatic impact on treatment and outcome of patients with follicular lymphoma. Unfortunately, the majority of responses to single-agent rituximab are incomplete, and all patients with follicular lymphoma will experience disease progression at some point following rituximab therapy. Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptotic signaling, and possible vaccinal effects. The cellular microenvironment within follicular lymphoma has a profound impact on which mechanism is dominant, and confers resistance in many situations. Both tumor-associated and host-associated factors also contribute to rituximab resistance. There are multiple potential approaches to overcoming rituximab resistance, including rational biologic combination immunotherapy, engineered antibodies, and radioimmunoconjugates. Improved ability to overcome resistance will require further elucidation of critical signaling pathways involved in rituximab induced cytotoxicity and a comprehensive understanding of interactions between its multiple mechanisms of action.
Reduced-Intensity Conditioning Regimens for Hematologic Malignancies: What Have We Learned over the Last 10 Years?
Authors: Giralt Sergio
Published: November 2005

Reduced-intensity conditioning (RIC) regimens have been investigated for more than 10 years as an alternative to traditional myeloablative conditioning regimens. RIC regimens are being commonly used in older patients as well as in disorders in which traditional myeloablative conditioning regimens are associated with high rates of non-relapse mortality. Hodgkin disease, myeloma, and low-grade lymphoid malignancies have been the diseases most impacted by RIC regimens. RIC regimens have also been shown to be safe and effective in older patients as well as patients with co-morbidities, although patients with chemorefractory disease still have high relapse rates and poor outcomes. Patients with chemosensitive disease have outcomes similar to those obtained with conventional ablative therapies, and thus comparative trials are warranted. RIC regimens are associated with lower rates of severe toxicity and non-relapse mortality; however, infections, graft-versus-host disease, and relapse of primary disease remain the most common obstacles to a successful outcome. The impact on survival and the relative benefits of RIC allografting compared with traditional conditioning regimens or alternative therapy remain to be defined. Incorporating targeted therapies as part of the conditioning regimens or as maintenance therapies is currently being explored to reduce relapse rates without increasing toxicity.
Inherited Platelet Disorders
Authors: Handin Robert I.
Published: November 2005

The inherited platelet disorders are a heterogeneous collection of rare diseases that are infrequently encountered in clinical practice. They are, however, fascinating abnormalities, which have taught us a great deal about normal platelet biochemistry and physiology. In this section of the presentation we will review disorders of the platelet membrane, platelet granule packaging disorders, the hereditary macrothrombocytopenias, platelet signaling disorders and disorders of platelet coagulant function. The molecular basis of the disorders, the cardinal features of their clinical presentation and best methods to make their diagnosis and the latest information regarding therapy will be presented.
The Cardiovascular Pharmacology of COX-2 Inhibition
Authors: Fries Susanne , Grosser Tilo
Published: November 2005

Selective inhibitors of cyclooxygenase (COX)-2, the coxibs, were developed to inhibit inflammatory prostaglandins derived from COX-2, while sparing gastroprotective prostaglandins primarily formed by COX-1. However, COX-2-derived prostaglandins mediate not only pain and inflammation but also affect vascular function, the regulation of hemostasis/ thrombosis, and blood pressure control. All coxibs depress COX-2-dependent prostacyclin (PGI2) biosynthesis without effective suppression of platelet COX-1-derived thromboxane (Tx) A2, unlike aspirin or traditional nonsteroidal anti-inflammatory drugs, which inhibit both COX-1 and COX-2. The actions of PGI2 oppose mediators, which stimulate platelets, elevate blood pressure, and accelerate atherogenesis, including TxA2. Indeed, structurally distinct inhibitors of COX-2 have increased the likelihood of hypertension, myocardial infarction and stroke in controlled clinical trials. The detection of these events in patients is related to the duration of exposure and to their baseline risk of cardiovascular disease. Thus, coxibs should be withheld from patients with preexisting cardiovascular risk factors, and exposed patients at low cardiovascular baseline risk should be monitored for changes in their risk factor profile, such as increases in arterial blood pressure.
Gene Therapy for β-Thalassemia
Authors: Malik Punam , Arumugam Paritha I.
Published: November 2005

Gene transfer for β-thalassemia requires gene transfer into hematopoietic stem cells using integrating vectors that direct regulated expression of β globin at therapeutic levels. Among integrating vectors, oncoretroviral vectors carrying the human β-globin gene and portions of the locus control region (LCR) have suffered from problems of vector instability, low titers and variable expression. In recent studies, human immunodeficiency virus–based lentiviral (LV) vectors were shown to stably transmit the human β-globin gene and a large LCR element, resulting in correction of β-thalassemia intermedia in mice. Several groups have since demonstrated correction of the mouse thalassemia intermedia phenotype, with variable levels of β-globin expression. These levels of expression were insufficient to fully correct the anemia in thalassemia major mouse model. Insertion of a chicken hypersensitive site-4 chicken insulator element (cHS4) in self-inactivating (SIN) LV vectors resulted in higher and less variable expression of human β-globin, similar to the observations with cHS4-containing retroviral vectors carrying the human γ-globin gene. The levels of β-globin expression achieved from insulated SIN-LV vectors were sufficient to phenotypically correct the thalassemia phenotype from 4 patients with human thalassemia major in vitro, and this correction persisted long term for up to 4 months, in xeno-transplanted mice in vivo. In summary, LV vectors have paved the way for clinical gene therapy trials for Cooley’s anemia and other β-globin disorders. SIN-LV vectors address several safety concerns of randomly integrating viral vectors by removing viral transcriptional elements and providing lineage-restricted expression. Flanking the proviral cassette with chromatin insulator elements, which additionally have enhancer-blocking properties, may further improve SIN-LV vector safety.
Evaluation of Hematopoietic Stem Cell Donors
Authors: Horowitz Mary M. , Confer Dennis L.
Published: November 2005

Donation of hematopoietic stem cells, either through bone marrow or peripheral blood collection, is a generally safe procedure for healthy donors. Serious adverse events are uncommon and death is exceedingly rare. Nevertheless, all donors must be carefully evaluated and fully informed prior to donation. This should be done by clinicians having good understanding of the potential physical and psychological complications of donation and the factors that may increase these risks. Additionally, donors and graft products must be evaluated for the potential to transmit infections and other diseases to the recipient and to satisfy an increasing number of national and international regulatory requirements. Donors must be able to provide informed consent without coercion or pressure. Special attention to the clinical, psychological and social needs of pediatric donors is necessary.