bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortical Reorganization After Modified Constraint-Induced Movement Therapy in Pediatric Hemiplegic Cerebral Palsy
Authors: Sutcliffe Trenna L. , Gaetz William C. , Logan William J. , Cheyne Douglas O. , Fehlings Darcy L.
Published: November 2007

Constraint-induced movement therapy improves motor function in the affected hand of children with hemiplegic cerebral palsy and results in cortical changes in adults with stroke. This study measured clinical improvement and cortical reorganization in a child with hemiplegia who underwent modified constraint-induced movement therapy for 3 weeks. Clinical, functional magnetic resonance imaging and magnetoencephalography measurements were done at baseline, after therapy, and 6 months after therapy. Modified constraint-induced movement therapy resulted in clinical improvement as measured by the Pediatric Motor Activity Log. Functional magnetic resonance imaging showed bilateral sensorimotor activation before and after therapy and a shift in the laterality index from ipsilateral to contralateral hemisphere after therapy. Magnetoencephalography showed increased cortical activation in the ipsilateral motor field and contralateral movement evoked field after therapy. Cortical reorganization was maintained at the 6-month follow-up. This is the first study to demonstrate cortical reorganization after any version of constraint-induced movement therapy in a child with hemiplegia.
Nephrogenic Diabetes Insipidus: A Rare Cause of Intracranial Calcification in Children
Authors: Bindu Parayil S. , Kovoor Jerry M. E.
Published: November 2007

Causes of intracranial calcification in children are numerous. This article describes an unusual cause of intracranial calcification and white matter changes in a child, namely, nephrogenic diabetes insipidus. A 4-year-old boy presented with history of polyuria, polydipsia, failure to thrive, and developmental delay. On examination, he had mild dysmorphic features and spastic paraparesis. Evaluation showed findings suggestive of nephrogenic diabetes insipidus. Computed tomography and magnetic resonance imaging revealed calcification and signal changes in the frontal and parietal subcortical white matter and gray white junction in the parietal and occipital lobes. The involvement of the white matter, in addition to the calcification in this disease, is stressed because it may predict the neurologic outcome.
Maternal Ulcerative Colitis and Fetal Brain Injury: Long-Term Neurologic Outcome
Authors: Scher Mark S.
Published: November 2007

Two maternal-fetal case presentations illustrate the possible association of active maternal ulcerative colitis during pregnancy and fetal brain injury resulting in long-term neurological sequelae. Thromboembolic complications may occur in the fetus based on similar mechanisms for stroke in children and adults with active inflammatory bowel disease. Identification of thrombophilia in the pregnant woman with active ulcerative colitis may better explain a pathophysiologic mechanism for long-term neurological morbidity in offspring.
A Preliminary Study of the Mini-Mental State Examination in a Spanish Child Population
Authors: Rubial-Álvarez Sandra , Machado María-Clara , Sintas Elena , de Sola Susana , Böhm Peter , Peña-Casanova Jordi
Published: November 2007

The Mini-Mental State Examination is one of the most widely used screening tests for the adult population in daily neurologic practice. The aim of this study was to describe and to analyze the results of the Mini-Mental State Examination administered to Spanish children and to assess the relationship between Mini-Mental State Examination scores and the child's mental age/intelligence quotient. The study population included 181 children whose ages ranged between 4 and 12 years. The neuropsychologic battery consisted of the Mini-Mental State Examination and Kaufman Brief Intelligence Test. Percentiles were obtained for the Mini-Mental State Examination total score according to age ranges. Performance gradually increased from 4 to 10 years of age when a plateau in the total Mini-Mental State Examination score was reached. At the age of 6 years, results exceeded 24 on average. Pairwise mean comparisons showed statistically significant differences between the age groups ( P < .05). Data distribution could be classified in 4 independent groups for the following chronologic ages: 4, 5, and 6 years and from 7 to 12 years of age. The total Mini-Mental State Examination score correlated significantly with the child's chronologic ( r = 0.80, P < .001) and mental ( r = 0.76, P < .001) ages. This is a preliminary study of the application of the Mini-Mental State Examination in a Spanish child population as well as a first step for the assessment of the usefulness of this instrument as a cognitive screening tool for children's development.
A Newborn With Spinal Muscular Atrophy Type 0 Presenting With a Clinicopathological Picture Suggestive of Myotubular Myopathy
Authors: Nadeau Amelie , D'Anjou Guy , Debray Guillaume , Robitaille Yves , Simard Louise R. , Vanasse Michel
Published: November 2007

We report a male term newborn with genetically confirmed spinal muscular atrophy type 0, presenting with arthrogryposis and severe generalized weakness and requiring ventilatory support. Muscle biopsy revealed fibers with central nuclei resembling myotubes and negative myotubularin immunohistochemical staining compared with a control muscle biopsy. The absence of myotubularin associated with survival motor neuron protein deficiency suggests that survival motor neuron protein may have a role in muscle fiber maturation and myotubularin expression. Studying the pathology of this rare and lethal neonatal form of spinal muscular atrophy may further our understanding of spinal muscular atrophy pathogenesis.
Epilepsy in Children With Delayed Presentation of Perinatal Stroke
Authors: Fitzgerald Karima C. , Williams Linda S. , Garg Bhuwan P. , Golomb Meredith R.
Published: November 2007

A subgroup of children with perinatal stroke do not present clinically until after the perinatal period. Detailed epilepsy outcomes in these children have not been well studied. A retrospective cohort study of 45 children with delayed presentation of perinatal stroke identified by review of pediatric stroke clinic records, physician referral, and International Classification of Diseases, Ninth edition, code searches of hospital records, was performed at a tertiary pediatric hospital in Indianapolis, Indiana. A modified version of the Engel scale was used to grade epilepsy outcomes. The χ2 test, Fisher's exact test, and relative risks were calculated to examine the association of epilepsy at time of last follow-up with initial presentation with seizures, infantile spasms, radiographic findings, and initial abnormal electroencephalogram (EEG). These tests were also used to examine the association of epilepsy with cognitive or motor disability and the association of initial abnormal EEG with motor disability. Patients presented with hemiparesis (40; 89%), seizures (4; 9%), or headaches (1; 2%). All had unilateral infarcts on cranial imaging. Four children (9%) had infantile spasms, 2 at presentation and 2 later. Nineteen children received at least 1 EEG for suspicious spells or frank seizures; initial EEG was abnormal in 16 patients (84%). At last follow-up, 17 patients (38%) had epilepsy, which was severe in 4 (24% of those with epilepsy). Initial presentation with seizures (relative risk = 3.2; 95% confidence interval, 2.0-4.9) and infantile spasms (relative risk = 3.2; confidence interval, 2.0-4.9) were associated with epilepsy at last follow-up. Infantile spasms were also associated with moderate-to-severe epilepsy at last follow-up (relative risk = 10.3; confidence interval, 1.9-54.4). Epilepsy at last follow-up was associated with cognitive disability ( P = .05). Initial abnormal EEG was not associated with cerebral palsy ( P = .30). Epilepsy is frequent in children with delayed presentation of perinatal stroke and is associated with initial presentation with seizures and infantile spasms at any point in time. Cognitive disability often accompanies epilepsy in these children.
Justice at Work, Job Stress, and Employee Health
Authors: Fujishiro Kaori , Heaney Catherine A.
Published: November 2007

A small but growing literature has documented an association between justice at work and employee health. However, the pathways and mechanisms underlying this association are not well understood. This article proposes a conceptual framework that bridges the organizational justice, occupational stress, and occupational epidemiology literatures. Justice appraisals are proposed to be both important mediators and moderators in the causal flow from exposure to the organizational environment to employee health. The potential role of justice in enhancing employee health is compared to that of the well-established concepts of social support and job control. Directions for future research are suggested, along with strategies for overcoming challenges inherent in this multidisciplinary area of research. Implications for work-site health interventions are discussed.
Stephen Neill'sAnglicanism: An Anglican Classic
Authors: Sachs W. L.
Published: November 2007

Stephen Neill'sAnglicanismhas been the classic book on Anglican history and tradition for a generation. Books which become classics endure because they exhibit timeless features. Neill'sAnglicanismsucceeds because he delineates core features of the church's tradition which originated in English circumstances and spread beyond them. The book's endurance also reflects its comprehensive narrative and objectivity. For Neill English precedent left an enduring mark without enshrining English authority. Anglicanism's genius has been its capacity to embrace local variations of expression. Yet Neill foresaw the tensions inherent in post-colonial Anglicanism. The irony of the church's adaptability and growth was the resulting strain on its consensual forms that began in his lifetime. Local variety would extend to a degree that would erode over-arching consensus and strain the structures which would enforce it, as Neill saw plainly.
Jesus Christ – The Centre of Theology in Richard Hooker'sOf the Lawes of Ecclesiastical Polity, Book V
Authors: Grislis Egil
Published: November 2007

Richard Hooker (1554–1600), while respected in his own time, has become famous in the twenty-first century. For a generally secular age of postmodernism, Hooker offers a remarkably coherent foundational methodology and presents a vigorous case for conservative Christianity. With central attention to Jesus Christ, he celebrates faith, appreciates tradition, and honours reason. Of course, Hooker wrote for his own times. But he has remained relevant, since he cherished truth that does not age. Of the eight books of hisLawes, in Book V Hooker recorded what may be called the most powerful witness for Evangelical and Catholic Christianity in a profound Anglican formulation. While the central orientation to Christ was characteristic of all of Hooker's works, Book V combined his methodological concerns with such central doctrines as the Church, the definition of prayer, Christology, and the holy sacraments. At the same time Hooker also reflected on the theological dimensions of a great variety of liturgical issues. This brief statement, however, precludes a detailed concern with all that is valuable, and focuses on the major doctrines. Moreover, Book V can also be viewed as a creative celebration and defence of theBook of Common Prayer.
Thrombophilia: Common Questions on Laboratory Assessment and Management
Authors: Heit John A.
Published: November 2007

Thrombophilia is an inherited or acquired predisposition to thrombosis. This article reviews the clinical manifestations of thrombophilia and addresses common questions on laboratory assessment and management: what are the potential indications for thrombophilia testing, who should be tested, what tests should be requested, when should testing be performed, and how should the test results affect primary prevention, acute therapy, and secondary prophylaxis of thrombosis.
Bleeding and Thrombosis Risks in Plasma Cell Dyscrasias
Authors: Eby Charles S.
Published: November 2007

Major, spontaneous bleeding is uncommon in patients with plasma cell dyscrasias despite frequent abnormal screening hemostasis tests. However, acquired von Willebrand deficiency and light-chain (AL) amyloidosis, and amyloidosis complicating multiple myeloma can present with serious hemorrhagic complications that are challenging to manage. While patients with monoclonal gammapathy of undetermined significance and multiple myeloma share an intrinsic increased risk of venous thromboembolic events (VTE), treatment with thalidomide and lenalidomide increases the incidence of VTE in certain multiple myeloma patient subsets. Our understanding of the complex interactions among malignant plasma cells, inflammatory and hemostasis pathways, and treatment modalities that combine to produce thrombotic complications is incomplete. Prospective, randomized trials are clearly needed to assist clinicians in providing optimal VTE prophylaxis to their patients with plasma cell dyscrasias.
The Evidence-Based Use of FFP and Cryoprecipitate for Abnormalities of Coagulation Tests and Clinical Coagulopathy
Authors: Stanworth Simon J.
Published: November 2007

There continues to be a general but unfounded enthusiasm for fresh frozen plasma (FFP) or frozen plasma (FP) usage across a range of clinical specialties in hospital practice. Plasma for transfusion is most often used where there are abnormal coagulation screening tests, either therapeutically in the face of bleeding, or prophylactically in nonbleeding patients prior to invasive procedures or surgery. Little evidence exists to inform best therapeutic transfusion practice, and most studies describe plasma use in a prophylactic setting. Laboratory abnormalities of coagulation are considered by many clinicians to be a predictive risk factor for bleeding prior to invasive procedures or in other clinical situations where bleeding risk exists, and plasma for transfusion is presumed to improve the laboratory results and reduce this risk. However, most guideline indications for the prophylactic use of plasma for transfusion are not supported by evidence from good-quality randomized trials. Arguably, the strongest randomized controlled trial (RCT) evidence indicates that prophylactic plasma for transfusion is not effective across a range of different clinical settings, and this is supported by data from nonrandomized studies in patients with mild to moderate abnormalities in coagulation tests. There is a need to undertake new trials evaluating the efficacy and adverse effects of plasma, both in bleeding and non-bleeding patients, to understand whether the presumed benefits outweigh the real risks. In addition, new hemostatic tests that better define the risk of bleeding and monitor the effectiveness of the use of FFP should be validated. Last, there is an opportunity to develop effective educational strategies aimed at addressing understanding and compliance with recommendations in guidelines.
Evaluation of the Risk of Therapy-Associated Complications in Survivors of Hodgkin Lymphoma
Authors: Travis Lois B.
Published: November 2007

Given the improvements in survival of patients with Hodgkin lymphoma (HL) in the last three decades, quantification of the late effects of successful treatment has become critical. Since the highest incidence rates of HL occur at ages 20 to 34 years, large numbers of patients remain at lifelong risk for the late effects of treatment. Deaths due to second cancers are now the most common cause of mortality among long-term survivors of HL, followed by cardiac disease. Risk measures of these and other late sequelae, however, can vary markedly between investigations, depending on the types of treatment, the rigor with which epidemiologic study designs are applied, ascertainment of events of interest, the duration and completeness of follow-up, and consideration of competing risks. Further, numerous influences apart from therapy can affect late effects, including patient age, sex, race, lifestyle factors (tobacco, alcohol, diet), comorbidities, and the underlying cancer process. In the future, it will become increasingly important for health-care providers to be able to critically evaluate the risk of late effects in HL survivors, which will include a working knowledge of various epidemiologic study designs and risk measures and an ability to judiciously review the medical literature. In this article, the methods, significance and caveats in calculating and reporting risks of complications of treatment for HL are reviewed.
Epstein-Barr Virus and Hodgkin Lymphoma
Authors: Ambinder Richard F.
Published: November 2007

Epstein-Barr virus (EBV) is detected in some Hodgkin lymphoma (HL) tumor cells. Primary infection is associated with infectious mononucleosis and EBV+ HL. Vaccines and antiviral drugs show promise in modulating the clinical course of infectious mononucleosis. Their impact on HL is entirely unknown. T-cell function may be important in the pathogenesis of HL. In HIV patients, higher CD4 counts are associated with an increased incidence of EBV+ HL. One of the roles of the virus in the pathogenesis of HL may be to mimic signals associated with surface immunoglobulin molecules. New approaches to imaging EBV-associated tumors may be on the horizon. Adoptive immunotherapy and virus-specific pharmacologic therapies offer promise for future treatment.
Aplastic Anemia: Pathogenesis and Treatment
Authors: Bacigalupo Andrea
Published: November 2007

This review highlights some of the contributions that have appeared in the literature in the past decade on the pathogenesis and treatment of aplastic anemia (AA). This summary is brief because the field is vast, spaning from stem cell biology to stem cell disorders, from autoimmunity to transplantation, from graft-versus-host disease to late effects. The immune pathogenesis of AA is now based on several lines of evidence and will be discussed. Immunosuppressive therapy (IST) remains an important option for AA patients who are not candidates for transplantation. Favorable prognostic indicators for IST are young age and a short interval from diagnosis; the neutrophil count seems to have lost its predictive value with current antithymocyte globulin–cyclsoporin combination therapy. The outcome of allogeneic bone marrow transplantations has significantly improved in the past decade, particularly in the unrelated donor setting, to such an extent that treatment strategies may be affected. A short interval between diagnosis and treatment will also improve results for bone marrow transplantation; these rare patients should be referred to an experienced center immediately.
Monoclonal Antibodies for B-Cell Lymphomas: Rituximab and Beyond
Authors: Bello Celeste , Sotomayor Eduardo M.
Published: November 2007

The year 2007 marks the 10th anniversary of approval by the U.S. Food and Drug Adminstration of the first monoclonal antibody for the treatment of cancer. Rituximab, an anti-CD20 chimeric monoclonal antibody, was approved for the treatment of patients with relapsed/refractory low-grade B-cell non-Hodgkin lymphomas. From an immunologic perspective, this therapeutic indication provided the long-elusive validation of immunotherapy as the fourth modality of treatment for patients with cancer. From a clinical perspective, it was hard to imagine then that this nonchemotherapeutic approach would dramatically impact the management of patients with almost every type of B-cell malignancy and that it would even find a place as a therapeutic option for patients with non-malignant disorders. Although thousands of patients have been treated worldwide with rituximab, there is still debate regarding its mechanism(s) of action. The demonstration that a number of patients do not benefit with this treatment and that no cures have been achieved with single-agent rituximab prompted several investigators to identify those barriers limiting the efficacy of this monoclonal antibody. Here, we summarize what we have learned in the past 10 years about rituximab efficacy and its mechanisms of action and resistance. We also discuss the new generation of monoclonal antibodies, the development of which has been spurred by the widespread success of anti-CD20 MAb therapy.
Molecular Signatures Define New Rational Treatment Targets in Large B-Cell Lymphomas
Authors: Shipp Margaret A.
Published: November 2007

Diffuse large B-cell lymphomas (DLBCLs), the most common lymphoid malignancies, are clinically and genetically heterogeneous disorders. Although DLBCL is a chemo-responsive tumor, many patients will not be cured with conventional empiric treatment regimens. Gene expression profiles, analyses of specific genetic abnormalities and functional assays have been used to develop comprehensive molecular signatures of tumors that share similar features and rely upon common survival pathways. These studies are leading to the identification of subtype-specific rational therapeutic targets and associated inhibitors for clinical investigation.
Diagnosis, Genetics, and Management of Inherited Bone Marrow Failure Syndromes
Authors: Alter Blanche P.
Published: November 2007

The inherited bone marrow failure syndromes are traditionally considered to be pediatric disorders, but in fact, many of the patients now are diagnosed as adults, and many diagnosed as children now live to reach adulthood. The most common of these rare disorders include Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome and amegakaryocytic thrombocytopenia, which often develop aplastic anemia and may evolve into myelodysplastic syndrome and acute myeloid leukemia; and Diamond-Blackfan anemia, severe congenital neutropenia, and thrombocytopenia absent radii, single cytopenias that rarely if ever become aplastic but have increased risks of leukemia. In addition, the first three syndromes have high risks of solid tumors: head and neck and anogenital squamous cell carcinoma in Fanconi anemia and dyskeratosis congenita, and osteogenic sarcoma in Diamond-Blackfan anemia. Diagnosis of a marrow failure syndrome requires recognition of characteristic physical abnormalities when present, and consideration of these disorders in the differential diagnosis of patients who present with “acquired” aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, or atypically early cancers of the types seen in the syndromes. Ultimate proof will come from identification of pathogenic mutations in genes associated with each syndrome.
Comprehensive Management of the CLL Patient: A Holistic Approach
Authors: Shanafelt Tait D. , Kay Neil E.
Published: November 2007

The current management of B-chronic lymphocytic leukemia (CLL) is no longer straightforward for the practicing hematologist. Rapid advances in diagnostic precision, methods of predicting prognosis, understanding of natural history of CLL, recognition of clinical complications, clarification of the quality of life (QOL) issues facing the CLL patient, and the exciting array of novel treatment approaches have made the care of the CLL patient more demanding. This review is focused on summarizing these advances in order to provide a framework for integrating this knowledge into routine hematologic practice.
Management of Infectious Complications in Patients with Chronic Lymphocytic Leukemia
Authors: Morrison Vicki A.
Published: November 2007

Infections remain a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The pathogenesis of these complications is related to immune defects inherent to the primary disease as well as to therapy-related immunosuppression. The spectrum of infections seen has evolved with the therapeutic use of purine analogs, which induce specific cellular immune defects, as well as the monoclonal antibodies alemtuzumab and rituximab. Although bacterial infections are most common, fungal and herpesvirus infections are also seen with use of these agents. This overview will summarize the pathogenesis of infection in patients with CLL as well as the spectrum of infection and approaches to the prophylactic and therapeutic management of these complications.
Thrombocytosis and Thrombosis
Authors: Vannucchi Alessandro M. , Barbui Tiziano
Published: November 2007

The aim of this review is to discuss current diagnostic approaches to, and classification of, patients presenting with thrombocytosis, in light of novel information derived from the discovery of specific molecular abnormalities in chronic myeloproliferative disorders (CMPD), which represent the most common cause of primary thrombocytosis. The JAK2V617F and the MPLW515L/K mutations have been found in patients with essential thrombocythemia, polycythemia vera, and primary myelofibrosis, and less frequently in other myeloproliferative disorders complicated by thrombocytosis. However, neither mutation is disease specific nor is it universally present in patients with elevated platelet counts due to a CMPD; therefore, distinguishing between reactive and primary forms of thrombocytosis, as well as among the different clinical entities that constitute the CMPD, still requires a multifaceted diagnostic approach that includes as a key step the accurate evaluation of bone marrow histology. The role of elevated platelet counts in thrombosis, which represent the predominant complication of CMPD,significantly affecting prognosis and quality of life as well as, paradoxically, in the pathogenesis of the hemorrhagic manifestations, will be discussed. Established and novel potential risk factors for thrombosis, including the clinical relevance of the JAK2V617F mutation, and current management strategies for thrombocytosis are also briefly discussed.
Genetic Pathways in the Pathogenesis of Therapy-Related Myelodysplasia and Acute Myeloid Leukemia
Authors: Pedersen-Bjergaard Jens , Andersen Morten T. , Andersen Mette K.
Published: November 2007

In therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML), at least eight alternative genetic pathways have been defined based on characteristic recurrent chromosome abnormalities. Patients presenting as t-MDS and patients presenting as overt t-AML cluster differently in these pathways. The cytogenetic pattern depends on the type of leukemogenic therapy received: alkylating agents, topoisomerase II inhibitors, or radiotherapy.

Three types of gene mutations are observed in MDS and AML: (1) Activating mutations of genes in the tyrosine kinase–RAS/BRAF signal transduction pathway, leading to increased cell proliferation (Class I mutations); (2) Inactivating mutations of genes encoding hematopoietic transcription factors, resulting in disturbed cell differentiation (Class II mutations); and (3) Inactivating mutations of the tumor suppressor gene p53. At least 14 different genes have been identified as mutated in t-MDS and t-AML, clustering differently and characteristically in the eight genetic pathways. Class I and Class II mutations are significantly associated, indicating their cooperation in leukemogenesis

The chromosome aberrations and gene mutations detected in the therapy-related and in the de novo subsets of MDS and AML are identical, although the frequencies with which they are observed may differ. Hence, therapy-related and de novo MDS and AML are identical diseases and should be subclassified and treated similarly.
Bone Marrow Failure as a Risk Factor for Clonal Evolution: Prospects for Leukemia Prevention
Authors: Bagby Grover C. , Meyers Gabrielle
Published: November 2007

Patients with bone marrow failure syndromes are at risk for the development of clonal neoplasms, including paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia (MDS), and acute myelogenous leukemia (AML). Approximately 10% to 20% of those who survive acquired aplastic anemia will develop a clonal disease within the decade following their diagnosis. The relative risk of clonal neoplasms is very significantly increased in children and adults with inherited bone marrow failure syndromes as well. Until recently, the mechanisms underlying clonal evolution have been opaque, but a sufficient amount of evidence has now accumulated to support a model in which cells resistant to extracellular apoptotic cues are selected from the stem cell pool. Indeed, in the past two years this paradigm has been validated in preclinical models that are robust enough to reconsider new therapeutic objectives in aplastic states and to support the planning and development of rationally designed leukemia prevention trials.
Philadelphia Chromosome–Positive Acute Lymphocytic Leukemia: A New Era of Challenges
Authors: Thomas Deborah A.
Published: November 2007

Significant advances in the treatment of Philadelephia chromosome (Ph)– or BCR-ABL–positive acute lymphocytic leukemia (ALL) have been made since the discovery of the selective ABL tyrosine kinase inhibitors (TKIs). Whereas the outcome with standard chemotherapy was previously dismal, incorporation of imatinib mesylate into frontline therapy has improved relapse-free and overall survival. The benefit of imatinib extends particularly to instances where allogeneic stem cell transplantation in first complete remission is prohibited by older age, comorbidities, or lack of a suitable donor. However, the emergence of resistance to imatinib presents new therapeutic challenges. The development of novel TKIs with enhanced inhibitory potency against ABL and other kinases may further improve on the results observed with imatinib. Optimal use of these novel agents in the treatment schema of Ph+ ALL will be paramount in ensuring continued success in the eradication of this disease. Herein, the new approaches to the management of Ph+ ALL are reviewed.
Etiology and Management of Therapy-Related Myeloid Leukemia
Authors: Larson Richard A.
Published: November 2007

The diagnosis of therapy-related myeloid leukemia (t-MDS/t-AML) identifies a group of high-risk patients with multiple and varied poor prognostic features. These neoplasms are thought to be the direct consequence of mutational events induced by cytotoxic therapy. Their outcomes have historically been poor compared with those of people who develop acute myeloid leukemia (AML) de novo. The question arises whether a diagnosis of t-AML per se indicates a poor prognosis, or whether their bad outcomes result from other clinical and biologic characteristics. Because of lingering damage from prior cytotoxic therapy and, in some cases, the persistence of their primary disorder, patients with t-AML are often poor candidates for intensive AML therapy. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is higher in t-AML. Survival varies according to cytogenetic risk group, with better outcomes observed in patients with t-AML with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. Patients with t-AML should be enrolled on front-line chemotherapy trials, appropriate for de novo AML patients with similar disease characteristics. Allogeneic hematopoietic cell transplantation can cure some patients with t-AML. Most important , the molecular and genetic differences that appear to determine the phenotype and the outcome of these patients need to be investigated further.
Limitations of Clinical Trials in Sickle Cell Disease: A Case Study of the Multi-center Study of Hydroxyurea (MSH) Trial and the Stroke Prevention (STOP) Trial
Authors: DeBaun Michael R. , Field Joshua J.
Published: November 2007

In the past two decades, two landmark randomized controlled trials (RCT) have been completed among individuals with sickle cell disease (SCD), the Multi-center Study of Hydroxyurea (MSH) trial and the Stroke Prevention (STOP) trial. The MSH trial tested the hypothesis that hydroxyurea will reduce the frequency of painful episodes for adults with hemoglobin SS who had a history of 3 or more painful episodes per year. The STOP trial tested the hypothesis that among children with hemoglobin SS and an elevated transcranial Doppler (TCD) velocity measurement, blood transfusion therapy would decrease the risk of an initial stroke. After completion, both trials have defined standard care for individuals with hemoglobin SS. The purpose of this review is to examine the limitations of the MSH and STOP trials. In the context of these trials, we will examine the effects of narrow inclusion criteria that primarily include participants with hemoglobin SS and secondary analyses that are prone to false-positive results. In addition, we describe how after publication of these two trials use of hydroxyurea and TCD assessment has drifted towards a standard practice without evidence of therapeutic efficacy among groups that were excluded from the trials. Finally, we suggest that rigorously conducted RCTs or at the minimum multicenter observation studies with strong methodology should be performed in these excluded subgroups to confirm a benefit of hydroxyurea or TCD measurement.
An Introduction to Foundation and Industry-Sponsored Research: Practical and Ethical Considerations
Authors: Margolin Kim A. , van Besien Koen , Peace David J.
Published: November 2007

Investigators face formidable challenges in securing adequate support for their research efforts. Federal subsidies for biomedical research have not expanded in the past several years, while applications to the National Institutes of Health for investigator-initiated studies have increased substantially. Faced with stiffening competition, investigators, particularly those at the outset of their careers, may consider alternative sources of funding and support. Philanthropic foundations, private donors, and commercial industry provide a diverse array of funding opportunities. Strategies to identify and solicit funding from these alternative sources are addressed herein. Emphasis is given to the development and support of investigator-initiated clinical research. Ethical considerations that frame investigators’ acceptance and utilization of research subsidies from for-profit entities, i.e., pharmaceutical or biotechnology companies, are reviewed. The importance of the protection of intellectual property and the preservation of academic integrity and autonomy, especially in the context of corporate sponsorship, also are highlighted.
GVHD—The Nuts and Bolts
Authors: Weisdorf Daniel
Published: November 2007

Acute graft-versus-host disease (GVHD) is the most frequent, morbid complication following allogeneic hematopoietic stem cell transplantation (HSCT). Its clinical toxicity, requirement for intensive immunosup-pressive management, and associated infections lead to the greatest risks of nonrelapse mortality in HSCT recipients. In acute GVHD, donor-derived T lymphocyte–mediated alloreactivity is complicated by inflammatory responses, cytokine release, direct tissue injury through target cell apoptosis, and secondary tissue injury. The therapeutic management includes effective GVHD prophylaxis to limit the incidence and severity of acute GVHD, prompt and effective therapy if it develops—modified if possible to protect against chronic GVHD—and intensive supportive care relevant to its association with delayed immune reconstitution. As the major ongoing morbid complication following allografting, chronic GVHD is another barrier to patients’ recovery and long-term survival. Recognition of the critical elements in the pathogenesis of GVHD has prompted new approaches to its management and its role in controlling the risks of malignant relapse after allotransplantation. Important elements in the practical management of GVHD will be reviewed.
The Y-box binding protein YB-1 is associated with progressive disease and mediates survival and drug resistance in multiple myeloma
Authors: Chatterjee Manik , Rancso Christoph , Stühmer Thorsten , Eckstein Niels , Andrulis Mindaugas , Gerecke Christian , Lorentz Heike , Royer Hans-Dieter , Bargou Ralf C.
Published: November 2007

Current knowledge about molecular mechanisms underlying disease progression and drug resistance in multiple myeloma (MM) is still limited. Here, we analyzed the potential pathogenetic role of the Y-box binding protein YB-1 in MM. YB-1 is a member of the cold-shock domain protein superfamily and involved in various cellular functions such as proliferation. Immunohistochemical analyses revealed that neither normal bone marrow (BM) plasma cells (PCs), premalignant PCs of patients with monoclonal gammopathy of unknown significance (MGUS), nor MM cells with a mature morphology showed expression of YB-1 in situ. In contrast, YB-1 was strongly expressed in situ in normal PC precursor blasts as well as in a MM subset and in vitro in all of the evaluated MM cell lines. The YB-1–expressing MM cells were characterized by an immature morphology and a highly proliferative phenotype as defined by Ki 67 expression. We observed that siRNA-mediated knockdown of YB-1 decreased proliferation and induced apoptosis in MM cells even in the presence of BM stromal cells. Furthermore, we found that overexpression of YB-1 mediated resistance toward doxorubicin-induced apoptosis in MM cells. Thus, YB-1 contributes to disease progression, survival, and drug resistance in MM and might therefore provide an attractive therapeutic target.
Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis
Authors: Sellick Gabrielle S. , Wade Rachel , Richards Susan , Oscier David G. , Catovsky Daniel , Houlston Richard S.
Published: November 2007

To identify genetic variants associated with outcome from chronic lymphocytic leukemia (CLL), we genotyped 977 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 755 genes with relevance to cancer biology in 425 patients participating in a phase 3 trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Selection of nsSNPs was biased toward those likely to be functionally deleterious. SNP genotypes were linked to individual patient outcome data and response to chemotherapy. The effect of genotype on progression-free survival (PFS) and overall survival (OS) was assessed by Cox regression analysis adjusting for treatment and clinico-pathologic variables. A total of 78 SNPs (51 dominantly acting and a further 27 recessively acting) were associated with PFS (9 also affecting OS) at the 5% level. These included SNPs mapping to the immune-regulation genes IL16 P434S (P = .03), IL19 S213F (P = .001), LILRA4 P27L (P = .004), KLRC4 S29I (P = .007), and CD5 V471A (P = .002); and DNA response genes POLB P242R (P = .04) and TOPBP1 S730L (P = .02), which were all independently prognostic of immunoglobulin heavy-chain variable region (IgVH) mutational status. The variants identified warrant further evaluation as promising prognostic markers of patient outcome. To facilitate the identification of prognostic markers through pooled analyses, we have made all data from our analysis publicly available.
Apoptosis of dendritic cells induced by decoy receptor 3 (DcR3)
Authors: You Ren-In , Chang Yung-Chi , Chen Po-Min , Wang Wei-Shu , Hsu Tsui-Ling , Yang Chih-Ya , Lee Chun-Ting , Hsieh Shie-Liang
Published: November 2007

Decoy receptor 3 (DcR3) is a soluble decoy receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily, and its expression is not only up-regulated in cancer cells derived from various cell lineages, but also correlates with overall survival of patients with cancer. It has been shown that DcR3 sensitize cells of hematopoietic origin to TNF-related apoptosis-inducing ligand (TRAIL)–induced apoptosis; therefore, we asked whether DcR3 down-regulated host immunity by inducing immune cell apoptosis. We demonstrate that DcR3 induces dendritic cell (DC) apoptosis by activating PKC-δ and JNK subsequently to up-regulate DR5 to recruit Fas-associated death domain (FADD) to propagate the apoptotic signals. The association of FADD with DR5 results in the formation of death-inducing signaling complex (DISC) to trigger the downstream apoptotic signaling cascade. PKC-δ is activated via cross-linking of heparan sulfate proteoglycan (HSPG) on DCs, because recombinant protein containing the heparin-binding domain (HBD) of DcR3 and the Fc portion of IgG1, the HBD.Fc fusion protein, is also able to trigger DC apoptosis. This provides the first evidence that cross-linking of HSPG on DCs can activate PKC-δ to induce DC apoptosis via the formation of DR5 DISC, and elucidates a novel mechanism of DcR3-mediated immunosuppression.
Peptide ligand screening of α-synuclein aggregation modulators by in silico panning
Authors: Abe Koichi , Kobayashi Natsuki , Sode Koji , Ikebukuro Kazunori
Published: November 2007

Background

α-Synuclein is a Parkinson's-disease-related protein. It forms aggregates in vivo, and these aggregates cause cell cytotoxicity. Aggregation inhibitors are expected to reduce α-synuclein cytotoxicity, and an aggregation accelerator has recently been reported to reduce α-synuclein cytotoxicity. Therefore, amyloid aggregation modulating ligands are expected to serve as therapeutic medicines.

Results

We screened peptide ligands against α-synuclein by in silico panning, a method which we have proposed previously. In this study, we selected as the target a very hydrophobic region known as the amyloid-core-forming region. Since this region cannot be dissolved in water, it is difficult to carry out the in vitro screening of its peptide ligand. We carried out 6 rounds of in silico panning using a genetic algorithm and a docking simulation. After the in silico panning, we evaluated the top peptides screened in silico by in vitro assay. These peptides were capable of binding to α-synuclein.

Conclusion

We demonstrated that it is possible to screen α-synuclein-binding peptides by in silico panning. The screened peptides bind to α-synuclein, thus affecting the aggregation of α-synuclein.
The [FeFe] hydrogenase of Nyctotherus ovalis has a chimeric origin
Authors: Boxma Brigitte , Ricard Guenola , van Hoek Angela HAM , Severing Edouard , Moon-van der Staay Seung-Yeo , van der Staay Georg WM , van Alen Theo A , de Graaf Rob M , Cremers Geert , Kwantes Michiel , McEwan Neil R , Newbold C Jamie , Jouany Jean-Pierre , Michalowski Tadeusz , Pristas Peter , Huynen Martijn A , Hackstein Johannes HP
Published: November 2007

Background

The hydrogenosomes of the anaerobic ciliate Nyctotherus ovalis show how mitochondria can evolve into hydrogenosomes because they possess a mitochondrial genome and parts of an electron-transport chain on the one hand, and a hydrogenase on the other hand. The hydrogenase permits direct reoxidation of NADH because it consists of a [FeFe] hydrogenase module that is fused to two modules, which are homologous to the 24 kDa and the 51 kDa subunits of a mitochondrial complex I.

Results

The [FeFe] hydrogenase belongs to a clade of hydrogenases that are different from well-known eukaryotic hydrogenases. The 24 kDa and the 51 kDa modules are most closely related to homologous modules that function in bacterial [NiFe] hydrogenases. Paralogous, mitochondrial 24 kDa and 51 kDa modules function in the mitochondrial complex I in N. ovalis. The different hydrogenase modules have been fused to form a polyprotein that is targeted into the hydrogenosome.

Conclusion

The hydrogenase and their associated modules have most likely been acquired by independent lateral gene transfer from different sources. This scenario for a concerted lateral gene transfer is in agreement with the evolution of the hydrogenosome from a genuine ciliate mitochondrion by evolutionary tinkering.
Gene expression profiling in a mouse model of infantile neuronal ceroid lipofuscinosis reveals upregulation of immediate early genes and mediators of the inflammatory response
Authors: Qiao Xingwen , Lu Jui-Yun , Hofmann Sandra L
Published: November 2007

Background

The infantile form of neuronal ceroid lipofuscinosis (also known as infantile Batten disease) is caused by hereditary deficiency of a lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1), and is characterized by severe cortical degeneration with blindness and cognitive and motor dysfunction. The PPT1-deficient knockout mouse recapitulates the key features of the disorder, including seizures and death by 7–9 months of age. In the current study, we compared gene expression profiles of whole brain from PPT1 knockout and normal mice at 3, 5 and 8 months of age to identify temporal changes in molecular pathways implicated in disease pathogenesis.

Results

A total of 267 genes were significantly (approximately 2-fold) up- or downregulated over the course of the disease. Immediate early genes (Arc, Cyr61, c-fos, jun-b, btg2, NR4A1) were among the first genes upregulated during the presymptomatic period whereas immune response genes dominated at later time points. Chemokine ligands and protease inhibitors were among the most transcriptionally responsive genes. Neuronal survival factors (IGF-1 and CNTF) and a negative regulator of neuronal apoptosis (DAP kinase-1) were upregulated late in the course of the disease. Few genes were downregulated; these included the α2 subunit of the GABA-A receptor, a component of cortical and hippocampal neurons, and Hes5, a transcription factor important in neuronal differentiation.

Conclusion

A molecular description of gene expression changes occurring in the brain throughout the course of neuronal ceroid lipofuscinosis suggests distinct phases of disease progression, provides clues to potential markers of disease activity, and points to new targets for therapy.
Effect of PlA1/A2 glycoprotein IIIa gene polymorphism on the long-term outcome after successful coronary stenting
Authors: Le Hello Claire , Morello Rémy , Lequerrec Agnès , Duarte Christine , Riddell John , Hamon Martial
Published: November 2007

Aim

To prospectively determine the role of platelet glycoprotein IIIa (GP IIIa) gene PlA1/PlA2 polymorphism on the long-term clinical outcome in patients with coronary artery disease undergoing coronary stenting.

Design and setting

Prospective observational study in the University Hospital of Caen (France).

Patients and methods

1 111 symptomatic consecutive Caucasian patients treated with percutaneous coronary intervention including stent implantation underwent genotyping for GP IIIa PlA1/A2.

Main outcome measures

Long-term clinical outcome in terms of the rate of major adverse cardiac events (MACE, ie death from any cause, non-fatal Q wave or non Q wave myocardial infarction, and need for coronary revascularisation) was obtained and subsequently stratified according to the GP IIIa PlA1/A2 polymorphism.

Results

Three groups of patients were determined according to the GP IIIa PlA1/A2 polymorphism (71.6% had the A1/A1, 25.8% had the A1/A2 and 2.6% had the A2/A2 genotype). These three groups were comparable for all clinical characteristics including sex ratio, mean age, vascular risk factors, previous coronary events, baseline angiographic exam, indication for the percutaneous coronary intervention and drug therapy). The incidence of MACE was similar in these 3 groups of patients during a mean follow-up period of 654+/-152 days. Independent risk factors for MACE were a left ventricular ejection fraction < 40%, absence of treatment with a beta-blocker and absence of treatment with an angiotensin converting enzyme inhibitor during follow-up.

Conclusion

The GP IIIa PlA1/A2 polymorphism does not influence the clinical long-term outcome in patients with symptomatic coronary disease undergoing percutaneous coronary intervention with stent implantation.