bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Evaluation of Wireless Simulation Assumptions
Authors: Newport Calvin , Kotz David , Yougu Yuan  , Gray Robert S. , Jason Liu  , Elliott Chip
Published: November 2007

All analytical and simulation research on ad hoc wireless networks must necessarily model radio propagation using simplifying assumptions. A growing body of research, however, indicates that the behavior of the protocol stack may depend significantly on these underlying assumptions. The standard response to this problem is a call for more realism in designing radio models. But how much realism is enough? This study is the first to approach this question by validating simulator performance (both at the physical and application layers) with the results of real-world data. Referencing an eXtensive set of measurements from a large outdoor routing eXperiment, we start by evaluating the relative realism of common assumptions made in radio model design, identifying those which provide a reasonable approXimation of reality. Although several such investigations have been made for static sensor networks, radio behavior in mobile network deployments is a much less-studied topic. We then reproduce our eXperimental setup in our simulator, and generate the same application-layer metrics under progressively smaller sets of these assumptions. By comparing the simulated outcome to the outcome of our eXperiment, we are able to discern at what point our balance of simplification and realism captures the real behavior of our target environment.
Histopathology of the Supraspinatus Tendon in Rotator Cuff Tears
Authors: Longo Umile Giuseppe , Franceschi Francesco , Ruzzini Laura , Rabitti Carla , Morini Sergio , Maffulli Nicola , Denaro Vincenzo
Published: November 2007

Background

Causes of rotator cuff pathology are poorly understood.

Hypothesis

Macroscopically intact supraspinatus tendon may show profound light microscopy changes. These changes may be the pathogenic precursor to a subsequent rotator cuff tear.

Study Design

Comparative laboratory study.

Methods

Tendon samples were harvested from 88 individuals (49 men, 39 women; mean age, 58.2 years) who had sustained a rotator cuff tear and underwent arthroscopic repair of the lesion, and from 5 male patients who died of cardiovascular events (mean age, 69. 6 years). A full-thickness supraspinatus tendon biopsy specimen was harvested en bloc within the arthroscopically intact middle portion of the tendon between the lateral edge of the tendon tear and the muscle-tendon junction. Slides stained with hematoxylin and eosin were interpreted twice by the same observer using a semiquantitative grading scale assessing fiber structure and arrangement, rounding of the nuclei, regional variations in cellularity, increased vascularity, decreased colagen stainability, and hyalinization. Intraobserver reliability of the subscore readings was calculated.

Results

The mean pathologic sum-score of ruptured tendons was significantly greater than the mean pathologic score of control tendons (15.66 ± 1.82 vs 3.7 ± 2.31, P = .001). Within each specific category of tendon abnormalities, the control and ruptured tendons were significantly different <χ2 test); all variables were significantly different (Mann-Whitney U test <0.05; P = .001). The agreement between the 2 readings ranged from 0.56 to 0.86 (kappa statistics).

Conclusion

Nonruptured supraspinatus tendons, even at an advanced age, and ruptured supraspinatus tendons are clearly part of 2 distinct populations.

Clinical Relevance

During cuff repair, it is not necessary to excessively freshen the torn tendon to bleeding tissue: the macroscopically intact supraspinatus tendon is degenerated as well, and the failed healing response is not limited to the ends of the torn tendon.
Mechanistic Analysis of the Fire Performance of a Fire Retardant System
Authors: Marney D.C.O. , Russell L.J. , Soegeng T.M. , Dowling V.P.
Published: November 2007

The behavior of a fire retardant in polypropylene is studied in order to improve the understanding of its activity in terms of its chemical behavior. The effect of a N-alkoxy hindered amine light stabilizer upon the fire performance of this system is also considered. The authors relate fire performance (UL 94, OI, NOI) and thermal analyses (TGA and thin film FTIR) results to cone calorimeter fire growth curves, in an attempt to extract meaning beyond peak heat release rate and time to ignition. It has been found that the fire retardant acts in both the condensed and gas phases and dynamic kinetic studies suggest that it acts by destabilizing the polymer. The addition of the light stabilizer augments the performance of the fire retardant.
Human Herpesvirus 6 Rhombencephalitis in Immunocompetent Children
Authors: Crawford John R. , Kadom Nadja , Santi Maria Rita , Mariani Brian , Lavenstein Bennett L.
Published: November 2007

This article describes the clinical presentation, diagnostic workup, and neurologic outcome of 3 immunocompetent pediatric patients diagnosed with human herpesvirus 6 (HHV6) rhombencephalitis. Presentation of HHV6 rhombencephalitis included new onset seizures, ataxia, encephalopathy, and opsoclonus-myoclonus. Neurologic examination revealed cranial neuropathies, cerebellar dysfunction, and extremity weakness. Magnetic resonance imaging abnormalities located in the cerebellum, basal ganglia/thalamus, and cerebral hemispheres were detected in 2 patients. Diagnosis of HHV6 encephalitis was made by real-time and nested polymerase chain reaction of serum and cerebrospinal fluid. The HHV6 variant A was detected in 2 patients by sequence analysis, and HHV6 protein was detected by immunomicroscopy in a patient who underwent biopsy secondary to progressive clinical and neuroradiographic findings. Therapy with intravenous ganciclovir did not correlate with resolution of neurologic symptoms, despite eventual non-detectable HHV6. Human herpesvirus 6 should be considered in the differential diagnosis of unexplained cases of rhombencephalitis in immunocompetent children. Features may be rapidly progressive and include profound encephalopathy, seizures, ataxia, and opsoclonus-myoclonus.
Identification of a Novel DHCR7 Mutation in a Korean Patient With Smith-Lemli-Opitz Syndrome
Authors: Jong Hee Chae  , Ki Joong Kim  , Yong Seung Hwang  , Ki Chang-Seok , Kim Jong-Won
Published: November 2007

Smith-Lemli-Opitz syndrome is a unique malformation syndrome characterized by a defect in cholesterol biosynthesis, which is very rare among populations in Middle and East Asia. The authors identified compound heterozygous mutations ([p.Arg352Trp] + [p.Lys376ArgfsX37]) in a Korean girl with clinical and laboratory features typical of Smith-Lemli-Opitz syndrome. The Lys376ArgfsX37 mutation is a novel mutation, and to the best of the authors' knowledge, this is the first report of a clinically and genetically confirmed case of Smith-Lemli-Opitz syndrome in Korea.
Current Therapies in Childhood and Adolescent Migraine
Authors: Pakalnis Ann
Published: November 2007

This review summarizes recent guidelines for diagnosis of migraine in children and adolescents and inherent issues regarding their headaches that influence evaluation of therapies. With the shorter duration of pediatric migraine attacks and the prominent placebo responder rate, design of randomized clinical trials becomes more problematic than in the adult population. Regarding abortive therapies, several agents have appreciable efficacy in randomized controlled trials. Ibuprofen, acetaminophen, and sumatriptan nasal spray are probably beneficial and safe to use in pediatric migraine. For the minority of children who should be candidates for prophylactic therapy, there is a limited amount of information available for clinicians to make judicious treatment decisions.
Semantics do Matter! Precision in Scientific Communication in Pediatric Neurology
Authors: Sarnat Harvey B.
Published: November 2007

Semantics matter. It is all about precision in communication. Specific terms should not be degraded to general terms by using them interchangeably with others of different meaning or nuance. Changes to traditional use of some terms are needed to recognize the historical context or new needs of modern technology, such as genetics. Prefixes are not independent words. Spelling conventions may be imposed by journals in accordance with national standards where the journal is edited, but the manner of speech or “voice” of the writer should be respected he/she prefers a grammatically correct alternative. Unfamiliar and excessive abbreviations should be avoided in manuscripts, titles, and PowerPoint presentations. Writers should be aware that computer programs may automatically alter spellings of technical terms, rendering them incorrect. One should respect correct grammar and orthography in both English and other languages, including accent marks in foreign words and names.
Nature Reserves and Authoritarian Rule in Egypt
Authors: Sowers Jeannie
Published: November 2007

This article explores how Egypt's system of authoritarian rule initially fostered and subsequently undermined nature conservation efforts. During the 1990s, international donors and local scientists established a well-managed network of nature preserves in the South Sinai region of Egypt. The concentration of state authority in a few executive institutions, such as the military and centrally appointed provincial governors, facilitated the creation of an effective management regime. However, these achievements have come under threat. Executive institutions charged with tourism development have challenged the authority of the protected areas division, and the capacity of the protected areas network has been undermined through systematic underinvestment and diversion of park revenues. In addition, local Bedouin communities that benefited from effectively managed parks remain politically marginalized. Although reformers in the authoritarian regimes of the Middle East can build environmental capacities, some of the economic and political logics associated with authoritarian rule limit the sustainability of these endeavors.
Aspirin and Clopidogrel Resistance
Authors: Fitzgerald Desmond J. , Maree Andrew
Published: November 2007

Aspirin and clopidogrel provide significant clinical benefit in patients with cardiovascular disease. However, given the complexity of platelet activation, it is not surprising that aspirin or clopidogrel prevent a small proportion of cardiovascular events. Of late, the terms aspirin and clopidogrel “resistance” have entered the physicians’ lexicon, and infer a lack of therapeutic response and a single underlying mechanism, which is misleading. The incidence of “resistance” detected in studies varies with the definition applied and assay used to measure response. Rather than true resistance, however, there is a variable response that reflects the unique pharmacology and pharmacokinetics of each drug, the clinical significance of which remains to be established.

True “aspirin resistance” implies that cyclooxygenase-1 is less sensitive to inactivation by aspirin. Despite 95% inhibition of serum thromboxane B2 by aspirin, residual platelet aggregation is detected in some cases, the clinical significance of which is unknown. Heritable factors directly and indirectly related to platelet cyclooxygenase may influence aspirin response. In contrast to aspirin, the response to clopidogrel is highly variable and reflects the bioavailability of the active metabolite and not “resistance” of the receptor to inhibition.
The Antiphospholipid Syndrome
Authors: Rand Jacob H.
Published: November 2007

The antiphospholipid syndrome (APS) is an autoimmune thrombophilic condition that is marked by the presence of antibodies that recognize phospholipid-binding proteins. The clinical manifestations of APS include vascular thrombosis and pregnancy complications, especially recurrent spontaneous miscarriages. This article provides an update on diagnostic and therapeutic approaches to this disorder.
Double Hazard of Thrombophilia and Bleeding in Leukemia
Authors: Kwaan Hau C.
Published: November 2007

The association between thrombosis and cancer has been extensively studied since first pointed out by Trousseau in 1895. It is, however, not commonly appreciated that the incidence of thrombosis in malignant hematologic disorders is as high or even higher than in solid tumors. Thrombotic complications in acute leukemia are often overlooked because bleeding complications generally dominate the clinical picture. Yet, the patient is at risk for both. While there are many thrombogenic factors shared by both solid tumors and leukemia, many additional prothrombotic features are present in leukemia. The prothrombotic factors include hyperleukocytosis, increased expression of tissue factor and its activation in leukemic cells, and the prothrombotic adverse effects of therapeutic agents and vascular access catheters. In addition, comorbid conditions including hereditary thrombophilia, infection, endothelial cell activation by cytokines, antiphospholipid syndrome and acquired activated protein C resistance are major contributory factors. Factors that increase the bleeding risk include thrombocytopenia, disseminated intravascular coagulation, and excessive fibrinolysis, which is enhanced by increased expression of Annexin II by leukemic cells. Therapeutic approaches to both bleeding and thrombotic conditions require special considerations of these factors.
Evidence-Based Platelet Transfusion Guidelines
Authors: Slichter Sherrill J.
Published: November 2007

Transfused platelets (plts) are either pooled random-donor platelet (plt) concentrates or single-donor apheresis plts. When stored for 5 days, all of these products are equally efficacious.

A 10,000/μL prophylactic plt transfusion trigger has been documented to be both hemostatically efficacious and cost effective in reducing plt transfusion requirements. The optimal plt dose/transfusion is being evaluated in an ongoing clinical trial. Therapeutic plt transfusions to control or prevent bleeding with trauma or surgical procedures require higher transfusion triggers of 100,000/μL for neurosurgical procedures and between 50,000/μL and 100,000/μL for other invasive procedures or trauma.

Leukoreduction has been documented to reduce plt alloimmunization rates, cytomegalovirus (CMV) transmission by transfusion, and febrile transfusion reactions. Whether it reduces immunomodulatory effects of transfusion (i.e., decreases infection rates and cancer recurrence) is still controversial, as is universal leukoreduction.

Poor responses to plt transfusions are often multifactorial. For alloimmune plt refractoriness, HLA matching, cross-matching, and identification of the specificity of the patient’s antibodies with avoidance of mismatched donor antigens are all equally effective in identifying compatible plts for transfusion. Other causes of poor plt responses are splenomegaly, ABO mismatching, females with 2 or more pregnancies and males, use of heparin or amphotericin, bleeding, fever, graft-vs-host disease (GVHD), and vaso-occlusive disease (VOD).
Blood and Coagulation Support in Trauma Care
Authors: Hess John R.
Published: November 2007

Injuries are common and account for almost 15% of all blood use in the U.S. The historic view that the coagulopathy associated with severe injury was largely dilutional is being replaced by epidemiologic and molecular evidence for a distinct syndrome of trauma-associated coagulopathy. This coagulopathy of trauma is the sum of the effects of blood loss and dilution, coagulation factor and platelet consumption, hypothermic platelet dysfunction and acidosis-induced decreases in coagulation factor activity, and fibrinolysis. Preventing the coagulopathy of trauma is best accomplished by preventing injury and hypothermia. Treating the coagulopathy of trauma requires its early recognition, prompt control of hemorrhage with local and systemic treatments, including in some patients the use of plasma instead of crystalloid solutions, and the prompt treatment of acidosis and hypothermia. The planned early use of allogenic plasma to treat many tens of thousands of massively transfused patients each year creates new demands for the immediate availability and improved safety of plasma products.
Risk, Cure and Complications in Advanced Hodgkin Disease
Authors: Horning Sandra J.
Published: November 2007

Current therapy for Hodgkin disease is aimed at high cure rates and optimal survivorship. Although intensified chemotherapy with the escalated BEACOPP regimen resulted in higher rates of cure and survival compared with COPP/ABVD in the high-profile HD9 randomized controlled trial (RCT), this regimen has not been universally adopted by patients and physicians due to the attendant increased risks of early and late complications. Appropriately, questions emerge as to whether the results of this trial should be interpreted as establishing the superiority of BEACOPP over the current standard ABVD therapy, and whether clinical or biologic prognostic factors can better select patients for more intensive treatment. The widespread availability and high predictive accuracy of functional imaging with PET scans has led to promising, preliminary studies assessing early response to therapy with this diagnostic tool. In this review, the characteristics and outcomes of patients treated with ABVD in RCT will be made and compared with COPP/ABVD in HD9; clinical and biologic prognostic factors will be discussed, including PET imaging; and newer strategies targeted at minimizing treatment complications while maximizing cure rates will be discussed. Although enthusiasm for PET imaging is great, the challenges for using this diagnostic tool for risk-adapted therapies are substantial. Importantly, physicians and patients should be aware of these challenges, support the RCT that seek to address them, and carefully weigh risks and benefits for individual patients.
Clinical Features, Prognosis and Treatment of Follicular Lymphoma
Authors: Salles Gilles A.
Published: November 2007

Follicular lymphoma constitutes the most frequent indolent lymphoma, well characterized by its clinical presentation related to nodal involvement and its morphologic and biologic features. Some rare locations of extranodal involvement, such as the gastrointestinal tract or skin, were recently further refined. The description of the Follicular Lymphoma International Prognostic Index (FLIPI) represents an important step in identifying patient subgroups with predictable outcome and comparing the results of clinical trials, although its use in clinical practice remains to be established. Analyses of gene expression profiles or constitutive gene variations may also provide additional insights for prognostication in the near future. Furthermore, these data underline the complex interactions between the tumor cells and their microenvironment; recent attempts to translate these findings with immunohistochemical studies remain unable to robustly predict patient outcome. The therapeutic strategies in follicular lymphoma have been transformed by monoclonal antibodies, used alone or in combination with chemotherapy. Treatment options should be adapted to the clinical features at diagnosis and appear to be able to modify the overall survival of some subgroups of patients. Further efforts may focus on strategies that can alter the natural history of this disease.
Mantle Cell Lymphoma: Identifying Novel Molecular Targets in Growth and Survival Pathways
Authors: O’Connor Owen A.
Published: November 2007

Mantle cell lymphoma (MCL) remains one of the more challenging sub-types of non-Hodgkin lymphoma. This entity, which is only approximately 10 years old, is characterized by response to many different chemotherapy regimens, though the duration of those responses remains often times quite short. Retreatment with second and third line combination regimens results in shorter and shorter durations of response, with the rapid emergence of a very drug-resistant phenotype. Despite these often frustrating clinical features, there is now a lot of new hope in managing patients with MCL. New insights into the molecular pathogenesis of MCL has revealed a plethora of new potential targets, while our continued efforts in novel targeted drug development has produced a host of agents that are already helping patients with this challenging disease. The use of proteasome inhibitors, for example, represents one example of a new strategy that has offered new hope for patients, and new opportunities for the physician treating this disease. In this review, we will put this biology into perspective, and describe how new revelations in MCL pathogenesis are leading to the identification of many exciting new drugs with promising activity.
Should Adolescents with NHL Be Treated as Old Children or Young Adults?
Authors: Sandlund John T.
Published: November 2007

The SEER (Surveillance, Epidemiology, and End Results) data for the years 1975–1998 show that children with non-Hodgkin lymphoma (NHL) have a better treatment outcome than do adults. Many factors may contribute to this age-related difference. Some factors are related to the patient (e.g., drug distribution and clearance, performance status, compliance, sex) whereas others pertain to tumor histology and biology. The spectrum of NHL subtypes is well known to differ in children and adults. From ages 5 through 14 years, Burkitt lymphoma is the predominant histologic subtype, whereas diffuse large B-cell lymphoma is most common in the 15- to 29-year age range. Because different treatment strategies are often used in children and adults with NHL, the choice of therapy for adolescents and young adults (ages 15 through 29 years) is challenging and somewhat controversial. It is reasonable to consider pediatric strategies for some adolescents and very young adults with NHL, and pediatric strategies are currently used to treat adults with certain subtypes of NHL (Burkitt lymphoma, lymphoblastic lymphoma). However, the use of pediatric strategies in adults does not guarantee a comparable outcome, as illustrated by trials for adult lymphoblastic lymphoma. There is clearly a need for further biologic study of NHL in children, adolescents, and young adults. Age-related differences in tumor biology have been demonstrated in anaplastic large-cell lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL). Additional biologic data will not only improve prognosis and treatment stratification but, more important, will lead to the identification of specific molecular targets for therapy.
Strategies for Risk-Adapted Therapy in Myeloma
Authors: Fonseca Rafael
Published: November 2007

It is clear that the clinical heterogeneity of multiple myeloma (MM) is dictated, in large part, by disease biology, predominantly genetics.1 As novel therapeutics have emerged, and augmented our treatment armamentarium against the disease, it is increasingly important to introduce a risk-adapted approach for the optimal management of patients.2 The selection of ideal candidates for high-dose chemotherapy with stem cell support (HDT) and maintenance will undoubtedly have to include baseline knowledge of the genetic nature of the individual. The limited duration of responses after HDT for patients with t(4;14)(p16;q32), t(14;16)(q32;q23) and 17p13 deletions highlight the need to develop a risk-adapted treatment strategy.3–5 Novel ways of determining outcome such as the use of gene expression profiling have demonstrated differentiating capabilities not previously observed.6 Likewise, the order of introduction of novel therapeutic agents (during induction and in the relapsing patient) will be potentially directed by similar information. As we have previously stated, MM is not only multiple but also “many.”7 Accordingly, treatment strategies will be tailored based on risk determination, genetic composition and host features.
The Treatment of Relapsed and Refractory Multiple Myeloma
Authors: Richardson Paul , Mitsiades Constantine , Schlossman Robert , Ghobrial Irene , Hideshima Teru , Chauhan Dharminder , Munshi Nikhil , Anderson Kenneth
Published: November 2007

Relapsed and refractory multiple myeloma (MM) constitutes a specific and unmet medical need. Median survival ranges from as little as 6 to 9 months, and responses to treatment are characteristically short. Patients with relapsed/refractory disease are defined as those who, having achieved minor response or better, relapse and then progress while on salvage therapy, or experience progression within 60 days of their last therapy. In the era prior to the development of novel biologically based therapies for MM, relapse from successive treatment regimens resulted in progressively shorter response durations, which typically reflected emerging drug resistance, as well as changes in disease biology within each patient, with tumor cells expressing a more aggressive phenotype, higher proliferative fraction and lower apoptotic rates.

Both bortezomid- and lenalidomide-based therapies are expecially active, with bortezomib in particular being shown to provide a platform for combinations able to overcome resistance in this setting. The addition of novel and conventional agents to the treatment backbone of lenalidomide, thalidomide, and bortezomib are areas of active study, with participation in clincial trials a clear priority for such patients. Clinical challenges in the relapsed/refractory population include light chain and IgA isotype, renal failure, extramedullary disease, hyposecretory myeloma, and advanced bone disease.
Familial CLL: Genes and Environment
Authors: Goldin Lynn R. , Slager Susan L.
Published: November 2007

Families with multiple individuals affected with chronic lymphocytic leukemia (CLL) and other related B-cell tumors have been described in the literature. Familial CLL does not appear to differ from sporadic CLL in terms of prognostic markers and clinical outcome. While some environmental factors (such as farming-related exposures and occupational chemicals) may increase risk of CLL, results of epidemiologic studies have been generally inconsistent. Rates of CLL in the population show significant international variation, with the highest rates in the U.S. and Europe and the lowest rates in Asia. Migrants from Asia to the U.S. also have low rates of CLL, which supports a greater role for genetic compared with environmental risk factors. Large, population-based case-control and cohort studies have also shown significant familial aggregation of CLL and related conditions including non-Hodgkin and Hodgkin lymphoma. Monoclonal B-cell lymphocytosis also aggregates in families with CLL. However, the clinical implication of familial aggregation is minimal given the overall rarity of CLL. Linkage studies have been conducted in high-risk CLL families to screen the whole genome for loci that contribute to susceptibility, but no gene mutations have yet been identified by this method. Association studies of candidate genes have implicated immune function and other genes, but more studies are needed to verify these findings. The ability to conduct large-scale genomic studies will play an important role in detecting susceptibility genes for CLL over the next few years and thereby help to delineate etiologic pathways.
Biology and Treatment of Primary Myelofibrosis
Authors: Hoffman Ronald , Rondelli Damiano
Published: November 2007

Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder associated with an average survival of less than 5 years. Therapy for PMF has used chemotherapeutic agents, immunomodulatory drugs, or biological-response modifiers that have not always been directed at the biological processes that underlie the origins of PMF. Such strategies are palliative and have an uncertain effect on survival. At present, allogeneic stem cell transplantation (ASCT) is the only means of altering the natural history of patients with PMF and provides the only hope for cure of this disorder. Enthusiasm for ASCT in PMF has been muted due to an unacceptable transplantation-related morbidity and mortality in patients receiving fully myeloablative conditioning regimens. Recently, a variety of reduced-intensity conditioning regimens have been utilized in older patients with PMF with significant comorbidities with promising results. Greater understanding of the cellular and molecular events that lead to the development of PMF have provided the opportunity for targeted therapies for PMF. Such therapies must be first evaluated in phase 1/2 trials using a variety of endpoints to assess their efficacy and their potential associated toxicities. The performance of randomized clinical trials comparing these agents to the present standard of care would permit for the first time evidence-based therapeutic decisions to be made for patients with PMF.
Implication of the Molecular Characterization of Acute Myeloid Leukemia
Authors: Döhner Hartmut
Published: November 2007

The identification of molecular genetic alterations such as gene mutations or deregulated gene expression in acute myeloid leukemia (AML) has greatly advanced our understanding of leukemogenesis. These markers now allow us to unravel the enormous heterogeneity seen within cytogenetically defined subgroups of AML. Furthermore, the molecular alterations are providing targets for molecular therapies. In this article, major molecular findings of prognostic and predictive significance are reviewed, with an emphasis on the discussion of gene mutations found in two major AML subgroups, cytogenetically normal and core-binding factor AML.
Prognostic Factors in Elderly Patients with AML and the Implications for Treatment
Authors: Erba Harry P.
Published: November 2007

The outcome of older patients with acute myeloid leukemia (AML) has not improved in the last three decades. These patients are more likely to have comorbid illness, poor performance status, and impaired organ function. These clinical features limit their ability to tolerate intensive cytotoxic chemotherapy and result in greater early mortality. The AML seen in elderly patients is also more likely to have evolved from a prior hematologic disorder, and the leukemic blasts are more likely to have poor-risk structural and numeric cytogenetic abnormalities and expression of multidrug resistance protein (MDR1). These blast features have been associated with greater resistance to therapy. Attempts to improve outcome have generally been unsuccessful. Priming of leukemic blasts with granulocyte colony-stimulating factors during cytarabine therapy, granulocyte colony-stimulating factor support to speed neutrophil recovery following induction therapy, inhibition of the MDR1 p-glycoprotein efflux pump, the use of alternative anthracyclines, and the addition of high-dose cytarabine have all been investigated in the last three decades. Further manipulation of standard cytotoxic chemotherapy alone is unlikely to improve the outcome for the majority of patients with AML. Incorporation of molecularly targeted therapies may prove to be less toxic and/or more efficacious. However, patient selection for clinical trials will continue to confound the interpretation of treatment outcomes on clinical trials of older patients with AML.
Update on Progress and Hurdles in Novel Genetic Therapies for Hemophilia
Authors: High Katherine A.
Published: November 2007

Among inherited disorders, hemophilia has a number of characteristics that make it attractive as a model for gene transfer approaches. Several trials of gene therapy for hemophilia were carried out earlier in this decade; these trials were all first-in-class, i.e. the first use of a particular vector system in a particular target tissue, and thus yielded important safety data for the approaches under investigation. None, however, resulted in long-term expression of the clotting factor at therapeutic levels, and each encountered a critical issue, either in terms of safety, efficacy, or feasibility, that required further laboratory or clinical investigation. Ongoing trials of gene transfer for hemophilia include AAV-mediated gene transfer to liver using modified vectors (alternate serotypes, self-complementary constructs) or adjuvant therapies (transient immunosuppression). Preclinical studies using lentiviral vectors to transduce liver or hematopoietic cells have been promising, and genome editing and translational bypass strategies are also being investigated. Challenges to successful development of each strategy will be discussed.
Membrane Lipid Alterations in Hemoglobinopathies
Authors: Kuypers Frans A.
Published: November 2007

The red blood cell (RBC) membrane is a complex mixture of lipids and proteins. Hundreds of phospholipid molecular species spontaneously arrange themselves in a lipid bilayer and move rapidly in the plane as well as across the bilayer in a dynamic but highly organized fashion. Areas enriched in certain lipids determine proper protein function. Phospholipids are asymmetrically distributed across the lipid bilayer with phosphatidylserine (PS) exclusively on the inside. Both the composition and organization of the RBC membrane is well maintained. Alterations lead to apoptosis during erythropoiesis or early demise of the cell in the circulation. The mechanisms that govern the maintenance of the lipid bilayer are only recently being unraveled at the individual protein level. Oxidized lipids are rapidly repaired using fatty acids taken up from plasma to maintain membrane integrity. Several isoforms of a RBC acyl-Coenzyme A (CoA) synthase have been reported, as well as the first member of a family of lysophospholipid acylCoA acyltransferases. Phospholipid asymmetry is maintained by the recently identified RBC amino-phospholipid translocase. These enzymes, essential in maintaining membrane lipid organization, are affected by oxidant stress or an increase in cytosolic calcium. Normal lipid composition and organization is lost in subpopulations of RBC in hemoglobinopathies such as sickle cell disease and thalassemia. Despite elaborate antioxidant systems, lipids and membrane proteins, including those that maintain lipid organization, are damaged in these cells. This in turn leads to improper repair of damaged RBC membranes and altered interactions of RBCs with other blood cells and plasma components that play a role in the pathology that defines these disorders. The altered lipid bilayer in RBCs in hemoglobinopathies leads to premature removal (anemia) and imbalance in hemostasis, and plays a role in vaso-occlusive crisis in sickle cell disease. Lipid breakdown products of PS-exposing cells result in vascular dysfunction, including acute chest syndrome in sickle cell disease. In summary, altered membrane lipids play an important role in the pathology of hemoglobinopathies and characterization of the proteins involved in lipid turnover will elucidate the pathways that maintain plasma membrane organization and cellular viability.
Hypercoagulability in Sickle Cell Disease: New Approaches to an Old Problem
Authors: Ataga Kenneth I. , Key Nigel S.
Published: November 2007

Patients with sickle cell disease (SCD) exhibit high plasma levels of markers of thrombin generation, depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system, and increased tissue factor expression, even in the non-crisis steady state. In addition, platelets and other cellular elements are chronically activated in the non-crisis state. Despite an abundance of evidence for coagulation and platelet activation, it remains uncertain whether these changes contribute to the pathophysiology of SCD or are, rather, simple epiphenomena. With the occurrence of macrovascular thrombotic complications in SCD, as well as the recognition that soluble CD40 ligand is biologically active in SCD, coagulation and platelet activation may indeed play a role in SCD pathophysiology. Defining a role for hypercoagulability in SCD requires further understanding of its pathogenesis. Furthermore, the conduct of well-controlled clinical trials using anticoagulants and antiplatelet agents and using a variety of clinical endpoints is warranted.
Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders
Authors: Pardanani Animesh , Fridley Brooke L. , Lasho Terra L. , Gilliland D. Gary , Tefferi Ayalew
Published: November 2007

JAK2V617F is an acquired mutation associated with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We tested the hypothesis that the paradox of a single disease allele associated with 3 distinctive clinical phenotypes could be explained in part by host-modifying influences. We screened for genetic variation within 4 candidate genes involved in JAK-STAT signaling, including receptors for erythropoietin (EPOR), thrombopoietin (MPL), and granulocyte colony-stimulating factor (GCSFR), and JAK2. We genotyped 32 linkage disequilibrium tag single nucleotide polymorphism (SNP) loci in 179 white patients: 84 had PV, 58 had PMF, and 37 had ET. Genotype-phenotype analysis showed 3 JAK2 SNPs (rs7046736, rs10815148, and rs12342421) to be significantly but reciprocally associated with PV (P < .001 for all; odds ratio = 0.16, 2.72, and 2.46, respectively) and ET (P < .001 for all; odds ratio = 3.05, 0.29, and 0.30, respectively) but not with PMF. Three additional JAK2 SNPs (rs10758669, rs3808850, and rs10974947) and a single EPOR SNP (rs318699) were also significantly associated with PV but not with ET or PMF. Finally, intragene haplotypes in JAK2 were significantly associated with PV only. Thus, host genetic variation may contribute to phenotypic diversity among myeloproliferative disorders, including in the presence of a shared disease allele.
Inferring activity changes of transcription factors by binding association with sorted expression profiles
Authors: Cheng Chao , Yan Xiting , Sun Fengzhu , Li Lei M
Published: November 2007

Background

The identification of transcription factors (TFs) associated with a biological process is fundamental to understanding its regulatory mechanisms. From microarray data, however, the activity changes of TFs often cannot be directly observed due to their relatively low expression levels, post-transcriptional modifications, and other complications. Several approaches have been proposed to infer TF activity changes from microarray data. In some models, a linear relationship between gene expression and TF-gene binding strength is assumed. In some other models, the target genes of a TF are first determined by a significance cutoff to binding affinity scores, and then expression differentiation is checked between the target and other genes.

Results

We propose a novel method, referred to as BASE (binding association with sorted expression), to infer TF activity changes from microarray expression profiles with the help of binding affinity data. It searches the maximum association between bind affinity profile of a TF and expression change profile along the direction of sorted differentiation. The method does not make hard target gene selection, rather, the significances of TF activity changes are evaluated by permutation tests of binding association at the end. To show the effectiveness of this method, we apply it to three typical examples using different kinds of binding affinity data, namely, ChIP-chip data, motif discovery data, and positional weighted matrix scanning data, respectively. The implications obtained from all three examples are consistent with established biological results. Moreover, the inferences suggest new and biological meaningful hypotheses for further investigation.

Conclusion

The proposed method makes transcription inference from profiles of expression and binding affinity. The same machinery can be used to deal with various kinds of binding affinity data. The method does not require a linear assumption, and has the desirable property of scale-invariance with respect to TF-specific binding affinity. This method is easy to implement and can be routinely applied for transcriptional inferences in microarray studies.
Analyses of six homologous proteins of Protochlamydia amoebophila UWE25 encoded by large GC-rich genes (lgr): a model of evolution and concatenation of leucine-rich repeats
Authors: Eugster Myriam , Roten Claude-Alain H , Greub Gilbert
Published: November 2007

Background

Along the chromosome of the obligate intracellular bacteria Protochlamydia amoebophila UWE25, we recently described a genomic island Pam100G. It contains a tra unit likely involved in conjugative DNA transfer and lgrE, a 5.6-kb gene similar to five others of P. amoebophila: lgrA to lgrD, lgrF. We describe here the structure, regulation and evolution of these proteins termed LGRs since encoded by "Large G+C-Rich" genes.

Results

No homologs to the whole protein sequence of LGRs were found in other organisms. Phylogenetic analyses suggest that serial duplications producing the six LGRs occurred relatively recently and nucleotide usage analyses show that lgrB, lgrE and lgrF were relocated on the chromosome. The C-terminal part of LGRs is homologous to Leucine-Rich Repeats domains (LRRs). Defined by a cumulative alignment score, the 5 to 18 concatenated octacosapeptidic (28-meric) LRRs of LGRs present all a predicted α-helix conformation. Their closest homologs are the 28-residue RI-like LRRs of mammalian NODs and the 24-meres of some Ralstonia and Legionella proteins. Interestingly, lgrE, which is present on Pam100G like the tra operon, exhibits Pfam domains related to DNA metabolism.

Conclusion

Comparison of the LRRs, enable us to propose a parsimonious evolutionary scenario of these domains driven by adjacent concatenations of LRRs. Our model established on bacterial LRRs can be challenged in eucaryotic proteins carrying less conserved LRRs, such as NOD proteins and Toll-like receptors.
N-myristoyltransferase: A potential novel diagnostic marker for colon cancer
Authors: Shrivastav Anuraag , Varma Shailly , Saxena Anurag , DeCoteau John , Sharma Rajendra K
Published: November 2007

Background

Colon cancer is the second leading cause of cancer deaths in the western world. If detected early, colorectal cancer is one of the most treatable forms of cancer. Unfortunately, very few people are screened. N-myristoyltransferase (NMT) catalyzes myristoylation of various proteins including oncoproteins. We have demonstrated earlier the alteration of NMT activity during the progression of colorectal cancer and established NMT as a putative therapeutic target for cancer.

Methods

Peripheral blood samples and bone marrow were collected from the colon cancer patients and azoxymethane induced colonic tumor rats and their controls respectively. NMT activity and expression was determined as reported earlier. Immunohistochemical studies were carried out using standard procedures.

Results

In this study we demonstrate for the first time altered expression and localization of NMT in the peripheral blood and bone marrow in colon cancer patients. Immunohistochemical analysis revealed weak to negative staining for NMT in peripheral blood mononuclear cells (PBMC) of controls, whereas strong positivity was observed in PBMC colon cancer patients. In addition, we observed that NMT was localized mostly in the nuclei of the bone marrow (BM) mononuclear cells of the colon cancer patients, whereas NMT remained cytoplasmic in the control bone marrow specimens.

Conclusion

The strikingly different NMT expression offers the basis of a potential adjunct investigative tool for screening or diagnosis of patients at risk for or suspected of having colon cancer. Furthermore, altered localization of NMT in BM of tumor bearing hosts may serve as an added investigative tool for the diagnostic purpose.
Parental attitudes and opinions on the use of psychotropic medication in mental disorders of childhood
Authors: Lazaratou Helen , Anagnostopoulos Dimitris C , Alevizos Elias V , Haviara Fotini , Ploumpidis Dimitris N
Published: November 2007

Background

The limited number of systematic, controlled studies that assess the safety and efficacy of psychotropic medications for children reinforce the hesitation and reluctance of parents to administer such medications. The aim of this study was to investigate the attitudes of parents of children with psychiatric disorders, towards psychotropic medication.

Methods

A 20-item questionnaire was distributed to 140 parents during their first contact with an outpatient child psychiatric service. The questionnaire comprised of questions regarding the opinions, knowledge and attitudes of parents towards children's psychotropic medication. Sociodemographic data concerning parents and children were also recorded. Frequency tables were created and the chi-square test and Fisher's exact tests were used for the comparison of the participants' responses according to sex, educational level, age and gender of the child and use of medication.

Results

Respondents were mostly mothers aged 25–45 years. Children for whom they asked for help with were mostly boys, aged between 6 and 12 years old. A total of 83% of the subjects stated that they knew psychotropic drugs are classified into categories, each having a distinct mechanism of action and effectiveness. A total of 40% believe that there is a proper use of psychotropic medication, while 20% believe that psychiatrists unnecessarily use high doses of psychotropic medication. A total of 80% fear psychotropic agents more than other types of medication. Most parents are afraid to administer psychotropic medication to their child when compared to any other medication, and believe that psychotherapy is the most effective method of dealing with every kind of mental disorders, including childhood schizophrenia (65%). The belief that children who take psychotropic medication from early childhood are more likely to develop drug addiction later is correlated with the parental level of education.

Conclusion

Parents' opinions and beliefs are not in line with scientific facts. This suggests a need to further inform the parents on the safety and efficacy of psychotropic medication in order to improve treatment compliance.
Experimental design for efficient identification of gene regulatory networks using sparse Bayesian models
Authors: Steinke Florian , Seeger Matthias , Tsuda Koji
Published: November 2007

Background

Identifying large gene regulatory networks is an important task, while the acquisition of data through perturbation experiments (e.g., gene switches, RNAi, heterozygotes) is expensive. It is thus desirable to use an identification method that effectively incorporates available prior knowledge – such as sparse connectivity – and that allows to design experiments such that maximal information is gained from each one.

Results

Our main contributions are twofold: a method for consistent inference of network structure is provided, incorporating prior knowledge about sparse connectivity. The algorithm is time efficient and robust to violations of model assumptions. Moreover, we show how to use it for optimal experimental design, reducing the number of required experiments substantially. We employ sparse linear models, and show how to perform full Bayesian inference for these. We not only estimate a single maximum likelihood network, but compute a posterior distribution over networks, using a novel variant of the expectation propagation method. The representation of uncertainty enables us to do effective experimental design in a standard statistical setting: experiments are selected such that the experiments are maximally informative.

Conclusion

Few methods have addressed the design issue so far. Compared to the most well-known one, our method is more transparent, and is shown to perform qualitatively superior. In the former, hard and unrealistic constraints have to be placed on the network structure for mere computational tractability, while such are not required in our method. We demonstrate reconstruction and optimal experimental design capabilities on tasks generated from realistic non-linear network simulators.

The methods described in the paper are available as a Matlab package at

http://www.kyb.tuebingen.mpg.de/sparselinearmodel.