bluuebunny/crossref_metadata_2025 huggingface dataset:
New Insights into Paroxysmal Nocturnal Hemoglobinuria
Authors: Brodsky Robert A.
Published: November 2006

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon intravascular hemolytic anemia that results from the clonal expansion of hematopoietic stem cells harboring somatic mutations in an X-linked gene, termed PIG-A. PIG-A mutations block glycosylphosphatidylinositol (GPI) anchor biosynthesis, resulting in a deficiency or absence of all GPI-anchored proteins on the cell surface. CD55 and CD59 are GPI-anchored complement regulatory proteins. Their absence on PNH red cells is responsible for the complement-mediated intravascular hemolysis. Intravascular hemolysis leads to release of free hemoglobin, which contributes to many of the clinical manifestations of PNH including fatigue, pain, esophageal spasm, erectile dysfunction and possibly thrombosis. Interestingly, rare PIG-A mutations can be found in virtually all healthy control subjects, leading to speculation that PIG-A mutations in hematopoietic stem cells are common benign events. However, negative selection of PIG-A mutant colony-forming cells with proaerolysin, a toxin that targets GPI-anchored proteins, reveals that most of these mutations are not derived from stem cells. Recently, a humanized monoclonal antibody directed against the terminal complement protein C5 has been shown to reduce hemolysis and greatly improve symptoms and quality of life for PNH patients.
Classification, Diagnosis and Management of Myeloproliferative Disorders in the JAK2V617F Era
Authors: Tefferi Ayalew
Published: November 2006

JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, occurs in nearly all patients with polycythemia vera (PV) but also in a variable proportion of patients with other myeloid disorders; mutational frequency is estimated at approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF), up to 20% in certain subcategories of atypical myeloproliferative disorder (atypical MPD), less than 3% in de novo myelodysplastic syndrome (MDS) or acute myeloid leukemia, and 0% in chronic myeloid leukemia (CML). Accordingly, there is now molecular justification for grouping PV, ET, and MF together in a distinct MPD category (i.e., classic, BCR-ABL− MPD) that is separate from chronic myeloid leukemia (CML), MDS, and atypical MPD. To date, JAK2V617F has not been described in patients with reactive myeloproliferation, lymphoid disorders, or solid tumor. Therefore, the presence of JAK2V617F strongly suggests an underlying MPD and it is therefore reasonable to consider JAK2V617F-based laboratory tests for the evaluation of polycythemia, primary thrombocytosis, unexplained leukocytosis, bone marrow fibrosis, or abdominal vein thrombosis. Current information on disease-specific prognostic relevance of JAK2V617F is inconclusive and confounded by inter-study differences in the performance of mutation screening assays. Regardless, the discovery of JAK2V617F has reinforced the pathogenetic contribution of JAK-STAT signaling in MPD and identifies JAK2 as a valid drug target.
Myeloproliferative Disease in Pregnancy and Other Management Issues
Authors: Barbui Tiziano , Finazzi Guido
Published: November 2006

The goal of this review is to assess the current treatment and outcomes of special clinical situations in patients with myeloproliferative disease (MPD) such as pregnancy, major thrombotic and bleeding complications and surgical interventions. However, only a limited literature to support optimal management strategies is available. Many of the proposed strategies are the results of common sense or derive from the extrapolation of data from other studies not specifically designed to solve these problems. Therefore, practical recommendations to guide clinical decisions in these settings still remain largely empirical.
Optimal Use of Prognostic Factors in Non-Hodgkin Lymphoma
Authors: Sehn Laurie H.
Published: November 2006

The management of non-Hodgkin lymphoma is complicated by wide heterogeneity within recognized subtypes. Patients with supposedly similar diagnoses can have remarkably varied clinical presentations, molecular profiles and clinical outcomes. Reliable prognostic markers could allow the identification of patient subsets that may benefit from alternate approaches. Historically, a large number of clinical and molecular prognostic factors have been elucidated. However, the recent introduction of new therapies such as monoclonal antibodies has revolutionized treatment practices and greatly improved outcomes. This has called into question the value of previously recognized prognostic factors that need to be revalidated in the era of immunochemotherapy. It would appear that the commonly used clinical indices (IPI and FLIPI) retain predictive capacity, although they may have limited ability to identify a very poor outcome group. Currently there are no molecular markers that have been revalidated and shown to retain significance in the setting of current treatment practices for diffuse large B-cell lymphoma or follicular lymphoma. The biologic insights provided by molecular studies should allow for more targeted therapies to be developed, which will increase treatment choice and the possibility of tailored therapy in the future. It is imperative that future steps forward be made in the context of well-designed clinical trials with prospective correlative studies of clinical and biologic markers. This will allow us to continuously assess outcome predictors in the context of treatment change and to rationally design tailored treatment algorithms.
Primary Cutaneous T-Cell Lymphomas
Authors: Rosen Steven T. , Querfeld Christiane
Published: November 2006

Primary cutaneous T-cell lymphomas (CTCLs) encompass a clinically and biologically heterogeneous group of non-Hodgkin lymphomas (NHLs) defined by clonal proliferation of skin-homing malignant T lymphocytes and natural killer cells. They account for up to 75% to 80% of all cutaneous lymphomas. The current WHO-EORTC classification of cutaneous lymphomas with primary cutaneous manifestations lists 13 entities. The most common subtypes—mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, and lymphomatoid papulosis—which represent approximately 95% of CTCLs, will be discussed in the following review. Each entity has unique biological characteristics and clinical course. Topical and/or systemic therapies are employed based on the stage of the disease and the tempo of progression.
Thrombotic Complications of Myeloma Therapy
Authors: Zonder Jeffrey A.
Published: November 2006

Patients with multiple myeloma are at relatively high baseline risk of developing thromboembolic events (TEE), usually deep vein thromboses. There are numerous contributing factors, among them certain treatment regimens that include thalidomide or related compounds such as lenalidomide combined with glucocorticoids and/or cytotoxic chemotherapy. The risk of developing TEE appears to be particularly high when these immunomodulatory agents are combined with anthracyclines as treatment of newly-diagnosed disease. Up-front combinations including thalidomide plus pulse dexamethasone and/or alkylating agents are associated with an intermediate risk, whereas the same regimens for relapsed/refractory myeloma seem to be associated with the lowest risk. Several different thromboprophylaxis strategies have been effective in lowering the risk of developing clots: daily aspirin (81–325 mg/day), full-intensity warfarin (INR 2–3), and prophylactic enoxaparin (40 mg SQ daily). Low, fixed-dose warfarin may also reduce the risk of TEE, but the data on this are disputable. None of these TEE prevention strategies have been prospectively compared head-to-head, so the choice often reflects physician and/or patient preferences. The available evidence upon which one might make such a decision is reviewed here.
Current Approaches to the Management of Hemochromatosis
Authors: Brissot Pierre , de Bels Frédéric
Published: November 2006

The term hemochromatosis encompasses at least four types of genetic iron overload conditions, most of them recently distinguished from one another as a result of the identification of a series of genes related to iron metabolism. At least three of these entities (HFE hemochromatosis, juvenile hemochromatosis and transferrin receptor 2 hemochromatosis) involve systemic hepcidin deficiency as a key pathogenetic factor. Major advances in the management of hemochromatosis influence the diagnostic approach to the disease, with the development of an overall non invasive strategy, mainly based on clinical, biological (iron parameters and genetic testing), and imaging (especially magnetic resonance imaging) data. Therapeutic management remains, on the curative side, dominated by phlebotomy (venesection), practical aspects of which have been recently revisited by the Guidelines Department of the French “Haute Autorité de Santé.” However, innovative treatment approaches, based on the improved pathophysiological understanding of these diseases and the progress in iron chelation therapy, are emerging. Preventive therapy, focused on family screening, remains a key part of the management of hemochromatosis.
Viral Hepatitis: Manifestations and Management Strategy
Authors: Firpi Roberto J. , Nelson David R.
Published: November 2006

Viral hepatitis is the third most common cause of liver disease in allogeneic transplant recipients and causes significant morbidity and mortality. When treating patients with hematological malignancies, an emphasis should be placed on identification of patients at risk for viral hepatitis with appropriate screening. Initial screening serology should include anti-HCV, HBsAg, anti-HBs, and anti-HBc testing. When hepatitis B exposure has been documented, prophylaxis of viral reactivation for all HBsAg-positive patients with a nucleoside analogue should be implemented. HCV infection appears to have little short-term impact on survival after bone marrow transplantation, but is a risk factor for veno-occlusive disease (VOD) and graft-versus-host disease (GVHD). In the long-term survivor, HCV infection can lead to significant morbidity and mortality due to the development of cirrhosis, decompensation, and liver cancer. Since effective antiviral therapies are available for both hepatitis B and C, routine screening and selected intervention is recommended once reactivation and disease recurrence is documented. In this chapter we will highlight the mechanisms of virus reactivation, clinical manifestations, and management strategies to minimize acute and chronic morbidity in this population.
Reduced-Intensity Regimens in Allogeneic Hematopoietic Stem Cell Transplantation for Hemoglobinopathies
Authors: Locatelli Franco
Published: November 2006

The only well-established curative therapy for patients with hemoglobinopathies is allogeneic hematopoietic stem cell transplantation (HSCT), which, in the last 20 years, has been mainly performed from an HLA-matched, related donor, using bone marrow as source of hematopoietic progenitors. More recent studies indicate that HSCT from unrelated donors may offer results comparable to those obtained with HLA-identical family donors, provided that stringent criteria of compatibility are employed for selecting the donor. Cord blood transplantation was also suggested to be an equally effective, but safer, procedure than bone marrow transplantation, due to the lower incidence and severity of both acute and chronic graft-versus-host disease. In view of the early, as well as late, morbidity and mortality associated with conventional myeloablative transplantation in patients with hemoglobinopathies, it is not surprising that great interest and relevant expectations for patients with hemoglobinopathies have been raised by the introduction in the clinical practice of reduced-intensity preparative regimens. However, few reports have demonstrated the feasibility of using reduced-intensity preparative regimens for successfully treating these patients and many treatment failures, mainly due to the lack of sustained donor engraftment, have been reported. Despite these limitations, some of the concepts obtained from the use of reduced intensity regimens, such as the substitution of fludarabine for cyclophosphamide, may be important to further improve the outcome of patients with hemoglobinopathies, especially of those with poor prognostic characteristics, given HSCT.
Management of Hereditary Hypercoagulable Disorders
Authors: Bockenstedt Paula L.
Published: November 2006

The clinical management of individuals with hereditary hypercoaguable disorders has evolved from initial broad recommendations of lifelong anticoagulation after first event of venous thromboembolism to a more intricate individualized risk-benefit analysis as studies have begun to delineate the complexity of interactions of acquired and hereditary factors which determine the predilection to thrombosis. The contribution of thrombophilic disorders to risk of thrombotic complications of pregnancy, organ transplantation, central venous catheter and dialysis access placement have been increasingly recognized. The risk of thrombosis must be weighed against risk of long-term anticoagulation in patients with venous thromboembolism. Thrombophilia screening in select populations may enhance outcome.
Prevention of Venous Thromboembolism in High-Risk Patients
Authors: Geerts William H.
Published: November 2006

The prevention of venous thromboembolism (VTE) in patients recovering from major trauma, spinal cord injury (SCI), or other critical illness is often challenging. These patient groups share a high risk for VTE, they often have at least a temporary high bleeding risk, and there are relatively few thromboprophylaxis trials specific to these populations. A systematic literature review has been conducted to summarize the risks and prevention of VTE in these three groups. It is concluded that routine thromboprophylaxis should be provided to major trauma, SCI and critical care patients based on an individual assessment of their thrombosis and bleeding risks. For patients at high risk for VTE, including those recovering from major trauma and SCI, prophylaxis with a low molecular weight heparin (LMWH) should commence as soon as hemostasis has been demonstrated. For critical care patients at lower thrombosis risk, either LMWH or low-dose heparin is recommended. For those with a very high risk of bleeding, mechanical prophylaxis should be instituted as early as possible and continued until pharmacologic prophylaxis can be initiated. The use of prophylactic inferior vena caval filters is strongly discouraged because their potential benefit has not been shown to outweigh the risks or substantial costs. Implementation of thromboprophylaxis in these patients requires a local commitment to this important patient safety priority as well as a highly functional delivery system, based on the use of pre-printed orders, computer prompts, regular audit and feedback, and ongoing quality improvement efforts.
Prevention and Management of Stroke in Sickle Cell Anemia
Authors: Platt Orah S.
Published: November 2006

As the overall health of patients with sickle cell anemia (SS) improves and diagnostic techniques become more sensitive, physicians are seeing patients with an increasingly wide range of subtle and not-so-subtle brain injury. The major breakthrough in the field of sickle-related brain injury has been the unprecedented success of transcranial Doppler ultrasonography (TCD) to identify asymptomatic patients at high risk of stroke, coupled with chronic transfusion therapy to prevent it. The evidence for TCD screening and preventive treatment is strong and compelling, but there are still important unanswered questions regarding the implications of “silent infarcts” found in the magnetic resonance images (MRIs) of asymptomatic individuals, and the growing awareness of the burden of neuropsychiatric dysfunction in otherwise apparently healthy individuals.
Pathophysiologic Mechanisms in Acquired Aplastic Anemia
Authors: Young Neal S.
Published: November 2006

Aplastic anemia, an unusual hematologic disease, is the paradigm of the human bone marrow failure syndromes. Absence of hematopoietic cells has been recognized from the characteristic morphology for a century; an immune pathophysiology has been inferred from improvement in blood counts with immunosuppressive therapy in the majority of patients. Molecular mechanisms underlying both T cell effector cells and the target marrow stem and progenitor cells are now being identified. Activated type 1 cytotoxic T cells and type 1 cytokines have been implicated in cell culture experiments; clues to the molecular basis of the aberrant immune response include cytokine gene polymorphisms and abnormalities in the regulatory pathways for γ-interferon. For stem cell depletion, mutations in genes of the telomere repair complex are present in some patients with apparently acquired aplastic anemia. Telomerase deficiency is associated with short telomeres and a quantitative reduction in marrow progenitors and likely also a qualitative deficiency in the repair capacity of hematopoietic tissue.
Making Therapeutic Decisions in Adults with Aplastic Anemia
Authors: Marsh Judith
Published: November 2006

The management of adults presenting with aplastic anemia (AA) requires careful exclusion of other causes of bone marrow failure. Late-onset inherited forms of AA may present in adulthood with subclinical disease. Recent long-term studies of HLA identical sibling donor BMT show excellent survival for patients under the age of 40 years, but chronic graft-versus-host disease (GVHD) is still a major problem, impacting on quality of life. Recent improvements in outcome after matched unrelated donor BMT may reflect better donor matching and use of reduced intensity conditioning regimens. For patients treated with immunosuppressive therapy (IST), antithymocyte globulin (ATG) and cyclosporin (CSA) remain the standard regimen with excellent overall survival but less impressive failure-free survival due to nonresponse, relapse and later clonal disorders. The benefit of adding granulocyte colony-stimulating factor (G-CSF) to ATG and CSA is unclear and being assessed in a further prospective European study. Patients who are refractory to conventional IST and currently ineligible for BMT represent difficult management problems. For these patients, new approaches to transplantation are being evaluated, such as fludarabine-based conditioning regimens and the potential use of double umbilical cord blood transplants, but there is a need for new immunosuppressive agents. Improved supportive care is likely to be a major factor in improved outcome of all AA patients whether treated with IST or BMT. Robust predictive factors for response to IST are needed to help in decision making at diagnosis and to help justify exploring novel approaches to therapy.
The growth factor fusion construct containing B-lymphocyte stimulator (BLyS) and the toxin rGel induces apoptosis specifically in BAFF-R–positive CLL cells
Authors: Nimmanapalli Ramadevi , Lyu Mi-Ae , Du Min , Keating Michael J. , Rosenblum Michael G. , Gandhi Varsha
Published: November 2006

The cytokine B lymphocyte stimulator (BLyS) mediates its effect through cell-surface receptors BAFF-R, TACI, and BCMA. BLyS receptors are expressed only on B cells and not present in other normal cells including normal T lymphocytes. Chronic lymphocytic leukemia (CLL) is a B-cell disease and CLL lymphocytes express BLyS receptors. Gelonin, a type 1 ribosome-inactivating toxin, lacks cell membrane binding domain and hence is nontoxic to intact cells. We generated a construct of recombinant gelonin (rGel) fused to BLyS to specifically target quiescent B-CLL lymphocytes. The construct rGel/BLyS specifically binds and internalizes through BAFF-R into CD19+ B-CLL lymphocytes and induces apoptosis at nanomolar concentrations. In contrast, rGel alone was not able to internalize into these leukemic lymphocytes. Mechanistically, the rGel/BLyS construct inhibits protein synthesis with an IC50 of less than 3 nM compared with more than 5000 nM for rGel toxin alone. This rGel/BLyS-mediated decrease in protein synthesis was associated with a decline in short-lived proteins such as MCL-1 and XIAP, the 2 survival proteins in B-CLL. There was a strong relationship between a decrease in these proteins and the cleavage of PARP, a hallmark feature of apoptosis. Taken together, these data suggest that the rGel/BLyS fusion toxin may have potential therapeutic efficacy for B-CLL patients.
Simultaneous host and parasite expression profiling identifies tissue-specific transcriptional programs associated with susceptibility or resistance to experimental cerebral malaria
Authors: Lovegrove Fiona E , Peña-Castillo Lourdes , Mohammad Naveed , Liles W Conrad , Hughes Timothy R , Kain Kevin C
Published: November 2006

Background

The development and outcome of cerebral malaria (CM) reflects a complex interplay between parasite-expressed virulence factors and host response to infection. The murine CM model,Plasmodium bergheiANKA (PbA), which simulates many of the features of human CM, provides an excellent system to study this host/parasite interface. We designed "combination" microarrays that concurrently detect genome-wide transcripts of both PbA and mouse, and examined parasite and host transcriptional programs during infection of CM-susceptible (C57BL/6) and CM-resistant (BALB/c) mice.

Results

Analysis of expression data from brain, lung, liver, and spleen of PbA infected mice showed that both host and parasite gene expression can be examined using a single microarray, and parasite transcripts can be detected within whole organs at a time when peripheral blood parasitemia is low. Parasites display a unique transcriptional signature in each tissue, and lung appears to be a large reservoir for metabolically active parasites. In comparisons of susceptible versus resistant animals, both host and parasite display distinct, organ-specific transcriptional profiles. Differentially expressed mouse genes were related to humoral immune response, complement activation, or cell-cell interactions. PbA displayed differential expression of genes related to biosynthetic activities.

Conclusion

These data show that host and parasite gene expression profiles can be simultaneously analysed using a single "combination" microarray, and that both the mouse and malaria parasite display distinct tissue- and strain-specific responses during infection. This technology facilitates the dissection of host-pathogen interactions in experimental cerebral malaria and could be extended to other disease models.
Distinct cellular responses differentiating alcohol- and hepatitis C virus-induced liver cirrhosis
Authors: Lederer Sharon L , Walters Kathie-Anne , Proll Sean , Paeper Bryan , Robinzon Shahar , Boix Loreto , Fausto Nelson , Bruix Jordi , Katze Michael G
Published: November 2006

Background

Little is known at the molecular level concerning the differences and/or similarities between alcohol and hepatitis C virus induced liver disease. Global transcriptional profiling using oligonucleotide microarrays was therefore performed on liver biopsies from patients with cirrhosis caused by either chronic alcohol consumption or chronic hepatitis C virus (HCV).

Results

Global gene expression patterns varied significantly depending upon etiology of liver disease, with a greater number of differentially regulated genes seen in HCV-infected patients. Many of the gene expression changes specifically observed in HCV-infected cirrhotic livers were expectedly associated with activation of the innate antiviral immune response. We also compared severity (CTP class) of cirrhosis for each etiology and identified gene expression patterns that differentiated ethanol-induced cirrhosis by class. CTP class A ethanol-cirrhotic livers showed unique expression patterns for genes implicated in the inflammatory response, including those related to macrophage activation and migration, as well as lipid metabolism and oxidative stress genes.

Conclusion

Stages of liver cirrhosis could be differentiated based on gene expression patterns in ethanol-induced, but not HCV-induced, disease. In addition to genes specifically regulating the innate antiviral immune response, mechanisms responsible for differentiating chronic liver damage due to HCV or ethanol may be closely related to regulation of lipid metabolism and to effects of macrophage activation on deposition of extracellular matrix components.
Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis. Results from a six-year observational study in southern Sweden
Authors: Kristensen Lars Erik , Saxne Tore , Nilsson Jan-Åke , Geborek Pierre
Published: November 2006

The objective of this work is to compare the adherence to therapy of patients receiving etanercept and infliximab during first tumour necrosis factor (TNF)-blocking treatment course in rheumatoid arthritis. Special emphasis is placed on potential predictors for treatment termination and the impact of concomitant methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs). Patients (n = 1,161) with active rheumatoid arthritis, not responding to at least two DMARDs including MTX starting etanercept or infliximab therapy for the first time, were included in a structured clinical follow-up protocol. Information on diagnosis, disease duration, previous and ongoing DMARDs, treatment start and termination, as well as cause of withdrawal was prospectively collected during the period of March 1999 through December 2004. Patients were divided into six groups according to TNF-blocking drugs and concomitant DMARDs. Five-year level (one-year) of adherence to therapy was 36% (69%) for patients receiving infliximab in combination with MTX compared with 65% (89%) for patients treated with etanercept and MTX (p < 0.001). Cox regression models showed that the risk for premature treatment termination of patients treated with infliximab was threefold higher than for etanercept (p < 0.001). Also, the regression analysis showed that patients receiving concomitant MTX had better treatment continuation than patients treated solely with TNF blockers (p < 0.001). Moreover, patients receiving concomitant MTX had superior drug survival than patients receiving other concomitant DMARDs (p < 0.010). The superior effect of MTX was associated primarily with fewer treatment terminations because of adverse events. In addition, the study identifies low C-reactive protein level, high age, elevated health assessment questionnaire score, and higher previous number of DMARDs as predictors of premature treatment termination. In summary, treatment with etanercept has higher adherence to therapy than treatment with infliximab. Concomitant MTX is associated with improved treatment continuation of biologics when compared with both TNF blockers as monotherapy and TNF blockers combined with other DMARDs.
Macromolecular Crystallization in Microgravity Generated by a Superconducting Magnet
Authors: WAKAYAMA N. I. , YIN D. C. , HARATA K. , KIYOSHI T. , FUJIWARA M. , TANIMOTO Y.
Published: November 2006

Abstract:  About 30% of the protein crystals grown in space yield better X‐ray diffraction data than the best crystals grown on the earth. The microgravity environments provided by the application of an upward magnetic force constitute excellent candidates for simulating the microgravity conditions in space. Here, we describe a method to control effective gravity and formation of protein crystals in various levels of effective gravity. Since 2002, the stable and long‐time durable microgravity generated by a convenient type of superconducting magnet has been available for protein crystal growth. For the first time, protein crystals, orthorhombic lysozyme, were grown at microgravity on the earth, and it was proved that this microgravity improved the crystal quality effectively and reproducibly. The present method always accompanies a strong magnetic field, and the magnetic field itself seems to improve crystal quality. Microgravity is not always effective for improving crystal quality. When we applied this microgravity to the formation of cubic porcine insulin and tetragonal lysozyme crystals, we observed no dependence of effective gravity on crystal quality. Thus, this kind of test will be useful for selecting promising proteins prior to the space experiments. Finally, the microgravity generated by the magnet is compared with that in space, considering the cost, the quality of microgravity, experimental convenience, etc., and the future use of this microgravity for macromolecular crystal growth is discussed.
Canceling Buoyancy of Gaseous Fuel Flames in a Gravitational Environment Using an Ion‐Driven Wind
Authors: PAPAC M. J. , DUNN‐RANKIN D.
Published: November 2006

Abstract:  Electric fields applied to combustion plasmas can be used to manipulate the thermofluid flow field to reduce buoyant forces and, hence, convection in locations near and within the flame. The resulting flow field is similar to that which is obtained in microgravity. Previous work has shown that buoyancy is modified in a non‐premixed methane‐air capillary flame when it burns in a capillary‐to‐plane configuration and an electric field is applied, and that regions of neutral or microbuoyancy exist, as indicated by the examined temperature and oxidizer profiles. The aim of this article is to examine in more detail this microbuoyancy condition and the coupling between the ion wind and resulting thermofluid flow field. To this end, the voltage‐current characteristics (VCC) of CH4, C2H2, C2H4, C2H6, and C3H8 are measured and compared. Soot generated in the C2HX and propane flames lead to a hysteresis in the VCC curve whereby increased sooting leads to lower ion currents at constant flow rates and applied potentials. Buoyancy regimes for these flames in this configuration are determined. Methane can achieve the highest flow rate without sooting at the microbuoyant condition, and does not exhibit hysteresis in the VCC for the flow rates examined here. Furthermore, in this geometry, the microbuoyant condition for methane is found to coincide with ion current saturation when the capillary‐to‐plane distance is varied. These results allow for several simplifications to be made when modeling the flame at these conditions: the imposition of a spherical flame boundary with known ion current, and negligible recombination in the domain.
Numerical Modeling of the Transport to an Intravascular Bubble in a Tube with a Soluble/Insoluble Surfactant
Authors: AYYASWAMY PORTONOVO S. , ZHANG JIE , ECKMANN DAVID M.
Published: November 2006

Abstract:  Using a newly developed algorithm in conjunction with the front tracking scheme, we have evaluated the transport associated with a deformable bubble moving in a tube in the presence of a soluble or an insoluble surfactant. Such evaluations are useful to the understanding of gas embolism—a common syndrome for decompression sickness. Decompression sickness may be encountered in performing extravehicular activity during space exploration. The numerical evaluations indicate that as the location of the adsorptive interface gets closer to the vessel wall, the surfactant amount on the wall gets depleted. The implication is that the process by which a bubble occluding a vessel dislodges may depend both on the strength of the diffusivity of the surfactant and the adsorption process. More detailed study is needed to clarify this observation. The numerical results evaluated include Marangoni flow, which causes a bubble to propel out of its initial static location, and bubble motion in Poiseuille flow. The presence of a soluble/insoluble surfactant slows down the bubble motion. For identical surface concentrations of the surfactant, the effect of the presence of a soluble surfactant is more severe on the retardation of the bubble motion than that of an insoluble surfactant.
Upside‐Down Protein Crystallization
Authors: KHURSHID SAHIR , CHAYEN NAOMI E.
Published: November 2006

Abstract:  The benefits of protein crystal growth in microgravity are well documented. The crystallization vessels currently employed for microgravity crystallization are far from optimal with regards to cost, sample volume, size, and ease of use. The use of microbatch experiments is a favorable alternative in each respect: 96 experiments of 0.5–2 μL volumes can be performed in a single microtiter tray measuring 5 × 8 cm and costing ££1 sterling each. To date, the use of microbatch has not been pursued on account of concerns of oil leakage. To address this issue, a novel approach to microbatch crystallization experiments is described, where the microbatch plates are inverted throughout the duration of the experiment. The findings intimate the application of the microbatch method to space flight and the potential to drastically increase the output of microgravity crystallization research .
Microgravity Experiments on the Effect of Internal Flow on Solidification of Fe‐Cr‐Ni Stainless Steels
Authors: HANLON ALAINA B. , MATSON DOUGLAS M. , HYERS ROBERT W.
Published: November 2006

Abstract:  A new hypothesis has been developed to explain the effect of internal fluid flow on the lifetime of a metastable phase in solidifying Fe‐Cr‐Ni alloys. The hypothesis shows excellent agreement with available experimental results, but microgravity experiments are required for complete validation.
Certain Fe‐Cr‐Ni stainless steel alloys solidify from an undercooled melt by a two‐step process in which the metastable ferrite phase forms first followed by the stable austenite phase. Recent experiments using containerless processing techniques have shown that the lifetime of the metastable phase is strongly influenced by flow within the molten sample.
Simulations using a commercial computational fluid dynamics (CFD) package, FIDAP, were performed to determine the time required for collision of dendrites and compared to experimental delay time. If the convective velocities are strong enough to bend the primary arms, then the secondary arms of adjacent dendrites can touch. The points of collision form low‐angle boundaries and result in high‐energy sites that can serve as nuclei for the transformation to the stable phase.
It has been determined that the convective velocities in electrostatic levitation (ESL) are not strong enough to cause collision. However, in ground‐based electromagnetic levitation (EML), the convective velocities are strong enough to cause the dendrites to deflect so that the secondary arms of adjacent dendrites collide. There is quantitative agreement between the numerically determined time to collision and the experimentally observed delay time in EML. The strong internal velocity due to convection within the EML samples is the reason for the observed difference in delay times between ESL and EML.
Microgravity testing is essential because the significant change in nucleation behavior occurs between the ranges accessible by ground‐based ESL and EML. Testing in microgravity using EML will permit a large range of internal convective velocities including those that are inaccessible in 1 g.
Handling Anticancer Drugs
Authors: SORSA MARJA , HÄMEILÄ MERVI , JÄRVILUOMA EIJA
Published: November 2006

Abstract:  The potential health hazards involved with antineoplastic agents have been known for decades. Many anticancer drugs are recognized as carcinogens and genotoxins in experimental assays. Second cancers have been recorded in follow‐up studies with treated patients. The first findings on occupational exposures among hospital personnel administering chemotherapy were reported only in 1979. Since that time a magnitude of studies have been published using various chemical and biological exposure measurements. These findings prompted improvements in the handling practices of personnel working with anticancer drugs.
In spite of strict guidelines for the safe handling of cancer chemotherapeutic agents and extensive improvements in the handling facilities in hospitals, also recent studies have revealed detectable, even if generally much decreased, amounts of indicator drugs in air and surface wipe samples, also including biological samples of personnel in hospital pharmacies and cancer therapy wards. Follow‐up measurements show that application of strict safety precautions in hospitals decreases the biological exposure and/or effect markers to the level of unexposed referents. Open information and constant tutoring of personnel to avoid the hazards when working with anticancer drugs is absolutely necessary with the increasing use of these important drugs.
Occupation and Breast Cancer
Authors: BROPHY JAMES T. , KEITH MARGARET M. , GOREY KEVIN M. , LUGINAAH ISAAC , LAUKKANEN ETHAN , HELLYER DEBORAH , REINHARTZ ABRAHAM , WATTERSON ANDREW , ABU‐ZAHRA HAKAM , MATICKA‐TYNDALE ELEANOR , SCHNEIDER KENNETH , BECK MATTHIAS , GILBERTSON MICHAEL
Published: November 2006

Abstract:  A local collaborative process was launched in Windsor, Ontario, Canada to explore the role of occupation as a risk factor for cancer. An initial hypothesis‐generating study found an increased risk for breast cancer among women aged 55 years or younger who had ever worked in farming. On the basis of this result, a 2‐year case–control study was undertaken to evaluate the lifetime occupational histories of women with breast cancer. The results indicate that women with breast cancer were nearly three times more likely to have worked in agriculture when compared to the controls (OR = 2.80 [95% CI, 1.6–4.8]). The risk for those who worked in agriculture and subsequently worked in automotive‐related manufacturing was further elevated (OR = 4.0 [95% CI, 1.7–9.9]). The risk for those employed in agriculture and subsequently employed in health care was also elevated (OR = 2.3 [95% CI, 1.1–4.6]). Farming tended to be among the earlier jobs worked, often during adolescence. While this article has limitations including the small sample size and the lack of information regarding specific exposures, it does provide evidence of a possible association between farming and breast cancer. The findings indicate the need for further study to determine which aspects of farming may be of biological importance and to better understand the significance of timing of exposure in terms of cancer risk.
Diesel Exhaust and Coal Mine Dust
Authors: HOFFMANN BARBARA , JÖCKEL KARL‐HEINZ
Published: November 2006

Abstract:  Conflicting evidence on the carcinogenicity of diesel exhaust (DE) and coal mine dust in occupational settings exist. Exposure measurement in most studies is inferred on the basis of job classifications and may lead to misclassification. Confounding behavioral factors (i.e., smoking) and occupational risk factors (exposure to asbestos, arsenic, radon) need to be considered. We evaluated the epidemiological evidence and current findings of the carcinogenicity of DE and coal mine dust in occupational settings. Pertaining literature was identified through Medline search and recent review articles. Strengths and limitations of recent approaches are discussed. Many epidemiological studies have addressed the question of carcinogenicity in workers exposed to DE, and most showed a low‐to‐medium increase in the risk of bronchial carcinoma. The pooled relative risk (RR) estimates lie between 1.33 and 1.47, and a consistent rise in risk across various job categories and study designs point to a causal relationship. Data on the carcinogenicity of coal mine dust are less consistent and the potential for confounding by unmeasured risk factors (arsenic, radon, DE) are higher. While silica as one of its components has been evaluated as carcinogenic, there is inadequate evidence for the carcinogenicity of pure coal dust according to the International Agency for Research on Cancer (IARC).There is sufficient evidence for a causal relationship between DE and lung cancer in occupational settings. The evidence for coal mine dust is less convincing, but individual studies show an increase in risk of lung cancer in exposed workers.
Toxicogenomics—A New Systems Toxicology Approach to Understanding of Gene–Environment Interactions
Authors: OLDEN KENNETH
Published: November 2006

Abstract:  Toxicogenomics is a new interdisciplinary area of research being developed to monitor the expression of multiple genes, proteins, and metabolites simultaneously. It combines new technologies in genomics, proteomics, and metabolomics with traditional tools of pathology and toxicology to study biological response to drugs and other environmental xenobiotics. The biological response to environmental exposure is so complex and involves so many interactive factors that the use of a systems biology analytical approach is required. In my opinion, the development of the field of toxicogenomics will provide powerful and relatively inexpensive tools to identify biomarkers and to relate exposure and biological events during disease progression.
Carcinogen Exposure and Epigenetic Silencing in Bladder Cancer
Authors: MARSIT CARMEN J. , KARAGAS MARGARET R. , SCHNED ALAN , KELSEY KARL T.
Published: November 2006

Abstract:  Tobacco smoking, certain occupational exposures, and exposure to inorganic arsenic in drinking water have been associated with the occurrence of bladder cancer. However, in these tumors the exposure‐associated pattern of somatic alterations in genes in the causal pathway for disease has been poorly characterized. Animal and in vitro studies have suggested that arsenic, tobacco carcinogens, and other exposures may act through epigenetic mechanisms. We, therefore, examined, in a population‐based study of human bladder cancer (n= 351), the relationship between epigenetic silencing of the tumor‐suppressor genes, p16INK4A, RASSF1A, PRSS3, and the four SFRP genes and exposure to both tobacco and arsenic in bladder cancer. Promotor methylation silencing of each of these genes occurred in approximately 30–50% of bladder cancers. Epigenetic silencing of RASSF1A and PRSS3 and any of the SFRP genes were each significantly associated with advanced tumor stage (P < 0.001, P < 0.04, and P < 0.005, respectively). Arsenic exposure, measured as toenail arsenic, was associated with RASSF1A (P < 0.02) and PRSS3 (P < 0.1) but not p16INK4A or SFRP promotor methylation, in models adjusted for stage and other risk factors. Cigarette smoking was associated with a greater than twofold increased risk of promotor methylation of the p16INK4A gene, with greater risk seen in patients with exposures more recent to disease diagnosis, and smoking was also significantly associated with any SFRP gene methylation (P < 0.01). These results from human bladder tumors, add to the body of animal and in vitro evidence that suggests bladder carcinogens play a crucial role in the induction of important epigenetic alterations.
Transcriptional Profiling and Functional Genomics Reveal a Role for AHR Transcription Factor in Nephrogenesis
Authors: RAMOS KENNETH S.
Published: November 2006

Abstract:  Transcriptional profiling and functional genomics experiments using E11.5 metanephros organ cultures from Ahr–/– and Ahr+/+ have shown that aryl hydrocarbon receptor (AHR) transcription factor is involved in the regulation of mesenchymal‐to‐epithelial transition (MET) during nephrogenesis.
This response is mediated by alterations in the post‐transcriptional control of Wilms' tumor suppressor (Wt1) gene and Wt1 splicing. In this article, biologically relevant gene predictor sets of the nephrogenic response were calculated for target genes of interest. The predictability of the gene set for each target was quantified by the coefficient of determination which provided a good criterion for identification of predictor sets that define the complex gene–gene interactions co‐regulated by Ahr and Wt1. A subset of the signature genes was found to be co‐regulated by Ahr and Wt1 and was responsible for shifts in renal cell transdifferentiation.
Carcinogens in the Construction Industry
Authors: JÄRVHOLM BENGT
Published: November 2006

Abstract:  The construction industry is a complex work environment. The work sites are temporary and rapidly changing. Asbestos has been widely used in construction industry, but the risks were primarily detected in specialized trades, such as insulation workers and plumbers. Today, the majority of cases related to asbestos exposure will occur in other occupational groups in the construction industry. In a large cohort of Swedish construction workers, insulators and plumbers constituted 37% of all cases of pleural mesothelioma between 1975 and 1984 while they constituted 21% of the cases between 1998 and 2002. It is estimated that 25–40% of all male cases of pleural mesothelioma in Sweden are caused by asbestos exposure in the construction trades. There are many other known carcinogens occurring in the construction industry, including PAHs, diesel exhausts, silica, asphalt fumes, solvents, etc., but it is difficult to estimate exposures and thus the size of the risk. The risk of cancer is less easy to detect with traditional epidemiological methods in the construction industry than in other industrial sectors. It is not sufficient to rely upon broad epidemiological data to estimate the risk of cancer due chemicals in the construction industry. Thus, a strategy to decrease exposure, e.g., to dust, seems a feasible way to reduce the risk.
New Directions in Managing Hazardous Wastes from an Industry Perspective
Authors: JOHNSON LYNN D.
Published: November 2006

Abstract:  In past decades waste was left to the lowest level of staff to dispose of at the lowest cost. Today, business managers in leading companies consider waste to be part of their responsibility. There is money to be made by eliminating waste problems. Leading companies are moving to the top of the waste disposal hierarchy and eliminating waste for themselves and their customers.
The Assessment of Occupational Exposure to Diazinon in Nicaraguan Plantation Workers Using Saliva Biomonitoring
Authors: LU CHENSHENG , RODRÍGUEZ TERESA , FUNEZ AURA , IRISH RENE S. , FENSKE RICHARD A.
Published: November 2006

Abstract:  A cross‐sectional study with repeated sample collection in multiple days was conducted to assess diazinon exposures. Saliva and limited blood samples were collected from 10 banana plantation workers involved with diazinon application and their children aged 2–12 years living in Chinandega, Nicaragua. Diazinon concentration‐time profiles in saliva varied between two plantations, which reflects the differences of work practices in each plantation. Salivary concentrations of diazinon measured in Plantation 1 applicators continued to increase 2 days after self‐reported diazinon application, suggesting an ongoing exposure among these workers. However, salivary diazinon concentrations measured in Plantation 2 applicators were peaked 12 h prior to the first application, and then decreased 36 h post the first application. Diazinon concentrations in saliva were significantly correlated with the time‐matched plasma samples collected from the same workers, which is in agreement with the previous published data from animal models. Children's exposure to diazinon through take‐home pathway does not exist, as evident by the majority of nondetected saliva samples, and this finding was confirmed by the results from the urine samples. Severe dehydration was observed in many plantation workers and their children, resulting in the loss of some saliva samples, which no doubt have impaired the overall quality of the study results. Regardless, this article has demonstrated that saliva can be used to assess exposures to diazinon in pesticide applicators and children.