bluuebunny/crossref_metadata_2025 huggingface dataset:
The Human Immunodeficiency Virus Type 1 Tat Protein EnhancesCryptosporidium parvum-Induced Apoptosis in Cholangiocytes via a Fas Ligand-Dependent Mechanism
Authors: O'Hara Steven P. , Small Aaron J. , Nelson Jeremy B. , Badley Andrew D. , Chen Xian-Ming , Gores Gregory J. , LaRusso Nicholas F.
Published: November 2006

WhileCryptosporidium parvuminfection of the intestine has been reported in both immunocompetent and immunocompromised individuals, biliary infection is seen primarily in adult AIDS patients and is associated with development of AIDS cholangiopathy. However, the mechanisms of pathogen-induced AIDS cholangiopathy remain unclear. Since we previously demonstrated that the Fas/Fas ligand (FasL) system is involved in paracrine-mediatedC. parvumcytopathicity in cholangiocytes, we also tested the potential synergistic effects of human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat)-mediated FasL regulation onC. parvum-induced apoptosis in cholangiocytes by semiquantitative reverse transcription-PCR, immunoblotting, immunofluorescence analysis, and immunogold electron microscopy. H69 cells do not express CXCR4 and CCR5, which are receptors required for direct HIV-1 viral infection. However, recombinant biologically active HIV-1-associated Tat protein increased FasL expression in the cytoplasm of cholangiocytes without a significant increase in apoptosis. We found thatC. parvum-induced apoptosis was associated with translocation of intracellular FasL to the cell membrane surface and release of full-length FasL from infected H69 cells. Tat significantly (P< 0.05) increasedC. parvum-induced apoptosis in bystander cells in a dose-dependent manner. Moreover, Tat enhanced bothC. parvum-induced FasL membrane translocation and release of full-length FasL. In addition, the FasL neutralizing antibody NOK-1 and the caspase-8 inhibitor Z-IETD-fmk both blockedC. parvum-induced apoptosis in cholangiocytes. The data demonstrated that HIV-1 Tat enhancesC. parvum-induced cholangiocyte apoptosis via a paracrine-mediated, FasL-dependent mechanism. Our results suggest that concurrent active HIV replication, with associated production of Tat protein, andC. parvuminfection synergistically increase cholangiocyte apoptosis and thus jointly contribute to AIDS-related cholangiopathies.
Expression of Merozoite Surface Protein Markers byPlasmodium falciparum-Infected Erythrocytes in Peripheral Blood and Tissues of Children with Fatal Malaria
Authors: Dobaño Carlota , Rogerson Stephen J. , Taylor Terrie E. , McBride Jana S. , Molyneux Malcolm E.
Published: November 2006

Sequestration ofPlasmodium falciparum-infected erythrocytes is a pathological feature of fatal cerebral malaria.P. falciparumis genetically diverse among, and often within, patients. Preferential sequestration of certain genotypes might be important in pathogenesis. We compared circulating parasites with parasites sequestered in the brain, spleen, liver, and lung in the same Malawian children with fatal malaria, classifying serotypes using antibodies to merozoite surface proteins 1 and 2 and immunofluorescence in order to differentiate parasites and to quantify the proportions of each serotype. We found (i) similar distributions of various serotypes in different tissues and (ii) concordance between parasite serotypes in peripheral blood and parasite serotypes in tissues. No serotypes predominated in the brain in cerebral malaria, and parasites belonging to a single serotype did not cluster within individual vessels or within single tissues. These findings do not support the hypothesis that cerebral malaria is caused by cerebral sequestration of certain virulent types.
Effect of low-xenon and krypton supplementation on signal/noise of regional CT-based ventilation measurements
Authors: Chon Deokiee , Beck Kenneth C. , Simon Brett A. , Shikata Hidenori , Saba Osama I. , Hoffman Eric A.
Published: November 2006

Xenon computed tomography (Xe-CT) is used to estimate regional ventilation by measuring regional attenuation changes over multiple breaths while rebreathing a constant Xe concentration ([Xe]). Xe-CT has potential human applications, although anesthetic properties limit [Xe] to ≤35%. We investigate effects of lower [Xe], including a low [Xe]-krypton (Kr) combination, on time constant (TC) determination. Six anesthetized sheep were scanned prone and supine using multidetector row CT. Lungs were imaged by respiratory gating during washin of a 30%, 40%, 55% Xe, and a 30% Xe/30% Kr mixture. Using Kr avoids unwanted effects of Xe. Mean TCs, coefficients of variation (CV), and half confidence intervals (CI)/mean served as indexes of sensitivity to noise. Mean supine and prone TCs of three [Xe] values were not significantly different. Average CVs of TCs increased from 57% (55% Xe), 58% (40% Xe), and 73% (30% Xe) ( P < 0.05: paired t-tests; 30% Xe vs. higher [Xe]). Monte Carlo simulation indicated a CV based on inherent image noise was 8% for 55% Xe and 17% for 30% Xe ( P < 0.05). Adding 30% Kr to 30% Xe gave a washin signal equivalent to 40% Xe. Half CI/mean using the 30% Xe/30% Kr mixture was not significantly different from 55 and 40% Xe. Although average TCs were not affected by changes in [Xe], the higher CV and half CI/mean suggested reduced signal-to-noise ratio at the 30% [Xe]. The 30% Xe/30% Kr mixture was comparable to that of 40% Xe, providing an important agent for CT-based assessment of regional ventilation in humans.
“Motor Oblique Effect”: Perceptual Direction Discrimination and Pointing to Memorized Visual Targets Share the Same Preference for Cardinal Orientations
Authors: Smyrnis Nikolaos , Mantas Asimakis , Evdokimidis Ioannis
Published: November 2006

In previous studies we observed a pattern of systematic directional errors when humans pointed to memorized visual target locations in two-dimensional (2-D) space. This directional error was also observed in the initial direction of slow movements toward visual targets or movements to kinesthetically defined targets in 2-D space. In this study we used a perceptual experiment where subjects decide whether an arrow points in the direction of a visual target in 2-D space and observed a systematic distortion in direction discrimination known as the “oblique effect.” More specifically, direction discrimination was better for cardinal directions than for oblique. We then used an equivalent measure of direction discrimination in a task where subjects pointed to memorized visual target locations and showed the presence of a motor oblique effect. We finally modeled the oblique effect in the perceptual and motor task using a quadratic function. The model successfully predicted the observed direction discrimination differences in both tasks and, furthermore, the parameter of the model that was related to the shape of the function was not different between the motor and the perceptual tasks. We conclude that a similarly distorted representation of target direction is present for memorized pointing movements and perceptual direction discrimination.
A Tracer Dose of Technetium-99m–Labeled Liposomes Can Estimate the Effect of Hyperthermia on Intratumoral Doxil Extravasation
Authors: Kleiter Miriam M. , Yu Daohai , Mohammadian Lenore A. , Niehaus Nelsen , Spasojevic Ivan , Sanders Linda , Viglianti Benjamin L. , Yarmolenko Pavel S. , Hauck Marlene , Petry Neil A. , Wong Terence Z. , Dewhirst Mark W. , Thrall Donald E.
Published: November 2006

Purpose: A noninvasive method to monitor intratumoral Doxil delivery in individual patients during targeted tumor therapy is important to predict treatment response. The purpose of this study was to determine if a small tracer dose of technetium-99m (99mTc)–labeled liposomes could be used to quantify the effect of local hyperthermia on intratumoral Doxil extravasation.

Experimental Design: Experiments were carried out in a rat fibrosarcoma model with transplanted thigh tumors. Liposomes of approximately same size and composition as Doxil were radiolabeled using [technetium-99m (99mTc)]exametazime. Eight treatment groups received either Doxil, a tracer dose or a large dose of 99mTc-labeled liposomes, or a combination of tracer and Doxil, with or without hyperthermia. This design was chosen to assure that coadministration of both liposomal formulations did not influence their intratumoral distribution. Hyperthermia was done for 45 minutes. Scintigraphic images were obtained at 5 and 18 hours. At 18 hours, tumors were removed and gamma counts as well as doxorubicin concentrations were measured.

Results: Intratumoral extravasation of the 99mTc-labeled tracer could be imaged scintigraphically under normothermic and hyperthermic conditions. The thermal enhancement ratio was slightly higher for radiolabeled liposomes than for doxorubicin concentration. However, there was a significant positive correlation of intratumoral doxorubicin concentration and intratumoral uptake of the radiolabeled tracer (expressed as percentage of the injected dose per gram of tissue). Coadministration of radiolabeled liposomes did not negatively influence the amount of drug delivered with Doxil.

Conclusions: The use of a radiolabeled tracer has potential value to monitor drug delivery and estimate the effect of an intervention aimed to increase liposomal accumulation, such as local hyperthermia.
A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model
Authors: Ohno Hiroaki , Kubo Kazuo , Murooka Hideko , Kobayashi Yoshiko , Nishitoba Tsuyoshi , Shibuya Masabumi , Yoneda Toshiyuki , Isoe Toshiyuki
Published: November 2006

In bone metastatic lesions, osteoclasts play a key role in the development of osteolysis. Previous studies have shown that macrophage colony-stimulating factor (M-CSF) is important for the differentiation of osteoclasts. In this study, we investigated whether an inhibitor of M-CSF receptor (c-Fms) suppresses osteoclast-dependent osteolysis in bone metastatic lesions. We developed small molecule inhibitors against ligand-dependent phosphorylation of c-Fms and examined the effects of these compounds on osteolytic bone destruction in a bone metastasis model. We discovered a novel quinoline-urea derivative, Ki20227 (N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N′-[1-(1,3-thiazole-2-yl)ethyl]urea), which is a c-Fms tyrosine kinase inhibitor. The IC50s of Ki20227 to inhibit c-Fms, vascular endothelial growth factor receptor-2 (KDR), stem cell factor receptor (c-Kit), and platelet-derived growth factor receptor β were found to be 2, 12, 451, and 217 nmol/L, respectively. Ki20227 did not inhibit other kinases tested, such as fms-like tyrosine kinase-3, epidermal growth factor receptor, or c-Src (c-src proto-oncogene product). Ki20227 was also found to inhibit the M-CSF-dependent growth of M-NFS-60 cells but not the M-CSF-independent growth of A375 human melanoma cells in vitro. Furthermore, in an osteoclast-like cell formation assay using mouse bone marrow cells, Ki20227 inhibited the development of tartrate-resistant acid phosphatase–positive osteoclast-like cells in a dose-dependent manner. In in vivo studies, oral administration of Ki20227 suppressed osteoclast-like cell accumulation and bone resorption induced by metastatic tumor cells in nude rats following intracardiac injection of A375 cells. Moreover, Ki20227 decreased the number of tartrate-resistant acid phosphatase–positive osteoclast-like cells on bone surfaces in ovariectomized (ovx) rats. These findings suggest that Ki20227 inhibits osteolytic bone destruction through the suppression of M-CSF-induced osteoclast accumulation in vivo. Therefore, Ki20227 may be a useful therapeutic agent for osteolytic disease associated with bone metastasis and other bone diseases. [Mol Cancer Ther 2006;5(11):2634–43]
Tumor localization and antitumor efficacy of novel sapphyrin compounds
Authors: Naumovski Louie , Sirisawad Mint , Lecane Philip , Chen Jun , Ramos Jason , Wang Zhong , Cortez Cecilia , Magda Darren , Thiemann Patti , Boswell Garry , Miles Dale , Cho Dong Gyu , Sessler Jonathan L. , Miller Richard
Published: November 2006

Sapphyrins are pentapyrrolic metal-free expanded porphyrins with potential medical use as anticancer agents. The novel sapphyrin derivative, PCI-2050, functionalized with 2-[2-(2-methoxyethoxy)ethoxy]ethoxy groups to enhance solubility and a modified bipyrrole moiety was found to be more potent in inducing apoptosis than the previously described sapphyrin PCI-2000. Because some sapphyrins may localize to tumors, we took advantage of the intrinsic fluorescence of these compounds to develop a flow cytometry–based assay to track sapphyrin biodistribution in tumor-bearing mice. Ex vivo analysis of sapphyrin-injected animals revealed that PCI-2050 preferentially localized to tumor, whereas PCI-2000 distributed into normal tissues rather than tumor. PCI-2050 uptake in xenograft tumor cells and resultant tumor cell cytotoxicity was dose dependent. To investigate structure–activity relationships, we focused on PCI-2050 and three derivatives that differ by their alkyl substituents on the bipyrrole moiety: PCI-2051, PCI-2052, and PCI-2053. Treatment of Ramos cells in culture or treatment of Ramos xenograft-bearing animals with each of the sapphyrins followed by ex vivo growth of tumor cells revealed the same pattern of cytotoxicity: PCI-2050 > PCI-2052 > PCI-2051 > PCI-2053. Thus, subtle changes in the alkyl substituents on the bipyrrole moiety result in significant changes in antitumor activity. PCI-2050 displayed significant antitumor efficacy in both Ramos and RKO xenograft models without hematologic, hepatic, or renal abnormalities as assessed by complete blood counts and serum chemistries. On the basis of these findings, it is concluded that the sapphyrin PCI-2050 warrants further evaluation as a potential anticancer agent due to its intrinsic proapoptotic activity and tumor localization ability. [Mol Cancer Ther 2006;5(11):2798–805]
The poor's curse: Exodus xxii 20-26 and curse literature in the ancient world
Authors: Ben-Dov Jonathan
Published: November 2006

In the passage Exod. xxii 20-26 the poor man cries to God after he had been mal-treated by a powerful creditor. In response God acts as an avenger against that evil individual. The article first clarifies the background to such violent acts by proprietors in Ancient Near Eastern Laws, and the response to it in the laws of Deuteronomy xxiv. The curse and revenge are then explained in the light of parallel practices from ancient Greek literature, mainly from the Oddesey. Curse practices meant to restore justice are explored on the basis of Greek binding spells and of the corpus of Greek literary curses. The image of the Mesopotamian god "ama" as an avenging god is analyzed according to the famous Babylonian "ama" hymn and to that god's epitheta. Finally, examples of Hebrew curse literature are highlighted in the Book of Job and in Psalm cix.
The "effected object" in contractual legal language: the semantics of "If you purchase a Hebrew slave" (Exod. xxi 2)
Authors: Levinson Bernard M.
Published: November 2006

This article investigates the semantics of the protasis of the manumission law of the Covenant Code (Exod. xxi 2a). Despite the proposal by John Van Seters that the slave there purchased must "already" have been a slave, such a restriction of meaning goes beyond the evidence. Critical for understanding the semantic issue is the overlooked distinction between two types of verbal object: "affected" and "effected" objects. Moreover, verbs of creation and appointment are frequently ditransitive. Such verbs may also leave the affected object implicit while specifying only the effected object. This construction emphasizes the change in status undergone by the grammatical patient, as in the case of the manumission law. Attention to the contractual language of biblical law permits, in turn, a more adequate concept of the grammatical concept of effected object.
Animal Liberationist Responses to Non-Anthropogenic Animal Suffering
Authors: Thornhill Richard , Morris Michael
Published: November 2006

Animal liberationists generally pay little attention to the suffering of animals in the wild, and it is arguable that this is a significant proportion of the total amount of animal suffering. We examine a range of different responses of animal liberationists to the issue of non-anthropogenic suffering, but find none of them entirely satisfactory. Responses that lead logically to the conclusion that anthropogenic suffering should be eliminated can apply equally logically to the suffering of animals in the wild. On the other hand, the solution of micro-managing habitats to prevent suffering is counter-intuitive, and on closer examination eliminates the intrinsic value of animals' lives. On balance, the approach that we favour is acceptance of the intrinsic value of individual animal lives, extending this from either individual human lives (as accepted predominantly by theists), or from biodiversity, species and ecosystems (as currently accepted by ecocentric philosophies). We also suggest that the combination of animal liberation and environmentalism only really makes sense in the context of a belief in the redeemable qualities of nature, as expressed in quasi-Hindu terms or in terms of some Biblical animal liberationist worldviews.
Dwelling in Dialogues: Being-at-home in Relation to Clutter, Nature, and People
Authors: Klenk Nicole , Kozak Robert , Bull Gary
Published: November 2006

"Home" may be understood as an intangible concept separate from its material manifestation—the tangible place where one dwells, the house. However, this is not necessarily the way people experience the two concepts of "home" and "house". In daily life, both the experience of the tangible and the intangible dimensions of "home" may be inextricably linked. To explore how lived religion and spirituality relate to these dimensions, we engaged practicing Buddhists and Christians in dialogue about the role of their home in the practice of their faiths. Three major topics emerged from the interview process: clutter, nature, and people. The overlapping but distinct perspectives on these topics that the two groups of participants offer illustrate common dialectics that characterize the experience of "home".
Churches as a Stock of Social Capital for Promoting Social Development in Western Cape Communities
Authors: Swart Ignatius
Published: November 2006

The aim of the article is to present a perspective on the manner and extent to which churches may be considered as an important stock of social capital for promoting social development outcomes in selected communities in the Western Cape, South Africa. Taking the recently presented policy outline on social capital formation in this province as the contextual framework for analysis and reflection, the results of recently executed demographic and socio-empirical research are utilised in particular to advance a perspective on churches. It is argued in conclusion that churches and other faith-based organisations in the researched communities have an important strategic significance for a social capital formation agenda, despite their apparent lack of progressive social praxis. Their comparative advantage over other institutions, the considerable levels of trust invested in them and the manner in which they inspire activities of voluntary outreach, caring and social service are highlighted as special features of the churches.
The railroadmen's social condition and the evolution of the American railroad system
Authors: Carré Stéphane
Published: November 2006

While Europe is commiting itself to operating its railway network more freely, the United States have been living since the beginning under competition in that branch. This situation brought about the development of hard working conditions for its employees at first. Yet, since the companies were compelled to operate on a high security level as well as to imperiously allow anybody to have access to this service, they were quickly subdued to stringent control restricting the way they were working and granting social advantages far beyond the rights of the employment law to their railroadmen. This set of rules was implemented by a specific federal organisation, the "Interstate Commerce Organisation", as well as by a special law, the "Railway Labor Act", building a tight frame when industrial disputes break out in that branch. The "Staggers Act", if loosening these rules, didn't aim at questioning them.
Truth and secret: the protection of privacy in ancient German, French and English law
Authors: Balthasar Stephan
Published: November 2006

Comparing the legal development in France, Germany and England from 1500–1800, this article analyses the protection of those interests which are covered today by the law of privacy. Continental law, influenced by the Roman actio iniuriarum, protected personal secrets, and it also restrained, to a certain extent, the divulgation of embarrassing truths. The English law of defamation however, afforded no comparable protection, the proof of truth ("justification") being a perfect defence against any claim for damages under the head of defamation. The conclusion that the civil law has a long tradition of preserving sensitive information against unwanted publicity is underlined by the fact that the ancient ideas of protecting secrets and restricting publication of the truth helped 19th century lawyers in France and in Germany to approach the modern concept of privacy ("vie privée", "Privatleben").
Hematopathological Concepts and Controversies in the Diagnosis and Classification of Myelodysplastic Syndromes
Authors: Vardiman James W.
Published: November 2006

Although the diagnosis and classification of most cases of the myelodysplastic syndromes (MDS) is usually accomplished without difficulty, a minority of cases may pose diagnostic problems. In many cases the diagnostic dilemma can be solved by adhering to basic guidelines recommended for evaluation of patients suspected of having MDS, and in particular to the quality of the blood and bone marrow specimens submitted for morphologic, immunophenotypic and genetic studies. In other cases, such as patients who have hypocellular MDS or MDS with fibrosis, the criteria for making a diagnosis may be difficult if not impossible to apply, and in still others the diagnostic uncertainty is because the minimal criteria necessary to establish the diagnosis of MDS are not always clearly stated. In this review, some of these diagnostic problems are addressed and some general guidelines for resolving them are suggested. In addition, data are presented that illustrate that the WHO classification offers a valuable tool in the diagnosis and classification of MDS.
Clinical Issues in the Management of Patients with Myelodysplasia
Authors: Schiffer Charles A.
Published: November 2006

The management of patients with myelodysplasia (MDS) can be quite complex and varies according to both the clinical manifestations in individual patients as well as complicating medical conditions. Allogeneic stem cell transplantation is the only curative treatment, but because of the older age of the patient population must be applied selectively, particularly in those with lower risk MDS as well as in patients whose clinical course is more frankly “preleukemic.” Issues pertinent to the use of 5-azacytidine, decitabine and lenalidomide in patients with both higher and lower International Prognostic Staging System (IPSS) stage disease are discussed.
Current and Investigational Therapies for Patients with CLL
Authors: Wierda William G.
Published: November 2006

Clinical and laboratory investigations are driving the rapid change in treatments for patients with chronic lymphocytic leukemia (CLL). Randomized trials have demonstrated superior activity for fludarabine combined with cyclophosphamide versus single-agent fludarabine or chlorambucil as initial treatment. Chemoimmunotherapy holds promise for further improvement and is being tested in randomized trials. New combinations and agents are being identified and tested. Eliminating minimal residual disease is a therapeutic endpoint that may prove to prolong survival and is also under investigation in prospective clinical trials. Work continues toward improving survival and potentially curing patients of this disease.
Think of HIT
Authors: Warkentin Theodore E.
Published: November 2006

Heparin-induced thrombocytopenia, or HIT, can present in many ways, ranging from common—isolated thrombocytopenia, venous thromboembolism, acute limb ischemia—to less common but specific presentations—necrotizing skin lesions at heparin injection sites, post-bolus acute systemic reactions, and adrenal hemorrhagic necrosis (secondary to adrenal vein thrombosis). Many patients with HIT have mild or moderate thrombocytopenia: the median platelet count nadir is 60 × 109/L, and ranges from 15 to 150 × 109/L in 90% of patients, most of whom evince a 50% or greater fall in the platelet count. HIT that begins after stopping heparin (“delayed-onset HIT”) is increasingly recognized. Factors influencing risk of HIT include type of heparin (unfractionated heparin > low-molecular-weight heparin), type of patient (surgical > medical), and gender (female > male). Since timely diagnosis and treatment of HIT may reduce the risk of adverse outcomes, this review focuses on those clinical circumstances that should prompt the clinician to “think of HIT.” Coumarin anticoagulants such as warfarin are ineffective in acute HIT and can even be deleterious by predisposing to micro-thrombosis via protein C depletion (venous limb gangrene and skin necrosis syndromes). Thus, it is important to avoid or postpone coumarin while managing HIT hypercoagulability, focusing on agents that inhibit thrombin directly (lepirudin, argatroban) or that inhibit its generation (danaparoid, ?fondaparinux). Post-marketing experience suggests that standard dosing of lepirudin is too high; current recommendations are to avoid the initial lepirudin bolus and to begin with lower infusion rates, even in patients without overt renal dysfunction.
Thrombotic Thrombocytopenic Purpura: A Moving Target
Authors: Sadler J. Evan
Published: November 2006

Almost 80 years after Eli Moschcowitz published the first description of the disease, most patients with idiopathic thrombotic thrombocytopenic purpura (TTP) were found to have acquired autoantibody inhibitors of the ADAMTS13 metalloprotease. Plasma ADAMTS13 normally cleaves von Willebrand factor within nascent platelet-rich thrombi, and ADAMTS13 deficiency allows unchecked thrombus growth to cause microangiopathic hemolysis, thrombocytopenia, and tissue infarction. At present, ADAMTS13 deficiency with a high-titer inhibitor level appears to be associated with an increased risk of early death and subsequent relapse. Thus, acquired ADAMTS13 deficiency identifies a specific mechanism of TTP and is a potential biomarker of disease activity or risk. At present, two major clinical questions in the field may be summarized as follows. First, by emphasizing TTP caused by ADAMTS13 deficiency, are we in danger of neglecting other causes that should be treated with plasma exchange? Second, should we treat asymptomatic patients who have severe ADAMTS13 deficiency to prevent future disease, and if so, how?
Bleeding Disorders in Premenopausal Women: (Another) Public Health Crisis for Hematology?
Authors: James Andra H. , Ragni Margaret V. , Picozzi Vincent J.
Published: November 2006

Premenopausal women with bleeding disorders represent a major public health problem. Estimates suggest up to 20% of women with menorrhagia have an underlying bleeding disorder (corresponding to a prevalence of 1.5–4 million American women). Von Willebrand disease (VWD) is the most common bleeding disorder among women with menorrhagia, affecting up to 20% of such patients. Besides menorrhagia, important consequences of bleeding disorders in premenopausal women include iron deficiency anemia, miscarriage, postpartum bleeding, uterine bleeding and hysterectomy. These patients face many obstacles in achieving optimum care. Recognition is difficult as women may consider their symptoms “normal” and come to attention only after serious bleeding events. Symptoms of VWD may also overlap with benign conditions, primary providers may not suspect the diagnosis, and convenient hematologic input may be unavailable. Diagnosis is difficult as there is no single definitive test for VWD, and test results are variable, often being affected by extragenic factors, including stress, contraceptives, hormones, and pregnancy. Hemostatic treatment is limited by DDAVP tachyphylaxis, the lack of recombinant VWD concentrates, and the ineffectiveness of hormonal therapy, leading to unnecessary procedures and early hysterectomy. Finally, significant controversy exists regarding classification of type 1 VWD as a disease: given the overlap in symptoms and laboratory assays within the normal population, evaluation for those with VWD might be seen as identification of potential bleeding risk rather than detection of a disease. This symposium seeks to explore these issues in greater detail from the combined perspectives of the obstetrician-gynecologist and the hematologist to promote a better public health approach to this problem.
Inherited Bone Marrow Failure Syndromes: Molecular Features
Authors: Shimamura Akiko
Published: November 2006

Recent advances resulting from the identification of the genes responsible for four inherited marrow failure syndromes, Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, are reviewed. The interpretation of genetic testing should be guided by an understanding of the limitations of such testing for each disorder. The possibility of an inherited basis for marrow failure must be considered for adults as well as children with aplastic anemia. Shared molecular themes are emerging from functional studies of the genes underlying the different inherited disorders. Genomic instability may result from impaired DNA repair in Fanconi anemia or telomere dysregulation in dyskeratosis congenita. Mutations affecting ribosome assembly or function are associated with Diamond-Blackfan anemia, dyskeratosis congenita, and Shwachman-Diamond syndrome. These findings raise new questions about the molecular mechanisms regulating hematopoiesis and leukemogenesis. Clinical implications arising from these molecular studies are explored.
Engulfment of apoptotic cells by microvascular endothelial cells induces proinflammatory responses
Authors: Kirsch Torsten , Woywodt Alexander , Beese Michaela , Wyss Kristin , Park Joon-Keun , Erdbruegger Uta , Hertel Barbara , Haller Hermann , Haubitz Marion
Published: November 2006

Circulating endothelial cells (CECs) have been detected in a variety of vascular disorders, but their interactions with healthy endothelium remain unknown. The aim of this study was to evaluate the response of human endothelial cells (ECs) to apoptotic or necrotic ECs in an in vitro model and to delineate pathogenetic pathways. Here we show that incubation of the human microvascular endothelial cell line (HMEC-1) with apoptotic ECs resulted in increased expression of chemokines and enhanced binding of leukocytes to HMEC-1 cells, whereas exposure of HMEC-1 cells to necrotic ECs caused no changes in leukocyte-binding affinity. Both apoptotic and necrotic cells were bound and engulfed by HMEC-1 cells and primary human umbilical vein endothelial cells (HUVECs). We therefore suggest that exposures to apoptotic and necrotic ECs induce different patterns of chemokine synthesis and leukocyte adhesion in healthy ECs. These data indicate that CECs are not only markers of vascular damage but may induce proinflammatory signals in the endothelium.
Arginase 1 is expressed in myelocytes/metamyelocytes and localized in gelatinase granules of human neutrophils
Authors: Jacobsen Lars C. , Theilgaard-Mönch Kim , Christensen Erik I. , Borregaard Niels
Published: November 2006

Arginase 1 (ARG1) metabolizes arginine, thus reducing the availability of arginine as a substrate for nitric oxide synthase (NOS). The decreased production of nitric oxide (NO) by NOS and the production of ornithine by ARG1 affect immune responses and tissue regeneration at sites of infection, respectively. We here demonstrate that ARG1 is synthesized in myelocytes/metamyelocytes and is stored in gelatinase granules. In accordance with this, activated neutrophils coreleased ARG1 and gelatinase to the extracellular environment on stimulation with phorbol-12-myristate 13-acetate (PMA), formyl-methionyl-leucyl-phenylalanine (fMLP), or tumor necrosis factor α (TNF-α). Overall, these findings define ARG1 as a genuine gelatinase granule protein and support a model in which activated neutrophils release ARG1 at sites of infection to modulate immune responses and promote tissue regeneration.
Transient Dynamics and Directional Solidification in Space Platforms
Authors: RUIZ X.
Published: November 2006

Abstract:  The impact of short impulsive forces on the semiconductor segregation patterns inside a generic μg Bridgman growth arrangement is discussed here with the help of a time‐dependent 2D numerical scheme. Impulses have been applied parallel to the growth interface, equivalently, orthogonal to the external thermal gradient. The present results indicate that for each one of the three semiconductors considered, the reduced longitudinal and radial solid segregation are practically insensitive to the pulse shape, rectangular or half‐sinusoidal. The reduced longitudinal segregation only depends on the growth velocity for constant g‐dose impulses. The reduced radial segregation depends on both the interface growth velocity and very weakly on the activity time of the constant g‐dose impulse externally applied. The thermal flux across the interface is shape‐dependent and does not act synchronically with half‐sinusoidal external impulses. Also, as before, this flux depends on the activity time and on the growth velocity for constant g‐dose impulses.
Some Parameter Boundaries Governing Microgravity Pool Boiling Modes
Authors: MERTE HERMAN
Published: November 2006

Abstract:  Pool boiling experiments were conducted in microgravity on five space shuttle flights, using a flat plate heater consisting of a semitransparent thin gold film deposited on a quartz substrate that also acted as a resistance thermometer. The test fluid was R‐113, and the vapor bubble behavior at the heater surface was photographed from beneath as well as from the side. Each flight consisted of a matrix of three levels of imposed heat flux and three levels of initial bulk liquid subcooling.
In many of the total of 45 experiments, steady nucleate boiling was observed from 16‐mm movie films, where a large vapor bubble formed and remained slightly removed from the heater surface, with small vapor bubbles growing on the heater surface, and on contact coalescing with the large bubble. Computations of the forces associated with the momentum transfer in this process, which counters the Marangoni convection effects tending to impel the large bubble toward the heater surface, have been completed for all cases where applicable.
The modes of pool boiling observed with successive increases in levels of heat flux in microgravity are categorized as: (i) minimum or incipient nucleate boiling; (ii) nucleate boiling with vigorous motion of the bubbles adjacent and parallel to the heater surface, impelled by Marangoni convection effects; (iii) nucleate boiling followed by coalescence with a neighboring large vapor bubble; (iv) partial dryout of the heater surface, in parallel with nucleate boiling; (v) complete dryout. The boundaries between these modes are delineated graphically as a function of the imposed heat flux and initial bulk liquid subcooling, together with the levels of the forces holding the large bubbles, acting as vapor reservoirs, away from the heater surface for the steady nucleate boiling mode.
Fluctuations in Diffusion Processes in Microgravity
Authors: MAZZONI STEFANO , CERBINO ROBERTO , VAILATI ALBERTO , GIGLIO MARZIO
Published: November 2006

Abstract:  It has been shown recently that diffusion processes exhibit giant nonequilibrium fluctuations (NEFs). That is, the diffusing fronts display corrugations whose length scale ranges from the molecular to the macroscopic one. The amplitude of the NEF diverges following a power law behavior ∝ q−4 (where q is the wave vector). However, fluctuations of wave number smaller than a critical “rolloff” wave vector are quenched by the presence of gravity. It is therefore expected that in microgravity conditions, the amplitude of the NEF should be boosted by the absence of the buoyancy‐driven restoring force. This may affect any diffusion process performed in microgravity, such as the crystallization of a protein solution induced by the diffusion of a salt buffer. The aim of GRADFLEX (GRAdient‐Driven FLuctuation EXperiment), a joint project of ESA and NASA, is to investigate the presence of NEFs arising in a diffusion process under microgravity conditions. The project consists of two experiments. One is carried out by UNIMI (University of Milan) and INFM (Istituto Nazionale per la Fisica della Materia) and is focused on NEF in a concentration diffusion process. The other experiment is performed by UCSB (University of California at Santa Barbara) concerning temperature NEF in a simple fluid. In the UNIMI part of the GRADFLEX experimental setup, NEFs are induced in a binary mixture by means of the Soret effect. The diagnostic method is an all‐optical quantitative shadowgraph technique. The power spectrum of the induced NEFs is obtained by the processing of the shadowgraph images. A detailed description of the experimental apparatus as well as the ground‐based experimental results is presented here for the UNIMI‐INFM experiment. The GRADFLEX payload is scheduled to fly on the FOTON M3 capsule in April 2007.
Flow Rate Limitation in Open Capillary Channel Flows
Authors: HAAKE DENNIS , ROSENDAHL UWE , OHLHOFF ANTJE , DREYER MICHAEL E.
Published: November 2006

Abstract:  This paper reports the experimental and theoretical investigations of forced liquid flows through open capillary channels under reduced gravity conditions. An open capillary channel is a structure that establishes a liquid flow path at low Bond numbers, when the capillary pressure caused by the surface tension force dominates in comparison to the hydrostatic pressure induced by gravitational or residual accelerations. In case of steady flow through the channel, the capillary pressure of the free surface balances the pressure difference between the liquid and the surrounding constant‐pressure gas phase. Because of convective and viscous momentum transport, the pressure along the flow path decreases and causes the free surface to bend inward. The maximum flow rate is achieved when the free surface collapses and gas ingestion occurs at the outlet. This critical flow rate depends on the geometry of the channel and the properties of the liquid. In this paper we present a comparison of the theoretical and experimental critical flow rates and surface profiles for convective dominated flows. For the prediction of the critical flow rate a one‐dimensional theoretical model taking into account the entrance pressure loss and the frictional pressure loss in the channel is developed.
Using Large Electric Fields to Control Transport in Microgravity
Authors: DUNN‐RANKIN DEREK , WEINBERG FELIX J.
Published: November 2006

Abstract:  Transport control by large electric fields in microgravity may be subdivided according to whether the charge carriers are flame ions, ions produced by corona discharges, or electrically charged particles. Using electric fields to induce and direct convection through the drag exercised on neutral gas by ions and to manipulate dispersions and trajectories of electrically charged droplets and particles is especially effective in the absence of Earth's gravity. We have explored applications associated with each of these, and this review collects and summarizes briefly the principal findings of our research, which is scattered widely over the literature of combustion, electrostatics, and experimental science.
Direct Computational Simulations and Experiments for Film Condensation inside Tubes and Channels
Authors: NARAIN AMITABH , PHAN LUCAS A. , WANG XIAOMIN , KURITA JORGE H. , SIEMIONKO ANNA , WEI NG TIAN , KULKARNI SHANTANU D.
Published: November 2006

Abstract:  This article presents accurate numerical solutions of the full 2D governing equations for steady and unsteady laminar/laminar internal condensing flows of pure vapor (FC‐72 and R‐113) inside a vertical tube and a channel. The film condensation is on the inside wall of a tube or one of the walls of a channel (the lower wall in case of a downward sloping channel). Both experiments and simulations find that exit condition specifications are important. The computations are able to predict whether or not a steady flow exists with a well‐defined and steady natural exit condition. If well‐defined natural steady/quasi‐steady flows exist—as is shown to be the case for gravity‐dominated or strong shear‐dominated condensate flows that remain parabolic up to the exit location—the computations are able to predict both the natural exit condition and any point of transition (from stable to unstable or smooth to wavy behavior) that may exist within this zone. Compared to gravity‐driven cases, shear‐driven cases (zero gravity or horizontal cases) tend to destabilize easily. It is found that only for gravity‐driven cases interfacial waves are able to cause a concurrent enhancement in heat transfer rates along with an enhancement in interfacial shear. Also it is found that this enhancement in interfacial wave energy is significant if the condensing surface noise is in resonance with the intrinsic waves.
Convection Effects on Crystallinity in the Growth of In0.3Ga0.7 as Crystals by the Traveling Liquidus Zone Method
Authors: KINOSHITA KYOICHI , OGATA YASUYUKI , ADACHI SATOSHI , YODA SHINICHI , TSURU TETSUYA , MIYATA HIROAKI , MURAMATSU YUJI
Published: November 2006

Abstract:  The influence of convection in a melt on the crystallinity of the TLZ‐grown In0.3Ga0.7As crystals has been investigated by growing crystals with various shapes and dimensions on the ground. No single crystals have been grown when the crystal diameter was 10 mm, but we were successful in growing single crystals by reducing crystal diameter to 2 mm. These results suggested the importance of suppressing convection in the melt during alloy crystal growth because constitutional supercooling tends to occur at the freezing interface or ahead of the interface by the segregation effect. Large area is required for substrate use in various applications. This requirement can be fulfilled by the crystal growth in microgravity because density difference–induced convection is suppressed in microgravity. Another means for suppressing convection without deteriorating area is plate‐shape crystal growth with reduced thickness. The latter can be applied on the ground and we succeeded in growing single crystals of plate‐shaped In0.3Ga0.7As by the traveling liquidus zone (TLZ) method. Dimensions of obtained single crystals were 10 mm in width and 2 mm in thickness and lengths ranged from 20 to 40 mm. Compositional uniformity was good and 0.3 ± 0.02 in InAs mole fraction was achieved.
Heat Transfer Enhancement by Electric Fields in Several Heat Exchange Regimes
Authors: GRASSI WALTER , TESTI DANIELE
Published: November 2006

Abstract:  With the present article, the authors summarize over 15 years of work dedicated to studying the effects of the electrical and the gravitational force fields on two‐phase and single‐phase thermofluid dynamics. Results obtained on several microgravity platforms are presented and the role played by the electric field in the different heat transfer processes is analyzed. In particular, the regimes of nucleate boiling and film boiling are treated. Also, the parameters controlling the liquid–vapor interface instability and the main consequences regarding the critical heat flux (CHF) are outlined. In the final section, the promising technique of ion injection for efficient heat transfer enhancement in single‐phase liquids is described, together with the main results obtained under different flow regimes and geometries. The following dielectrics were compared: R113, Vertrel XF, and FC‐72 for the pool boiling research; again FC‐72 and HFE‐7100 for the single‐phase convection heat transfer experiments.
Endocrine Disruptors
Authors: WOLFF MARY S.
Published: November 2006

Abstract:  During the past 10 years, there has been a worldwide decline in the use and human exposure to many chemicals, including pesticides and persistent organic pollutants (POPs). However, a new generation of chemicals that have endocrine disrupting (ED) potential have emerged. Their presence in the environment and concomitant levels in humans are prevalent, although the sources of these contemporary‐use industrial chemicals are not entirely identified. They include the phthalates, alkylphenols, brominated diphenyl ethers, and perfluorinated organics (PFOCs). The alkylphenols, especially bisphenol A, are potent EDs. Levels vary by geography, race/ethnicity, age and gender, and human health effects are just beginning to be assessed. This article discusses the toxicology, human exposure, and potential health effects of EDs that are likely to be important in the 21st century.
Use of Carcinogenicity Bioassays in the IARC Monographs
Authors: COGLIANO VINCENT JAMES
Published: November 2006

Abstract:  Carcinogenicity bioassays generally provide the best means of assessing the potential for a chemical to be a human carcinogenic hazard. The results of carcinogenicity bioassays are usually the key determinants of IARC Monograph evaluations. Along with carcinogenicity bioassays and epidemiological studies, the International Agency for Research on Cancer (IARC) also encourages the consideration of mechanistic data and other relevant data. During 2005 IARC is updating the Preamble to the IARC Monographs, which describes the principles and procedures used in developing the Monographs, including the criteria that guide the evaluations. Proposed revisions to the Preamble make some changes in the criteria for evaluating carcinogenicity in experimental animals to reflect the greater confidence that can be placed in Good Laboratory Practice (GLP) studies. Other changes will give more specific guidance for the evaluation of mechanistic data. Sections on mechanistic data will be given more prominence in future Monographs and will be more closely linked with toxicokinetics. Future Monographs will also include a new section on susceptible individuals, populations, and life stages that will often be based on the understanding of mechanisms. In addition, the draft Preamble discusses IARC's procedures for promoting impartial evaluations by avoiding conflicts of interests and ensuring that working groups are free from interference.
Measurements of Asbestos Burden in Tissues
Authors: DODSON RONALD F. , ATKINSON MARK A.L.
Published: November 2006

Abstract:  Asbestos inhaled into the lung is recognized as a potential causal agent for the development of diseases in man. The diseases induced by asbestos include lung cancer, fibrosis of the lung (asbestosis), and extrapulmonary tumors including mesothelioma (a tumor of the serosal membrane), as well as fibrosis and other changes in the pleura linings. The cause of these diseases can often be more specifically linked to asbestos exposure once tissue burden of asbestos is established. The asbestos burden in tissue can be defined as the number of asbestos bodies and/or the numbers and types of asbestos fibers found in the tissue. In either of these cases the quality of information is directly dependent on the preparative techniques and instrumentation used in the analysis. The present article will discuss the significance of findings of tissue burden based on both these variables.