bluuebunny/crossref_metadata_2025 huggingface dataset:
Life‐Cycle Assessment of Biosolids Processing Options
Authors: Peters Gregory M. , Lundie Sven
Published: July 2002

Biosolids, also known as sewage sludge, are reusable organic materials separated from sewage during treatment. They can be managed in a variety of ways. Different options for biosolids handling in Sydney, Australia, are compared in this study using life‐cycle assessment. Two key comparisons are made: of system scenarios (scenario 1 is local dewatering and lime amendment; scenario 2 is a centralized drying system) and of technologies (thermal drying versus lime amendment). The environmental issues addressed are energy consumption, global warming potential (GWP), and human toxicity potential (HTP).

Scenario 2 would consume 24% more energy than scenario 1. This is due to the additional electricity for pumping and particularly the petrochemical methane that supplements biogas in the drier. A centralized system using the same technologies as scenario 1 has approximately the same impacts. The GWP and HTP of the different scenarios do not differ significantly.

The assessment of technology choices shows significant differences. The ample supply of endogenous biogas at North Head sewage treatment plant for the drying option allows reductions, relative to the lime‐amendment option, of 68% in energy consumption, 45% in GWP, and 23% in HTP.

Technology choices have more significant influence on the environmental profile of biosolids processing than does the choice of system configurations. Controlling variables for environmental improvement are the selection of biogas fuel, avoidance of coalsourced electrical energy, minimization of trucking distances, and raising the solids content of biosolids products.
Climate Change and the Oil Industry: Common Problems, Different Strategies
Authors: Skjærseth Jon Birger , Skodvin Tora
Published: July 2002

The primary focus of most academic climate policy studies has been the robustness of climate science and the development of international negotiations and institutions, in which states, and sometimes societies, have been pinpointed as the key players. Systematic comparative studies of multinational and even global non-governmental actors have been in short supply. This research lacuna is particularly glaring since the position of a major non-state actor—the oil industry—may be crucial to the viability of the climate regime. This analysis shows that there are striking differences in the ways European-based and US-based oil companies have responded to the climate issue—here represented by the Royal Dutch/Shell Group and Exxon Mobil—and that one major source of explanation for this difference is found in the national political contexts of the companies' home-base countries. The importance of political context implies that the conditions for changing oil companies' climate strategies are likely to be located in the political context rather than in the companies themselves.
WHAT IF THE CHRONICLER DID USE THE DEUTERONOMISTIC HISTORY?
Authors: Auld A. Graeme
Published: July 2002

The Chronicler's presumed familiarity with Deuteronomy, Joshua, Judges, and 1 Samuel is first briefly explored. Closer scrutiny of the David story in 2 Samuel and 1 Chronicles suggests that the Chronicler's use of 2 Samuel as source, while possible, is unlikely. Similar results for the story of Solomon in 1 Kings and 2 Chronicles are noted. And consideration of the counterfactual leads helpfully to a new question about the books of the Former Prophets.
INDEXING THE SELF: INTENT AND EXPRESSION IN ISLAMIC LEGAL ACTS
Authors: Messick Brinkley
Published: July 2002

This is a discussion of the theory of intent in Islamic law. In an extended example, I focus on the doctrinal views of Zaydī school jurists from Yemen, but I also indicate that the issues and the analytic distinctions characterize the Sunnī schools as well. As in western law, ascertaining intent is fundamental to applied Islamic legal analyses in sharī'a courts, in matters ranging from contracts to criminal cases. My discussion here, however, is limited to the doctrinal theory of such intent-based legal analyses, about which the Muslim jurists, including the Yemeni jurists of my extended example, hold divergent opinions. Following the Yemeni jurists in their analyses, I consider the relation of intent and manifest expression, including words and writings, across the different domains of bilateral and unilateral acts.
UNTAMED HEARTS: EROS AND SUICIDE IN LATE IMPERIAL CHINESE FICTION
Authors: Zamperini Paola
Published: July 2002

In Chinese fiction there are heroines who use suicide as a vehicle to convey to eternity the strength of their passions, from love to hatred, from jealousy to thirst for revenge. The present paper is an exploration of late imperial literary representations which depict women's suicide as an act of passion and self-reassertion: this act, rather than being constructed as defeat in the face of adversities, a response to abuse suffered, or as a last resort to preserve chastity, is presented as a path of independence that shows these female characters not as virtuous martyrs or victims of an unjust patriarchal system, but as passionate agents of free will. These sources challenge the assumption that women's suicide in Ming and Qing fictional sources is primarily related to chastity. In this sense, they are useful in furthering understanding of the complex ways in which legal and moral mandates around the issue of women's suicide could be resisted, absorbed, and ignored in late imperial vernacular fiction.
SACRED MOUNTAINS, RELIGIOUS PARADIGMS, AND IDENTITY AMONG THE MESCALERO APACHE
Authors: Ball Martin
Published: July 2002

This article carefully examines the roles that sacred mountains play in Mescalero Apache religious tradition and ''religious paradigms'' of sacred space and ceremonial practice. For the Mescalero, sacred mountains are intimately associated with conceptions of spiritual ecology, ceremonial traditions, prayer, and cultural identity. To understand these aspects of Mescalero tradition as they relate to cultural practices, this article focuses on the Mescalero Apache Mountain Spirit tradition. In this tradition men are masked, painted as ''Mountain Spirits'' and are understood to embody the power of the sacred mountains, the four cardinal directions, and the power of the Creator. Through analyzing this ceremonial tradition, Mescalero conceptions of how spiritual power is linked to sacred geographies and spiritual ecology is brought to light. The Mountain Spirits are also analyzed for how, through oral tradition and spiritual revelation, mountains become significant for the Mescalero within their religious system. The Mountain Spirits and their connections to sacred mountains are furthermore contrasted with the female initiation ceremony of the ''Big Tipi.'' It is proposed in this paper that these two ceremonial traditions, through their different relationships to the land and sacred geographies, feature differently in Mescalero self-conceptions of their cultural and religious identity.
THE FUNCTIONAL SIGNIFICANCE OF DIANA MONKEY 'CLEAR' CALLS
Authors: Uster Dana , Zuberbühler Klaus
Published: July 2002

In their natural West African rainforest habitat, Diana monkeys continuously produce high rates of a close-range clear-sounding call, but the function of this behaviour is unknown. In other primate species, close-range calls are typically given in socially relevant situations, for example, to gain access to grooming partners or food. Quite contrarily, we tested a number of hypotheses and found that Diana monkey 'clear' calls primarily function to avoid predation. Call rates were significantly elevated when predation threat was high, for instance when the visibility was poor, when the group spread was large, when the group was not associated with other monkey species, or after alarm calls. Call rates were not significantly elevated, however, in circumstances of high social competition, for instance when the group spread was small, during resting phases, while feeding on clumped food sources, or when foraging in the periphery where inter-group encounters were more likely to occur. Calling was contagious in that calls typically elicited vocal responses from out-of-sight group members within a few seconds. Because of this, callers can effectively monitor a much larger area than is visually accessible to single individuals, suggesting that Diana monkey clear calls act as an essential element in a mutualistic system of co-ordinated vigilance.
BEHAVIORAL DEVELOPMENT IN WILD BOTTLENOSE DOLPHIN NEWBORNS (TURSIOPS SP.)
Authors: Barbara Janet Mann
Published: July 2002

Newborn characteristics, patterns of motoric and social behavioural development, and mother-infant relationships in free-ranging and semi-provisioned bottlenose dolphins (Tursiops sp.) are examined. Nine newborns were observed for 189 hours over the first 10 weeks of life. Newborn infants breathe more often than their mothers, and synchronize their breathing and swimming with her soon after birth, but show a gradual decline in synchrony as they age. Virtually all patterns of infant behaviour, mother-infant proximity, and spatial relationships with the mother changed as a function of infant age. Maternal activity, however, does not change over time, except that mothers decrease their role in maintaining proximity to their infants from the first month to the second month of infant life. Infants spend less time close to their mothers, less time echelon swimming (close, alongside the mother), and more time infant-position swimming (in contact under the mother) as they age. Infants spend more time traveling and socializing independently over time. They also separate from their mothers more often and for longer periods of time. Infants do not forage during the newborn period, but are observed 'practice foraging' by the end of the first month. Rubbing, petting, chasing, and displaying with other animals (including the mother) were common forms of socializing. Infants frequently initiate rubbing with their mothers, with particular focus on her head region. Infants typically associate with young females, adult females and other infants, but not with adult or subadult males. Developmental shifts and overall patterns are discussed in the context of the bottlenose dolphin's fission-fusion social organization and ecology. The effects of provisioning on dolphin behaviour are addressed.
THE STRUCTURE OF SOCIAL RELATIONSHIPS AMONG FEMALE SAVANNA BABOONS IN MOREMI RESERVE, BOTSWANA
Authors: Silk Joan , Seyfarth Robert , Cheney Dorothy
Published: July 2002

Here we examine the effects of maternal kinship, reciprocity, and dominance rank on the social relationships of female baboons (Papio cynocephalus ursinus) in a well-habituated, free-ranging group in the Okavango Delta of Botswana. These data are useful for testing comparative hypotheses about the ecological and demographic factors that shape the evolution of social organization in primates and other animals. In this group, adult females had well-differentiated grooming relationships with one another, and limited their grooming to a relatively small subset of available partners. Although there were 19 adult females in the group, the average female groomed only 8 other females, and devoted at least 5% of her grooming to only four other females. Females groomed maternal kin at significantly higher rates and for significantly longer periods than they groomed other females. The bias in favor of maternal kin was not an artifact of a general attraction toward females of adjacent rank. However, members of high-ranking lineages did devote a relatively greater fraction of grooming to maternal kin than members of low-ranking lineages did. Females most often groomed the females from whom they received the most grooming and grooming was very evenly balanced within the majority of dyads. Female rank had little impact upon grooming patterns and there was no evidence that females competed overtly over access to high-ranking partners.
Nematicidal activity of essential oil components against the root-knot nematode Meloidogyne javanica
Authors: Oka Yuji
Published: July 2002

Nematicidal activity of eight essential oil components; trans -anethole, anis alcohol, p-anisaldehyde, benzaldehyde, 4-methoxyphenol, trans-cinnamaldehyde, (R)-(+)-pulegone, 2-furaldehyde, and a non-essential oil component anisole, was tested against the root-knot nematode Meloidogyne javanica in solutions in 200-ml and 3-l pots and in microplots. Among the anisole derivatives, p-anisaldehyde showed the highest nematicidal activity in solutions and in soil. However, trans-cinnamaldehyde, 2-furaldehyde and benzaldehyde showed higher nematicidal activity than p-anisaldehyde in the 3-l pot experiments. EC50 values of trans-cinnamaldehyde for juvenile immobilisation and hatching inhibition in vitro were as low as 15 and 11.3 μl/l, respectively. In the 3-l pot experiments, trans-cinnamaldehyde, 2-furaldehyde, benzaldehyde and carvacrol at a concentration of 100 mg/kg greatly reduced the root galling of tomato, whereas trans-anethole was not effective. In a microplot experiment, soil treatment with trans-cinnamaldehyde (50 ml/m2) reduced the galling index and increased the shoot weight of tomato plants. Although further experiments, such as development of formulations and application methods, are needed, some essential oil components, especially aldehydes, can be developed into lowtoxicity nematicides.
Keeping the Faith: The German Syndicalists in the First World War
Authors: Thorpe Wayne
Published: July 2002

In December 1918, in its first conference since the outbreak of the Great War, the revolutionary syndicalist Free Association of German Trade Unions (Freie Vereinigung deutscher Gewerkschaften — FVdG) noted that it was the only trade union organization in the country that did not have to readjust its program with the return of peace. The syndicalists were alluding to the fact that theirs had been the only German workers' organization to have adopted an internationalist rather than a patriotic response to the war. The FVdG had neither supported the national cause nor endorsed the Burgfrieden, or civil truce, whereby all factional disputes were to be set aside and all sectoral interests subordinated to the higher interests of the imperiled nation. Its opposition to the war, its refusal to cooperate with the state and the employers, moreover, had made the FVdG a beneficiary of the growing radicalization of German workers. In the immediate postwar period it expanded at a rate six times greater than any other labor organization in the country.
Effect of particle size on the flocculation behaviour of ultra-fine clays in salt solutions
Authors: Kotlyar L. S. , Sparks B. D. , LePage Y. , Woods J. R.
Published: July 2002

The Athabasca oil sands deposit in Alberta contains ~5 x 109 m3 of bitumen accessible by surface mining. During bitumen separation from the mined ore, ultra-fine (<300 nm) aluminosilicate clays only a few layers thick (U/F) are mobilized and become dispersed in the process water. In this water containing dissolved salts from natural deposits, U/F are capable of forming thixotropic gels. The consequence of this is the production of large volumes of mature fine tailings (MFT) with a high water holding capacity. For mine planning purposes, the objective of predicting and possibly mitigating MFT formation requires an understanding of the colloidal behaviour of U/F particles in salt solutions. In this work, photon correlation spectroscopy and the deuterium NMR method are used to provide an insight into the U/F floc formation process. These results are correlated with conventional analysis of settling data.
Plagioclase-rich microgranular inclusions from the late-Caledonian Galway Granite, Connemara, Ireland
Authors: Graham N. T. , Feely M. , Callaghan B.
Published: July 2002

We report on the occurrence, petrology and geochemistry of recently recognized leucocratic plagioclase-rich microgranular inclusions hosted by two granite facies in the late-Caledonian Galway Granite, Connemara, Ireland. They have been recorded at 66 localities along an ESE trending, 4 km wide corridor which incorporates the contact zone between their host granites (i.e. The Megacrystic Granite and the Mingling and Mixing Zone Granodiorite). The inclusions are discoidal in shape and oriented parallel to the general ESE trending foliation in the granites with the most elongate (6.0 × 0.6 cm) occurring in zones of strongest fabric intensity. Contacts between the inclusions and the host granite are sharp with no chilled margin visible. They display a fine-grained (<1 mm) interlocking texture with occasional crystals of plagioclase ranging up to 2 mm in length. Microprobe analysis shows that the plagioclase is essentially oligoclase (An22–32) in composition and is similar to that (i.e. An21–30) occurring in the host granites. Furthermore, the oligoclase accounts for between 61 and 78% of the mode which is reflected in the major element chemistry of the inclusions. Other minerals (in decending order of abundance) include K-feldspar, quartz, biotite and magnetite. The origin of the inclusions is unclear. However, the results of the microprobe analysis provide evidence of a link between them and their host granites.
Impaired production of naive T lymphocytes in human T-cell leukemia virus type I–infected individuals: its implications in the immunodeficient state
Authors: Yasunaga Jun-ichirou , Sakai Tatsunori , Nosaka Kisato , Etoh Ken-ichiro , Tamiya Sadahiro , Koga Shin , Mita Shuji , Uchino Makoto , Mitsuya Hiroaki , Matsuoka Masao
Published: July 2002

Opportunistic infections frequently occur in patients with adult T-cell leukemia (ATL) and human T-cell leukemia virus type I (HTLV-I) carriers. However, the underlying mechanisms of such infections remain unknown. To clarify the mechanism of immunodeficiency in those infected with HTLV-I, this study analyzed the T-cell subsets in HTLV-I carriers and patients with HTLV-I–associated myelopathy/tropical spastic paraparesis and ATL using 3-color fluorescence with CD62L and CD45RA coexpression either with CD4+ or CD8+ T cells. The number of naive T lymphocytes was markedly suppressed in patients with ATL, particularly in those with acute form, compared with uninfected control individuals. The number of naive T cells was low in HTLV-I–infected individuals under 50 years old compared with uninfected individuals, whereas the number of memory T lymphocytes was greater in HTLV-I–infected individuals. Although the increase of memory T lymphocytes correlated with HTLV-I provirus loads, no relationship was found between naive T-cell counts and provirus loads. T-cell receptor rearrangement excision circles (TRECs), which are generated by DNA recombination during early T lymphopoiesis, were quantified to evaluate thymic function in HTLV-I–infected individuals. TREC levels were lower in HTLV-I–infected individuals than in uninfected individuals. In HTLV-I carriers less than 70 years old, an increase of Epstein-Barr virus DNA in peripheral blood mononuclear cells was observed in 6 of 16 (38%) examined, whereas it was detectable in only 1 of 11 uninfected controls. These results suggested that the low number of naive T lymphocytes was due to suppressed production of T lymphocytes in the thymus, which might account for immunodeficiency observed in HTLV-I–infected individuals.
A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model
Authors: Moskowitz Craig H. , Nimer Stephen D. , Zelenetz Andrew D. , Trippett Tania , Hedrick Eric E. , Filippa Daniel A. , Louie Diane , Gonzales Maria , Walits Janine , Coady-Lyons Nancy , Qin Jing , Frank Richard , Bertino Joseph R. , Goy Andre , Noy Ariela , O'Brien James P. , Straus David , Portlock Carol S. , Yahalom Joachim
Published: July 2002

Salvage of patients with relapsed and refractory Hodgkin disease (HD) with high-dose chemoradiotherapy (HDT) and autologous stem cell transplantation (ASCT) results in event-free survival (EFS) rates from 30% to 50%. Unfortunately, the reduction in toxicity associated with modern supportive care has improved EFS by only 5% to 10% and has not reduced the relapse rate. Results of a comprehensive 2-step protocol encompassing dose-dense and dose-intense second-line chemotherapy, followed by HDT and ASCT, are reported. Sixty-five consecutive patients, 22 with primary refractory HD and 43 with relapsed HD, were treated with 2 biweekly cycles of ifosfamide, carboplatin, and etoposide (ICE). Peripheral blood progenitor cells from responding patients were collected, and the patients were given accelerated fractionation involved field radiotherapy (IFRT) followed by cyclophosphamide-etoposide and either intensive accelerated fractionation total lymphoid irradiation or carmustine and ASCT. The EFS rate at a median follow-up of 43 months, as analyzed by intent to treat, was 58%. The response rate to ICE was 88%, and the EFS rate for patients who underwent transplantation was 68%. Cox regression analysis identified 3 factors before the initiation of ICE that predicted for outcome: B symptoms, extranodal disease, and complete remission duration of less than 1 year. EFS rates were 83% for patients with 0 to 1 adverse factors, 27% for patients with 2 factors, and 10% for patients with 3 factors (P < .001). These results compare favorably with other series and document the feasibility and efficacy of giving uniform dose-dense and dose-intense cytoreductive chemotherapy and integrating accelerated fractionation radiotherapy into an ASCT treatment program. This prognostic model provides a basis for risk-adapted HDT.
The arginine-552-cysteine (R1315C) mutation within the A1 loop of von Willebrand factor induces an abnormal folding with a loss of function resulting in type 2A–like phenotype of von Willebrand disease: study of 10 patients and mutated recombinant von Willebrand factor
Authors: Ribba Anne-Sophie , Hilbert Lysiane , Lavergne Jean-Maurice , Fressinaud Edith , Boyer-Neumann Catherine , Ternisien Catherine , Juhan-Vague Irène , Goudemand Jenny , Girma Jean-Pierre , Mazurier Claudine , Meyer Dominique
Published: July 2002

The study identified 10 patients from 6 families with prolonged bleeding time, decreased von Willebrand factor (vWF) ristocetin cofactor activity (RCoF) to vWF:Ag (antigen) ratio, and reduced ristocetin-induced platelet agglutination as well as ristocetin- or botrocetin-induced binding of plasma vWF to platelet glycoprotein Ib (GpIb). In addition, all patients showed a decrease of intermediate-molecular-weight (intermediate-MW) and high-molecular-weight (HMW) multimers of vWF. In the heterozygous state, a cysteine-to-threonine (C → T) transversion was detected at nucleotide 4193 of the VWF gene of all patients and lead to the arginine (R)522C substitution in the A1 loop of vWF mature subunit (R1315C in the preprovWF). By in vitro mutagenesis of full-length complementary DNA (cDNA) of vWF and transient expression in COS-7 cells, the mutated C552 recombinant vWF (C552rvWF) was found to exhibit decreased expression, abnormal folding, and lack of intermediate-MW and HMW multimers. In addition, direct binding of botrocetin to C552rvWF, as well as ristocetin- and botrocetin-induced binding of C552rvWF to GpIb, was markedly decreased. Although being localized in an area of the A1 loop of vWF where most of the type 2B mutations that induce a gain-of-function have been identified, the R552C mutation induces a 2A-like phenotype with a decrease of intermediate-MW and HMW multimers as well as a loss-of-function of vWF in the presence of either ristocetin or botrocetin.
Expression of DNA methyltransferases DNMT1,3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia
Authors: Mizuno Shin-ichi , Chijiwa Takahito , Okamura Takashi , Akashi Koichi , Fukumaki Yasuyuki , Niho Yoshiyuki , Sasaki Hiroyuki
Published: July 2002

Aberrant hypermethylation of tumor suppressor genes plays an important role in the development of many tumors. Recently identified new DNA methyltransferase (DNMT) genes, DNMT3Aand DNMT3B, code for de novo methyltransferases. To determine the roles of DNMT3A, DNMT3B, as well as DNMT1, in the development of leukemia, competitive polymerase chain reaction (PCR) assays were performed and the expression levels of DNMTs were measured in normal hematopoiesis, 33 cases of acute myelogenous leukemia (AML), and 17 cases of chronic myelogenous leukemia (CML). All genes were constitutively expressed, although at different levels, in T lymphocytes, monocytes, neutrophils, and normal bone marrow cells. Interestingly, DNMT3B was expressed at high levels in CD34+ bone marrow cells but down-regulated in differentiated cells. In AML, 5.3-, 4.4-, and 11.7-fold mean increases were seen in the levels of DNMT1, 3A, and3B, respectively, compared with the control bone marrow cells. Although CML cells in the chronic phase did not show significant changes, cells in the acute phase showed 3.2-, 4.5-, and 3.4-fold mean increases in the levels of DNMT1, 3A, and3B, respectively. Using methylation-specific PCR, it was observed that the p15INAK4B gene, a cell cycle regulator, was methylated in 24 of 33 (72%) cases of AML. Furthermore, AML cells with methylatedp15INAK4B tended to express higher levels ofDNMT1 and 3B. In conclusion, DNMTswere substantially overexpressed in leukemia cells in a leukemia type- and stage-specific manner. Up-regulated DNMTs may contribute to the pathogenesis of leukemia by inducing aberrant regional hypermethylation.
Homodimers but not monomers of Rituxan (chimeric anti-CD20) induce apoptosis in human B-lymphoma cells and synergize with a chemotherapeutic agent and an immunotoxin
Authors: Ghetie Maria-Ana , Bright Helen , Vitetta Ellen S.
Published: July 2002

In 1997, a chimeric anti-CD20 monoclonal antibody (mAb) (Rituxan) was approved for the treatment of low-grade/follicular B-cell lymphoma. Rituxan has a long half-life and low immunogenicity, and it mediates effector function. Rituxan induces apoptosis in some tumor cell lines in vitro. Previous studies with mAbs that react with neoplastic B cells have demonstrated that homodimers of immunoglobulin G ([IgG]2) often inhibit cell growth more effectively than their monomeric (IgG)1counterparts. In this study, the ability of IgG or F(ab′)2 homodimers vs monomers of Rituxan were compared for their ability to inhibit the growth of several different B-lymphoma cell lines in vitro. It was found that homodimers of Rituxan had superior antigrowth activity in vitro and that F(ab′)2 homodimers were the most active. Homodimers, but not monomers, of Rituxan induced both apoptosis and necrosis of several B-cell lymphoma lines in vitro; the inhibition of cell growth was not dependent upon the presence of Fc receptors or upon 10-fold or greater differences in the density of CD20 on the target cells. Rituxan homodimers, compared with monomers, also rendered drug-resistant CD20+ B-lymphoma cells more sensitive to chemotherapeutic agents and synergized with an anti-CD22 immunotoxin in vitro.
Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide
Authors: Unnikrishnan Dilip , Dutcher Janice P. , Varshneya Nikita , Lucariello Richard , Api Marietta , Garl Susan , Wiernik Peter H. , Chiaramida Salvatore
Published: July 2002

Arsenic trioxide is used in clinical trials in the treatment of relapsed and resistant cases of acute promyelocytic leukemia. Adverse effects from arsenic in these studies have been multisystemic. Arsenic is known to cause corrected QT-interval prolongation and T-wave changes, but the potential for serious ventricular arrhythmias is less well understood. Torsades de pointes, a form of ventricular tachycardia, has been reported with arsenic poisoning but not at therapeutic doses used in protocols for hematologic malignancies. We describe 3 patients in whom this arrhythmia developed while they were treated with arsenic trioxide. Early recognition of the arrhythmia or correction of contributory factors is important because arsenic induced ventricular arrhythmias are known to be resistant to most chemical methods and electrical cardioversion.
Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo
Authors: Lluı́s Frederic , Roma Josep , Suelves Mònica , Parra Maribel , Aniorte Gloria , Gallardo Eduard , Illa Isabel , Rodrı́guez Luciano , Hughes Simon M. , Carmeliet Peter , Roig Manuel , Muñoz-Cánoves Pura
Published: July 2002

Plasminogen activators urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) are extracellular proteases involved in various tissue remodeling processes. A requirement for uPA activity in skeletal myogenesis was recently demonstrated in vitro. The role of plasminogen activators in skeletal muscle regeneration in vivo in wild-type, uPA-deficient, and tPA-deficient mice is investigated here. Wild-type and tPA−/− mice completely repaired experimentally damaged skeletal muscle. In contrast, uPA−/− mice had a severe regeneration defect, with decreased recruitment of blood-derived monocytes to the site of injury and with persistent myotube degeneration. In addition, uPA-deficient mice accumulated fibrin in the degenerating muscle fibers; however, the defibrinogenation of uPA-deficient mice resulted in a correction of the muscle regeneration defect. A similar severe regeneration deficit with persistent fibrin deposition was also reproducible in plasminogen-deficient mice after injury, suggesting that fibrinolysis by uPA-mediated plasminogen activation plays a fundamental role in skeletal muscle regeneration. In conclusion, the uPA-plasmin system is identified as a critical component of the mammalian skeletal muscle regeneration process, possibly because it prevents intramuscular fibrin accumulation and contributes to the adequate inflammatory response after injury. These studies demonstrate the requirement of an extracellular proteolytic cascade during muscle regeneration in vivo.
Allele-dependent transcriptional regulation of the human integrin α2 gene
Authors: Jacquelin Beatrice , Tarantino Michael D. , Kritzik Marcie , Rozenshteyn Diana , Koziol James A. , Nurden Alan T. , Kunicki Thomas J.
Published: July 2002

Genetically controlled variation in α2β1 expression by human blood platelets was previously described. Sixty-two haplotype sequences corresponding to the proximal 5′ regulatory region (−1096 to +1) of the α2 gene were compared, and a dimorphic sequence −52C>T was identified that is located precisely between 2 tandem Sp1/Sp3 binding elements previously shown to be absolutely required for transcriptional activity of this gene in epithelial cell lines and the erythroleukemic cell line K562. The gene frequency of −52T in a random Caucasian population is approximately 0.35, and the expression of −52T correlates directly with reduced densities of platelet α2β1. In mobility shift analyses, the −52T substitution attenuates complex formation with both Sp1 and Sp3. When transfected into the erythroleukemia cell line Dami, promoter-luciferase constructs bearing the −52T sequence exhibit a 5-fold decrease in activity relative to the −52C construct. In transfected CHRF-288-11 megakaryocytic cells, the corresponding activity decreases by 10-fold. The −52T sequence appears to be in linkage disequilibrium with the previously defined allele A3 (807C; HPA-5b), known to be associated with diminished expression of platelet α2β1. In summary, a natural dimorphism has been identified within the proximal 5′ regulatory region of the human integrin α2 gene that is responsible for decreased expression levels of the integrin α2β1 on blood platelets through a mechanism that is probably mediated by the nuclear regulatory proteins Sp1 and Sp3.
Regulation of nuclear factor of activated T cells by phosphotyrosyl-specific phosphatase activity: a positive effect on HIV-1 long terminal repeat–driven transcription and a possible implication of SHP-1
Authors: Fortin Jean-François , Barbeau Benoit , Robichaud Gilles A. , Paré Marie-Ève , Lemieux Anne-Marie , Tremblay Michel J.
Published: July 2002

Although protein tyrosine phosphatase (PTP) inhibitors used in combination with other stimuli can induce interleukin 2 (IL-2) production in T cells, a direct implication of nuclear factor of activated T cells (NFAT) has not yet been demonstrated. This study reports that exposure of leukemic T cells and human peripheral blood mononuclear cells to bis-peroxovanadium (bpV) PTP inhibitors markedly induce activation and nuclear translocation of NFAT. NFAT activation by bpV was inhibited by the immunosuppressive drugs FK506 and cyclosporin A, as well as by a specific peptide inhibitor of NFAT activation. Mobility shift assays showed specific induction of the NFAT1 member by bpV molecules. The bpV-mediated NFAT activation was observed to be important for the up-regulation of the human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR) and the IL-2 promoter; NFAT1 was demonstrated to be particularly important in bpV-dependent positive action on HIV-1 LTR transcription. The active participation of p56lck, ZAP-70, p21ras, and calcium in the bpV-mediated signaling cascade leading to NFAT activation was confirmed, using deficient cell lines and dominant-negative mutants. Finally, overexpression of wild-type SHP-1 resulted in a greatly diminished activation of NFAT by bpV, suggesting an involvement of SHP-1 in the regulation of NFAT activation. These data were confirmed by constitutive NFAT translocation observed in Jurkat cells stably expressing a dominant-negative version of SHP-1. The study proposes that PTP activity attenuates constitutive kinase activities that otherwise would lead to constant NFAT activation and that this activation is participating in HIV-1 LTR stimulation by PTP inhibition.
Platelet glycoprotein Ibα Kozak polymorphism is associated with an increased risk of ischemic stroke
Authors: Baker Ross I. , Eikelboom John , Lofthouse Elizabeth , Staples Nicole , Afshar-Kharghan Vahid , López José A. , Shen Yang , Berndt Michael C. , Hankey Graeme
Published: July 2002

Platelets are pivotal to the process of arterial thrombosis resulting in ischemic stroke. Occlusive thrombosis is initiated by the interaction of von Willebrand factor (vWf) and platelet glycoprotein (GP) Ibα. Three polymorphisms have been described in GP Ibα (Kozak T/C polymorphism, variable number of tandem repeats [VNTR], and the human platelet antigen 2a [HPA-2a] [Thr] or HPA-2b [Met] at position 145), each of which may enhance the vWf and GP Ibα interaction. This study investigated whether these polymorphisms are candidate genes for first-ever ischemic stroke. A hospital-based case-control study was conducted of 219 cases of first-ever ischemic stroke and 205 community controls randomly selected from the electoral roll and stratified by age, sex, and postal code. The subtypes of stroke were classified, the prevalence of conventional risk factors was recorded, and blood was collected to perform genotyping analysis for Kozak C or T alleles, VNTR, and HPA-2a/b. It was found that the Kozak T/C genotype was over-represented in the stroke group (32.2%) compared with controls (22.8%) (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.03-2.54; P < .03), and the association was still present even after adjusting for conventional risk factors. There was a trend in the increased prevalence of HPA-2a/b in stroke patients (15%) compared with controls (9.9%) (adjusted OR, 1.8; 95% CI, 0.94-3.4; P = .07). No associations were seen with the VNTR polymorphism or with any of the polymorphisms with stroke subtype. It was concluded that the Kozak T/C polymorphism, which is associated with an increase in platelet GP Ibα surface expression, is an independent risk factor for first-ever ischemic stroke.
Tumor necrosis factor-α induces coordinated changes in major histocompatibility class I presentation pathway, resulting in increased stability of class I complexes at the cell surface
Authors: Hallermalm Kristian , Seki Katzutake , Wei Chenhong , Castelli Chiara , Rivoltini Licia , Kiessling Rolf , Levitskaya Jelena
Published: July 2002

It is demonstrated that similar to interferon γ (IFN-γ), tumor necrosis factor-α (TNF-α) induces coordinated changes at different steps of the major histocompatibility complex (MHC) class I processing and presentation pathway in nonprofessional antigen-presenting cells (APCs). TNF-α up-regulates the expression of 3 catalytic immunoproteasome subunits—LMP2, LMP7, and MECL-1—the immunomodulatory proteasome activator PA28α, the TAP1/TAP2 heterodimer, and the total pool of MHC class I heavy chain. It was also found that in TNF-α–treated cells, MHC class I molecules reconstitute more rapidly and have an increased average half-life at the cell surface. Biochemical changes induced by TNF-α in the MHC class I pathway were translated into increased sensitivity of TNF-α–treated targets to lysis by CD8+ cytotoxic T cells, demonstrating improved presentation of at least certain endogenously processed MHC class I–restricted peptide epitopes. Significantly, it was demonstrated that the effects of TNF-α observed in this experimental system were not mediated through the induction of IFN-γ. It appears to be likely that TNF-α–mediated effects on MHC class I processing and presentation do not involve any intermediate messengers. Collectively, these data demonstrate the existence of yet another biologic activity exerted by TNF-α, namely its capacity to act as a coordinated multi-step modulator of the MHC class I pathway of antigen processing and presentation. These results suggest that TNF-α may be useful when a concerted up-regulation of the MHC class I presentation machinery is required but cannot be achieved by IFN-γ.
Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults
Authors: Hochberg Ephraim P. , Chillemi Antoinette C. , Wu Catherine J. , Neuberg Donna , Canning Christine , Hartman Kelly , Alyea Edwin P. , Soiffer Robert J. , Kalams Spyros A. , Ritz Jerome
Published: July 2002

Following myeloablative therapy, it is unknown to what extent age-dependent thymic involution limits the generation of new T cells with a diverse repertoire. Normal T-cell receptor gene rearrangement in T-cell progenitors results in the generation of T-cell receptor rearrangement excision circles (TRECs). In this study, a quantitative assay for TRECs was used to measure T-cell neogenesis in adult patients with leukemia who received myeloablative therapy followed by transplantation of allogeneic hematopoietic stem cells. Although phenotypically mature T cells had recovered by 1 to 2 months after bone marrow transplantation (BMT), TREC levels remained low for 3 months after BMT. T-cell neogenesis became evident by 6 months, and normal levels of adult thymic function were restored at 6 to 12 months after BMT. Subsequent leukemia relapse in some patients was associated with reduced TREC levels, but infusion of mature donor CD4+ T cells resulted in rapid restoration of thymic function. These studies demonstrate that T-cell neogenesis contributes to immune reconstitution in adult patients and suggest that thymic function can be manipulated in vivo.
P-selectin mediates the adhesion of sickle erythrocytes to the endothelium
Authors: Matsui Neil M. , Borsig Lubor , Rosen Steven D. , Yaghmai Mitra , Varki Ajit , Embury Stephen H.
Published: July 2002

The adherence of sickle red blood cells (RBCs) to the vascular endothelium may contribute to painful vaso-occlusion in sickle cell disease. Sickle cell adherence involves several receptor-mediated processes and may be potentiated by the up-regulated expression of adhesion molecules on activated endothelial cells. Recent results showed that thrombin rapidly increases the adhesivity of endothelial cells for sickle erythrocytes. The current report presents the first evidence for the novel adhesion of normal and, to a greater extent, sickle RBCs to endothelial P-selectin. Studies of the possible interaction of erythrocytes with P-selectin revealed that either P-selectin blocking monoclonal antibodies or sialyl Lewis tetrasaccharide inhibits the enhanced adherence of normal and sickle cells to thrombin-treated endothelial cells. Both RBC types also adhere to immobilized recombinant P-selectin. Pretreating erythrocytes with sialidase reduces their adherence to activated endothelial cells and to immobilized recombinant P-selectin. Herein the first evidence is presented for the binding of normal or sickle erythrocytes to P-selectin. This novel finding suggests that P-selectin inhibition be considered as a potential approach to therapy for the treatment of painful vaso-occlusion in sickle cell disease.
Interleukin-5 inhibits translocation of Bax to the mitochondria, cytochrome c release, and activation of caspases in human eosinophils
Authors: Dewson Grant , Cohen Gerald M. , Wardlaw Andrew J.
Published: July 2002

The apoptosis and subsequent clearance of eosinophils without histotoxic mediator release is thought to be crucial in the resolution of airway inflammation in asthma. Interleukin-5 (IL-5) is a potent suppressor of eosinophil apoptosis. The mechanism by which IL-5 inhibits spontaneous eosinophil apoptosis was investigated. Freshly isolated eosinophils constitutively expressed the conformationally active form of Bax in the cytosol and nucleus. During spontaneous and staurosporine-induced apoptosis, Bax underwent a caspase-independent translocation to the mitochondria, which was inhibited by IL-5. Eosinophil apoptosis was associated with the release of cytochrome c from the mitochondria, which was also inhibited by IL-5. IL-5 and the cell-permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone (z-VAD.fmk), prevented phosphatidylserine (PS) externalization, although only IL-5 inhibited loss of mitochondrial membrane potential (ΔΨm). Peripheral blood eosinophils endogenously expressed “initiator” caspase-8 and -9, and “effector” caspase-3, -6, and -7. Spontaneous eosinophil apoptosis was associated with processing of caspase-3, -6, -7, -8, and -9. IL-5 and z-VAD.fmk prevented caspase activation in spontaneous apoptosis. The results suggest that spontaneous eosinophil apoptosis involves Bax translocation to the mitochondria, cytochrome crelease, caspase-independent perturbation of the mitochondrial membrane, and subsequent activation of caspases. IL-5 inhibits spontaneous eosinophil apoptosis at a site upstream of Bax translocation.
Blood coagulation at the site of microvascular injury: effects of low-dose aspirin
Authors: Undas Anetta , Brummel Kathleen , Musial Jacek , Mann Kenneth G. , Szczeklik Andrew
Published: July 2002

The sequence of coagulant reactions in vivo following vascular injury is poorly characterized. Using quantitative immunoassays, the time courses were evaluated for activation of prothrombin, factor (F)V, FXIII, fibrinogen (Fbg) cleavage, and FVa inactivation in bleeding-time blood collected at 30-second intervals from 12 healthy subjects both before and after aspirin ingestion. Prothrombin decreased at a maximum rate of 14.2 ± 0.6 nM per second to 10% of initial values at the end of bleeding. Significant amounts of α-thrombin B chain appeared rapidly at 90 seconds of bleeding and increased at a maximum rate of 0.224 ± 0.03 nM per second to a peak value of 38 nM. Kinetics of prethrombin 2 generation was almost identical. Prothrombinase concentration reached a peak value of 22 pM at 150 seconds and then decreased to 9 pM at the end of bleeding. Prothrombin fragment 1.2 (F1.2) was produced explosively (0.673 ± 0.05 nM per second), whereas thrombin-antithrombin III (TAT) complexes were generated at a much slower rate (0.11 ± 0.008 nM per second;P = .002). FVa light chain was detectable 30 seconds later than the heavy chain (150 seconds) and was produced at a slightly slower rate (0.027 ± 0.001 nM per second) when compared with the heavy chain (0.032 ± 0.002 nM per second; P = .041). The 30 000 fragment (residues 307-506) of FVa heavy chain produced by activated protein C appeared as early as at 90 seconds and increased with time. Fbg was removed from the blood shed with a high rate of 0.047 ± 0.02 μM/s and became undetectable at approximately 180 seconds of bleeding. The velocity of FXIII activation correlated with thrombin B-chain formation. A 7-day aspirin administration (75 mg/d) resulted in significant reductions in maximum rates of (1) prothrombin removal (by 29%; P = .008); generation of α-thrombin B-chain (by 27.2%; P = .022), and prethrombin 2 (by 26%; P = .014); formation of F1.2 (by 31.4%;P = .009) and TAT (by 30.3%; P = 0.013); (2) release of FVa heavy chain (by 25%; P = .003) and FVa light chain (by 29.6%; P = .007); (3) Fbg depletion from solution (by 30.5%; P = .002); and (4) FXIII activation (by 28.6%; P = .003). Total amounts of the proteins studied, collected at every interval, also significantly decreased following aspirin ingestion. These results indicate that low-dose aspirin impairs thrombin generation and reactions catalyzed by this enzyme at the site of the injury.
Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells
Authors: Reyes Morayma , Lund Troy , Lenvik Todd , Aguiar Dean , Koodie Lisa , Verfaillie Catherine M.
Published: July 2002

It is here reported that mesenchymal stem cells known to give rise to limb-bud mesoderm can, at the single-cell level, also differentiate into cells of visceral mesoderm and can be expanded extensively by means of clinically applicable methods. These cells were named mesodermal progenitor cells (MPCs). MPCs were selected by depleting bone marrow mononuclear cells from more than 30 healthy human donors of CD45+/glycophorin-A (GlyA)+ cells. Cells were cultured on fibronectin with epidermal growth factor and platelet-derived growth factor BB and 2% or less fetal calf serum. It was found that 1/5 × 103CD45−GlyA− cells, or 1/106 bone marrow mononuclear cells, gave rise to clusters of small adherent cells. Cell-doubling time was 48 to 72 hours, and cells have been expanded in culture for more than 60 cell doublings. MPCs are CD34−, CD44low, CD45−, CD117 (cKit)−, class I–HLA−, and HLA-DR−. MPCs differentiated into cells of limb-bud mesoderm (osteoblasts, chondrocytes, adipocytes, stroma cells, and skeletal myoblasts) as well as visceral mesoderm (endothelial cells). Retroviral marking was used to definitively prove that single MPCs can differentiate into cells of limb bud and visceral mesoderm. Thus, MPCs that proliferate without obvious senescence under clinically applicable conditions and differentiate at the single-cell level not only into mesenchymal cells but also cells of visceral mesoderm may be an ideal source of stem cells for treatment of genetic or degenerative disorders affecting cells of mesodermal origin.