bluuebunny/crossref_metadata_2025 huggingface dataset:
US National Longitudinal Lesbian Family Study: Psychological Adjustment of 17-Year-Old Adolescents
Authors: Gartrell Nanette , Bos Henny
Published: June 2010

OBJECTIVES:

The objective of this study was to document the psychological adjustment of adolescents who were conceived through donor insemination by lesbian mothers who enrolled before these offspring were born in the largest, longest running, prospective, longitudinal study of same-sex–parented families.

METHODS:

Between 1986 and 1992, 154 prospective lesbian mothers volunteered for a study that was designed to follow planned lesbian families from the index children's conception until they reached adulthood. Data for the current report were gathered through interviews and questionnaires that were completed by 78 index offspring when they were 10 and 17 years old and through interviews and Child Behavior Checklists that were completed by their mothers at corresponding times. The study is ongoing, with a 93% retention rate to date.

RESULTS:

According to their mothers' reports, the 17-year-old daughters and sons of lesbian mothers were rated significantly higher in social, school/academic, and total competence and significantly lower in social problems, rule-breaking, aggressive, and externalizing problem behavior than their age-matched counterparts in Achenbach's normative sample of American youth. Within the lesbian family sample, no Child Behavior Checklist differences were found among adolescent offspring who were conceived by known, as-yet-unknown, and permanently unknown donors or between offspring whose mothers were still together and offspring whose mothers had separated.

CONCLUSIONS:

Adolescents who have been reared in lesbian-mother families since birth demonstrate healthy psychological adjustment. These findings have implications for the clinical care of adolescents and for pediatricians who are consulted on matters that pertain to same-sex parenting.
Ações judiciais: estratégia da indústria farmacêutica para introdução de novos medicamentos
Authors: Chieffi Ana Luiza , Barata Rita de Cássia Barradas
Published: June 2010

OBJETIVO: Analisar a concentração na distribuição dos processos judiciais segundo medicamento (fabricante), médico prescritor e advogado impetrante da ação. MÉTODOS: Estudo descritivo que analisou processos judiciais cadastrados em sistema de controle judicial do Estado de São Paulo, em 2006, gastos realizados com o atendimento às ações judiciais e gastos totais de medicamentos. RESULTADOS: Em 2006, foram gastos 65 milhões de reais pelo estado de São Paulo com o cumprimento das decisões judiciais para atender a cerca de 3.600 pessoas. O gasto total em medicamentos foi de 1,2 bilhão de reais. No período estudado foram analisadas 2.927 ações, que foram ajuizadas por 565 agentes, dos quais 549 eram advogados particulares (97,2% do total de agentes). Os medicamentos solicitados nas demandas judiciais analisadas foram prescritos por 878 médicos diferentes. Ao analisar o número de ações ajuizadas por advogado, observa-se que 35% das ações foram apresentadas por 1% dos advogados. CONCLUSÕES: Os dados das ações com os medicamentos classificados pelo seu fabricante mostram que poucos advogados são responsáveis pela maioria das demandas judiciais desses medicamentos. A observação de que mais de 70% das ações ajuizadas para certos medicamentos são de responsabilidade de um advogado pode sugerir uma relação estreita entre o advogado e o fabricante do medicamento.
Iniciativa STROBE: subsídios para a comunicação de estudos observacionais
Authors: Malta Monica , Cardoso Leticia Oliveira , Bastos Francisco Inacio , Magnanini Monica Maria Ferreira , Silva Cosme Marcelo Furtado Passos da
Published: June 2010

Freqüentemente, a descrição de pesquisas de natureza observacional é inadequada, dificultando a avaliação de seus pontos fracos e fortes e, em conseqüência, a generalização de seus resultados. A iniciativa denominada Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), formulou uma lista de verificação que contém 22 itens, denominada STROBE Statement ("Declaração STROBE"), com recomendações sobre o que deveria ser incluído em uma descrição mais precisa e completa de estudos observacionais. Entre junho e dezembro de 2008, um grupo de pesquisadores brasileiros dedicou-se à tradução e adaptação da "Declaração STROBE" para o português. O objetivo do estudo foi apresentar a tradução para o português, bem como introduzir a discussão sobre o contexto de utilização, as potencialidades e limitações da Iniciativa STROBE.
The Next Public Health Revolution: Public Health Information Fusion and Social Networks
Authors: Khan Ali S. , Fleischauer Aaron , Casani Julie , Groseclose Samuel L.
Published: June 2010

Social, political, and economic disruptions caused by natural and human-caused public health emergencies have catalyzed public health efforts to expand the scope of biosurveillance and increase the timeliness, quality, and comprehensiveness of disease detection, alerting, response, and prediction. Unfortunately, efforts to acquire, render, and visualize the diversity of health intelligence information are hindered by its wide distribution across disparate fields, multiple levels of government, and the complex interagency environment. Achieving this new level of situation awareness within public health will require a fundamental cultural shift in methods of acquiring, analyzing, and disseminating information. The notion of information “fusion” may provide opportunities to expand data access, analysis, and information exchange to better inform public health action.
QoS testing in a live private IP MPLS network with CoS implemented
Authors: Bojovic Zivko , Secerov Emil , Delic Vlado
Published: June 2010

This paper describes a testing conducted on a private IP/MPLS network of a Telecom operator during service introduction. We have applied DiffServ and E-LSP policies for bandwidth allocation for predefined classes of service (voice, video, data and VPN). We used a traffic generator to create the worst possible situations during the testing, and measured QoS for individual services. UML considerations about NGN structure and packet networks traffic testing are also presented using the deployment, class and state diagrams. Testing results are given in tabular and graphical forms, and the conclusions derived will be subsequently used as a basis for defining the stochastic traffic generator/simulator.
Distributed parameter tuning for genetic algorithms
Authors: Barrero David , González-Pardo Antonio , Camacho David , R-Moreno María
Published: June 2010

Genetic Algorithms (GA) is a family of search algorithms based on the mechanics of natural selection and biological evolution. They are able to efficiently exploit historical information in the evolution process to look for optimal solutions or approximate them for a given problem, achieving excellent performance in optimization problems that involve a large set of dependent variables. Despite the excellent results of GAs, their use may generate new problems. One of them is how to provide a good fitting in the usually large number of parameters that must be tuned to allow a good performance. This paper describes a new platform that is able to extract the Regular Expression that matches a set of examples, using a supervised learning and agent-based framework. In order to do that, GA-based agents decompose the GA execution in a distributed sequence of operations performed by them. The platform has been applied to Language induction problem, for that reason the experiments are focused on the extraction of the regular expression that matches a set of examples. Finally, the paper shows the efficiency of the proposed platform (in terms of fitness value) applied to three case studies: emails, phone numbers and URLs. Moreover, it is described how the codification of the alphabet affects to the performance of the platform.
The Dialogical Self: Research and Applications
Authors: Batory Anna , Bąk Wacław , Oleś Piotr , Puchalska-Wasyl Małgorzata
Published: June 2010

The Dialogical Self: Research and Applications

The paper presents dialogical self theory and its current theoretical and empirical status. We start with some inspirations from philosophy and literature and then describe the main thesis of the theory - self-multiplicity conceptualized in terms of I-positions and the dynamic relations between them. In the next section we present examples of empirical explorations of inner dialogical activity. Although dialogical self theory is generally perceived as a qualitative approach, there is a growing number of quantitative studies conducted both in correlational and experimental designs. Moreover, numerous interesting and promising topics are still open for further research - e.g. temporal dialogues, dialogical interpretations of personal identity, values and valuation, relations between self and culture. After reviewing these empirical results we try to explore the relations between the dialogical and the cognitive approach to self-multiplicity. We propose that those two approaches can be seen as complementary rather than competing. The last section discusses some practical implications of dialogical self theory for psychotherapy and counseling.
Environmental Responsibility: Teachers' Views
Authors: Manolas Evangelos , Tampakis Stilianos
Published: June 2010

Environmental Responsibility: Teachers' Views

This research paper investigates the views of the teachers of elementary and secondary schools in Greece with regard to who bears the responsibility for the state of the environment, as well as who should bear the cost of its protection. The research was carried out at the Environmental Education Centre of Kissavos-Mavrovounio. The research subjects were 144 teachers undergoing training in environmental education. The teachers believe that today the quality of both the natural and the urban environments worsens with those most responsible, in order of importance, being the industrialists and businesses, public administration and control mechanisms, politicians and laws, the citizens as consumers, judges and the judicial system and the farmers as producers. According to the respondents, the parties less responsible are the journalists and the mass media, researchers and scientists and, finally, teachers and the educational system in general. With regard to who should bear the cost of environmental protection, the vast majority think that the government should be the one to pay. The ideas of indirect and direct taxation, the adoption of a lower standard of living are much less accepted.
Sustainable Leadership of Senior Students: The Case Study of Madeira
Authors: Bento António , Ribeiro Isabel
Published: June 2010

Sustainable Leadership of Senior Students: The Case Study of Madeira

Secondary education plays a key role in developing sustainable leadership skills in students. This research analyses the characteristics of sustainable leadership of students at 2 secondary schools in Madeira Island (Portugal) in order to determine whether the type of school or gender of the students affect eight distinct domains: 1) self management; 2) interpersonal relations; 3) problem solving/decision making; 4) cognitive critical development/analysis; 5) organization and planning; 6) self-confidence; 7) diversity awareness; 8) technology. The Student Leadership Outcomes Inventory (SLOI) (Vann, 2000) was used to measure the leadership experiences of 158 senior students in these eight areas. Participants revealed moderate levels of sustainable leadership in the eight sub-scales. The findings show that students of Madeira Island who finish secondary education possess several well-developed sustainable leadership skills.
2010
Authors: Gedžūne Ginta , Gedžūne Inga
Published: June 2010

2010

This study explores pre-service teachers' views on the features and causes of social exclusion in the context of educational unsustainability. The data from expert questionnaires, assessment of research participants' personal experience with social exclusion in educational setting, their current understanding of the problem and individual suggestions for solving it were analysed qualitatively. The results indicate that, in teachers' opinion, social exclusion in education can be caused by subjective and objective factors – pupils' personal characteristics, school climate, parental influence and social causes. The research participants particularly emphasise teacher's role in reducing pupils' social exclusion by adhering to values, such as fairness, equality, empathy, cooperation and respect. The research results highlight the need for addressing the issue of social exclusion in teacher education programmes by raising future teachers' awareness of the problem and their responsibility to overcome it.
Foreign Direct Investment in the New European Union Member States and Developing Countries of Asia under Conditions of the Global Financial and Economic Crisis: Comparative Aspects
Authors: Witkowska Janina
Published: June 2010

The objective of this article is a comparative analysis of the changing position of new European Union member states and the developing countries of Asia in global and regional FDI flows as well as an assessment of the impact of the global crisis on the position of these regions and selected countries in terms of FDI. The analysis encompasses European Union member states that received membership as a part of the enlargement of 2004 and 2007 as well as the developing sub–regions of Asia—i.e. East, South-East, and South Asia. The conducted analysis demonstrates that the position of the developing countries of Asia is significantly stronger than that of the new European Union member states, which is mainly determined by the scale of the economies of countries such as China and India. Subject to conditions of global crisis, Asia and Oceania as a whole noted growth in the inflow of FDI in 2008 by almost 17%, where the European Union member states saw a 2% fall. The situation inside the analyzed regions is extremely varied in terms of noticeable effects of the crisis in the FDI sphere. It is dependent on not only processes of economic growth, but also on the character of investments made in the individual countries and sub– regions as well as motives behind the actions of investors.
The Development of Gender Achievement Gaps in Mathematics and Reading During Elementary and Middle School
Authors: Robinson Joseph Paul , Lubienski Sarah Theule
Published: June 2010

Using K–8 national longitudinal data, the authors investigate males’ and females’ achievement in math and reading, including when gender gaps first appear, whether the appearance of gaps depends on the metric used, and where on the achievement distribution gaps are most prevalent. Additionally, teachers’ assessments of males and females are compared. The authors find no math gender gap in kindergarten, except at the top of the distribution; however, females throughout the distribution lose ground in elementary school and regain some in middle school. In reading, gaps favoring females generally narrow but widen among low-achieving students. However, teachers consistently rate females higher than males in both subjects, even when cognitive assessments suggest that males have an advantage. Implications for policy and further research are discussed.
Extended Time Testing Accommodations for Students With Disabilities
Authors: Lovett Benjamin J.
Published: June 2010

Extended time is one of the most common testing accommodations provided to students with disabilities. It is also controversial; critics of extended time accommodations argue that extended time is used too readily, without concern for how it changes the skills measured by tests, leading to scores that cannot be compared fairly with those of other students. Advocates argue, instead, that many students with disabilities are only able to demonstrate their skills with extended time. This article reviews a wide variety of empirical evidence to draw conclusions about the appropriateness of extended time accommodations. The evidence reviewed raises concerns with the way that extended time accommodations are currently provided, although the same literature also points to potential solutions and best practices.
Trends in pregnancy outcomes in Malawian adolescents receiving antimalarial and hematinic supplements
Authors: MSYAMBOZA KELIAS , SAVAGE EMMA , KALANDA GERTRUDE , KAZEMBE PETER , GIES SABINE , D'ALESSANDRO UMBERTO , BRABIN BERNARD J.
Published: June 2010

Objective. To describe pregnancy outcomes of adolescent and adult primigravidae receiving antimalarials and hematinic supplementation and compare findings with a survey in this area a decade earlier. Design. Cross‐sectional surveys in intervention and control sites. Setting. Community, antenatal and delivery facilities in Chikwawa, Malawi. A rural area with year round malaria transmission. Methods. Data on antenatal attendance, uptake of intermittent preventive treatment with sulfadoxine‐pyrimethamine (IPTp‐SP), birthweight, malaria, anaemia, for 2,152 primigravidae. Outcome measures. Place of delivery, anaemia, malaria, birthweight. Results. Fewer adolescent than adult primigravidae received ≥2 IPTp‐SP doses (66 vs. 77.2%, p < 0.001), although more attended for two or more antenatal visits (92.0 vs. 76.7%, p < 0.001). Only 24.1% of adolescent primigravidae attended for hospital delivery. Women resident in intervention sites receiving IPTp‐SP community distribution were more likely to choose a community delivery (p < 0.01), and have higher uptake of IPTp‐SP (p = 0.036) than women not resident in these villages. Postnatal malaria prevalence was low and did not differ by age or place of delivery. Postnatal anaemia and low birthweight prevalence were higher in adolescents with community deliveries. Maternal anaemia and low birthweight prevalence were lower amongst adolescents in this study compared to estimates from the same population a decade previously. Conclusions. Adolescents had higher anaemia risk, lower IPTp‐SP uptake than adults and under a quarter had a hospital delivery. Pregnancy outcomes improved compared to the survey a decade earlier. Monitoring and surveillance is required to reinforce to policy makers the need to improve adolescent coverage for available interventions.
Gendered Treatment: Girls and Treatment Orders in Bail Court
Authors: Sprott Jane B. , Doob Anthony N.
Published: June 2010

Historically, girls, more so than boys, have been the recipients of rehabilitative efforts within the youth justice system. While the rehabilitative focus of youth justice legislation has diminished over the decades, there is still concern that girls may be more likely than boys to be recipients of treatment-based responses. We investigated this at the pre-trial stage, examining bail conditions placed on youths. Examining a sample of bail cases from a large youth court in Toronto, extending from April 2003 through to December 2008, we found that girls were significantly more likely than boys to be given a condition of attending a “treatment program,” especially if the offence was a minor non-violent offence. While the Youth Criminal Justice Act (YCJA) is very clear that youths cannot be detained or sentenced to custody for child welfare reasons (ss. 29 and 39(5)), there is nothing that explicitly prohibits the imposition of “rehabilitative” bail conditions. While the paternalistic treatment/rehabilitation efforts from earlier in the twentieth century may have faded considerably ( Sprott and Doob 2009 ), they appear to cast a long shadow, especially over girls in the bail process.
Inflammatory Genetic Markers of Prostate Cancer Risk
Authors: Tindall Elizabeth A. , Hayes Vanessa M. , Petersen Desiree C.
Published: June 2010

Prostate cancer is the most common cancer in Western society males, with incidence rates predicted to rise with global aging. Etiology of prostate cancer is however poorly understood, while current diagnostic tools can be invasive (digital rectal exam or biopsy) and/or lack specificity for the disease (prostate-specific antigen (PSA) testing). Substantial histological, epidemiological and molecular genetic evidence indicates that inflammation is important in prostate cancer pathogenesis. In this review, we summarize the current status of inflammatory genetic markers influencing susceptibility to prostate cancer. The focus will be on inflammatory cytokines regulating T-helper cell and chemokine homeostasis, together with the Toll-like receptors as key players in the host innate immune system. Although association studies indicating a genetic basis for prostate cancer are presently limited mainly due to lack of replication, larger and more ethnically and clinically defined study populations may help elucidate the true contribution of inflammatory gene variants to prostate cancer risk.
New Laser Fusion and Its Gain by Intense Laser
Authors: Imasaki Kazuo , Li Dazhi
Published: June 2010

The feasibility of a new approach of laser fusion in plasma without implosion has been proposed and is discussed using an intense laser. The cross section of the nuclear reaction is increased by enhancing the penetrability of nuclei through the Coulomb barrier. In this approach, an intense laser field of more than 100 PW was required to distort the Coulomb barrier to obtain enough penetrability. An energy gain even with Deuterium-Deuterium (D-D) reaction can be obtained using this scheme in Deuterium plasma. A reactor with neutron and direct conversion of charged particle beam individually is proposed. Charged particles from D-D reaction are guided to the end of the reactor and are directly converted by a MHD scheme into electric energy. The energy recovery rate is high and requires a small amount of laser energy, which may make the energy cost cheaper than that of a fission reactor.
3-Hydroxy-4-{[(4-methoxyphenyl)imino]methyl}phenyl Octadecanoate
Authors: Ha Sie-Tiong , Beh Jun-Kit , Foo Kok-Leei , Koh Teck-Ming , Ong Siew-Teng
Published: June 2010

A new Schiff base ester, 3-hydroxy-4-{[(4-methoxyphenyl)imino]methyl}phenyl octadecanoate, was synthesized and its IR, 1H NMR, 13C NMR and MS spectroscopic data are presented.
Real-Time Plasma Process Condition Sensing and Abnormal Process Detection
Authors: Yang Ryan , Chen Rongshun
Published: June 2010

The plasma process is often used in the fabrication of semiconductor wafers. However, due to the lack of real-time etching control, this may result in some unacceptable process performances and thus leads to significant waste and lower wafer yield. In order to maximize the product wafer yield, a timely and accurately process fault or abnormal detection in a plasma reactor is needed. Optical emission spectroscopy (OES) is one of the most frequently used metrologies in in-situ process monitoring. Even though OES has the advantage of non-invasiveness, it is required to provide a huge amount of information. As a result, the data analysis of OES becomes a big challenge. To accomplish real-time detection, this work employed the sigma matching method technique, which is the time series of OES full spectrum intensity. First, the response model of a healthy plasma spectrum was developed. Then, we defined a matching rate as an indictor for comparing the difference between the tested wafers response and the health sigma model. The experimental results showed that this proposal method can detect process faults in real-time, even in plasma etching tools.
Windows on the Human Body – in Vivo High-Field Magnetic Resonance Research and Applications in Medicine and Psychology
Authors: Moser Ewald , Meyerspeer Martin , Fischmeister Florian Ph. S. , Grabner Günther , Bauer Herbert , Trattnig Siegfried
Published: June 2010

Analogous to the evolution of biological sensor-systems, the progress in “medical sensor-systems”, i.e., diagnostic procedures, is paradigmatically described. Outstanding highlights of this progress are magnetic resonance imaging (MRI) and spectroscopy (MRS), which enable non-invasive, in vivo acquisition of morphological, functional, and metabolic information from the human body with unsurpassed quality. Recent achievements in high and ultra-high field MR (at 3 and 7 Tesla) are described, and representative research applications in Medicine and Psychology in Austria are discussed. Finally, an overview of current and prospective research in multi-modal imaging, potential clinical applications, as well as current limitations and challenges is given.
Enzymatic Determination of Diglyceride Using an Iridium Nano-Particle Based Single Use, Disposable Biosensor
Authors: Hsu Shu-Yi , Bartling Brandon , Wang Christina , Shieu Fuh-Sheng , Liu Chung-Chiun
Published: June 2010

A single use, disposable iridium-nano particle contained biosensor had been developed for the determination of diglyceride (DG). In this study hydrogen peroxide, formed through the enzymatic breakdown of DG via lipase, glycerol kinase and glycerol 3-phosphate oxidase, was electrochemically oxidized at an applied potential of +0.5 V versus the Ag/AgCl reference electrode. The oxidation current was then used to quantify the diglyceride concentration. Optimum enzyme concentrations and the surfactant loading used were established for successful sensor response. Good linear performance was observed over a DG concentration range of 0 to 25 µM in phosphate buffer and bovine serum media.
T Cell and APC Dynamics In Situ Control the Outcome of Vaccination
Authors: Khanna Kamal M. , Blair David A. , Vella Anthony T. , McSorley Stephen J. , Datta Sandip K. , Lefrançois Leo
Published: June 2010

The factors controlling the progression of an immune response to generation of protective memory are poorly understood. We compared the in situ and ex vivo characteristics of CD8 T cells responding to different forms of the same immunogen. Immunization with live Listeria monocytogenes, irradiated L. monocytogenes (IRL), or heat-killed L. monocytogenes (HKL) induced rapid activation of CD8 T cells. However, only IRL and live L. monocytogenes inoculation induced sustained proliferation and supported memory development. Gene and protein expression analysis revealed that the three forms of immunization led to three distinct transcriptional and translational programs. Prior to cell division, CD8 T cell–dendritic cell clusters formed in the spleen after live L. monocytogenes and IRL but not after HKL immunization. Furthermore, HKL immunization induced rapid remodeling of splenic architecture, including loss of marginal zone macrophages, which resulted in impaired bacterial clearance. These results identify initial characteristics of a protective T cell response that have implications for the development of more effective vaccination strategies.
The Overexpression of Heparin-Binding Epidermal Growth Factor Is Responsible for Th17-Induced Airway Remodeling in an Experimental Asthma Model
Authors: Wang Qing , Li Hequan , Yao Yinan , Xia Dajing , Zhou Jianying
Published: June 2010

Th17 cells that produce IL-17 have been found to participate in the development of allergy-triggered asthma. However, whether they play a causative role in the pathogenesis of airway remodeling in chronic asthma remains unclear. In this study, we investigated the role of Th17 cells in airway remodeling and the possible involvement of epidermal growth factor (EGF) receptor signals downstream of Th17. We established a C57BL/6 mouse model of prolonged allergen challenge that exhibits many characteristics of airway remodeling. Prolonged allergen challenge induced a progressive increase in the number of airway-infiltrating Th17 cells, and Th17 counts positively correlated with the severity of airway remodeling. Increases in mucus production, airway smooth muscle (ASM) mass, peribronchial collagen deposition, and airway heparin-binding EGF (HB-EGF) expression have been observed in sensitized mice following prolonged allergen exposure or adoptive Th17 transfer; remarkably, these effects can be abrogated by treatment with anti–IL-17 mAb. Both the EFGR inhibitor AG1478 and an anti–HB-EGF mAb ameliorated all of these effects, except for peribronchial collagen deposition in the presence of high levels of IL-17. In vitro, Th17 cells enhanced the airway epithelial expression of HB-EGF in a coculture of the two cells. The conditioned medium obtained from this coculture system effectively promoted ASM proliferation; this response was dramatically abolished by anti–HB-EGF mAb but not Abs against other EGF receptor ligands or IL-17. These observations demonstrated that overexpression of airway HB-EGF induced by IL-17 secreted from redundant expanding Th17 cells might contribute to excessive mucus expression and ASM proliferation in chronic asthma.
Mouse Mast Cell Protease-4 Deteriorates Renal Function by Contributing to Inflammation and Fibrosis in Immune Complex-Mediated Glomerulonephritis
Authors: Scandiuzzi Lisa , Beghdadi Walid , Daugas Eric , Åbrink Magnus , Tiwari Neeraj , Brochetta Cristiana , Claver Julien , Arouche Nassim , Zang Xingxing , Pretolani Marina , Monteiro Renato C. , Pejler Gunnar , Blank Ulrich
Published: June 2010

Mast cells exert protective effects in experimental antiglomerular basement membrane-induced glomerulonephritis (GN), yet the responsible mediators have not been identified. In this study, we investigated the role of mouse mast cell protease (mMCP)-4, the functional homolog of human chymase, using mMCP-4–deficient mice. Compared with wild type animals, mMCP-4–deficient mice exhibited lower proteinuria, blood creatinine, and blood urea nitrogen levels, indicating an aggravating role of mMCP-4. Kidney histology confirmed less severe renal damage in mMCP-4–deficient mice with reduced deposits, glomerular and interstitial cellularity, and fibrosis scores. High amounts of mMCP-4 were detected in renal capsules, but not in the whole kidney, from wild type mice. Its expression in renal capsules was markedly decreased after GN induction, suggesting that locally released enzyme by degranulated mast cells could contribute to the functional and physiopathological hallmarks of GN. Supporting a proinflammatory role, glomerular and interstitial macrophage and T cell infiltration, levels of proinflammatory TNF and MCP-1 mRNA, and the expression of the profibrotic peptide angiotensin II together with type I collagen were markedly downregulated in kidneys of mMCP-4−deficient mice. We conclude that mMCP-4 chymase, contrary to the global anti-inflammatory action of mast cells, aggravates GN by promoting kidney inflammation. These results highlight the complexity of mast cell-mediated inflammatory actions and suggest that chymase inhibition may represent a novel therapeutic target in GN.
Slam Haplotypes Modulate the Response to Lipopolysaccharide In Vivo through Control of NKT Cell Number and Function
Authors: Aktan Idil , Chant Alan , Borg Zachary D. , Damby David E. , Leenstra Paige C. , Lilley Graham W. G. , Petty Joseph , Suratt Benjamin T. , Teuscher Cory , Wakeland Edward K. , Poynter Matthew E. , Boyson Jonathan E.
Published: June 2010

CD1d-restricted NKT cells make up an innate-like T cell subset that plays a role in amplifying the response of innate immune leukocytes to TLR ligands. The Slam locus contains genes that have been implicated in innate and adaptive immune responses. In this study, we demonstrate that divergent Slam locus haplotypes modulate the response of macrophages to the TLR4 ligand LPS through their control of NKT cell number and function. In response to LPS challenge in vivo, macrophage TNF production in Slam haplotype-2+ 129S1/SvImJ and 129X1/SvJ mice was significantly impaired in comparison with macrophage TNF production in Slam haplotype-1+ C57BL/6J mice. Although no cell-intrinsic differences in macrophage responses to LPS were observed between strains, 129 mice were found to be deficient in liver NKT cell number, in NKT cell cytokine production in response to the CD1d ligand α-galactosylceramide, and in NKT cell IFN-γ production after LPS challenge in vivo. Using B6.129c1 congenic mice and adoptive transfer, we found that divergent Slam haplotypes controlled the response to LPS in vivo, as well as the diminished NKT cell number and function, and that these phenotypes were associated with differential expression of signaling lymphocytic activation molecule family receptors on NKT cells. These data suggest that the polymorphisms that distinguish two Slam haplotypes significantly modulate the innate immune response in vivo through their effect on NKT cells.
Conformation-Dependent High-Affinity Monoclonal Antibodies to Prion Proteins
Authors: Stanker Larry H. , Serban Ana V. , Cleveland Elisa , Hnasko Robert , Lemus Azucena , Safar Jiri , DeArmond Stephen J. , Prusiner Stanley B.
Published: June 2010

Prion diseases are fatal, neurodegenerative illnesses caused by the accumulation of PrPSc, an aberrantly folded isoform of the normal, cellular prion protein. Detection of PrPSc commonly relies on immunochemical methods, a strategy hampered by the lack of Abs specific for this disease-causing isoform. In this article, we report the generation of eight mAbs against prion protein (PrP) following immunization of Prnp-null mice with rPrP. The eight mAbs exhibited distinct differential binding to cellular prion protein and PrPSc from different species as well as PrP-derived synthetic peptides. Five of the eight mAbs exhibited binding to discontinuous PrP epitopes, all of which were disrupted by the addition of 2-ME or DTT, which reduced the single disulfide bond found in PrP. One mAb F20-29 reacted only with human PrP, whereas the F4-31 mAb bound bovine PrP; the KD values for mAbs F4-31 and F20-29 were ~500 pM. Binding of all five conformation-dependent mAbs to PrP was inhibited by 2-ME in ELISA, Western blots, and histoblots. One conformation-dependent mAb F4-31 increased the sensitivity of an ELISA-based test by nearly 500-fold when it was used as the capture Ab. These new conformation-dependent mAbs were found to be particularly useful in histoblotting studies, in which the low backgrounds after treatment with 2-ME created unusually high signal-to-noise ratios.
Asymmetric Cell Division of T Cells upon Antigen Presentation Uses Multiple Conserved Mechanisms
Authors: Oliaro Jane , Van Ham Vanessa , Sacirbegovic Faruk , Pasam Anupama , Bomzon Ze’ev , Pham Kim , Ludford-Menting Mandy J. , Waterhouse Nigel J. , Bots Michael , Hawkins Edwin D. , Watt Sally V. , Cluse Leonie A. , Clarke Chris J. P. , Izon David J. , Chang John T. , Thompson Natalie , Gu Min , Johnstone Ricky W. , Smyth Mark J. , Humbert Patrick O. , Reiner Steven L. , Russell Sarah M.
Published: June 2010

Asymmetric cell division is a potential means by which cell fate choices during an immune response are orchestrated. Defining the molecular mechanisms that underlie asymmetric division of T cells is paramount for determining the role of this process in the generation of effector and memory T cell subsets. In other cell types, asymmetric cell division is regulated by conserved polarity protein complexes that control the localization of cell fate determinants and spindle orientation during division. We have developed a tractable, in vitro model of naive CD8+ T cells undergoing initial division while attached to dendritic cells during Ag presentation to investigate whether similar mechanisms might regulate asymmetric division of T cells. Using this system, we show that direct interactions with APCs provide the cue for polarization of T cells. Interestingly, the immunological synapse disseminates before division even though the T cells retain contact with the APC. The cue from the APC is translated into polarization of cell fate determinants via the polarity network of the Par3 and Scribble complexes, and orientation of the mitotic spindle during division is orchestrated by the partner of inscuteable/G protein complex. These findings suggest that T cells have selectively adapted a number of evolutionarily conserved mechanisms to generate diversity through asymmetric cell division.
Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener’s Granulomatosis
Authors: Kuhl Angelika , Korkmaz Brice , Utecht Bert , Kniepert Andrea , Schönermarck Ulf , Specks Ulrich , Jenne Dieter E.
Published: June 2010

Anti-neutrophil cytoplasmic Abs (cANCAs) against conformational epitopes of proteinase 3 (PR3) are regarded as an important pathogenic marker in Wegener’s granulomatosis (WG). Although the three-dimensional structure of PR3 is known, binding sites of mAbs and cANCAs have not been mapped to date. Competitive binding and biosensor experiments suggested the existence of four nonoverlapping areas on the PR3 surface. In this paper, we present an approach to identify these discontinuous surface regions that cannot be mimicked by linear peptides. The very few surface substitutions found in closely related PR3 homologs from primates, which were further varied by the construction of functional human-gibbon hybrids, resulted in the differential loss of three Ab binding sites, two of which were mapped to the N-terminal β-barrel and one to the linker segment connecting the N- and C-terminal barrels of PR3. The sera from WG patients differed in their binding to gibbon PR3 and the gibbon-human PR3 hybrid, and could be divided into two groups with similar or significantly reduced binding to gibbon PR3. Binding of almost all sera to PR3–α1-protease inhibitor (α1–PI) complexes was even more reduced and often absent, indicating that major antigenic determinants overlap with the active site surface on PR3 that associates with α1-PI. Similarly, the mouse mAbs CLB12.8 and 6A6 also did not react with gibbon PR3 and PR3–α1-PI complexes. Our data strongly suggest that cANCAs from WG patients at least in part recognize similar surface structures as do mouse mAbs and compete with the binding of α1-PI to PR3.
Dicer-Dependent MicroRNAs Control Maturation, Function, and Maintenance of Langerhans Cells In Vivo
Authors: Kuipers Harmjan , Schnorfeil Frauke M. , Fehling Hans-Jörg , Bartels Helmut , Brocker Thomas
Published: June 2010

Dendritic cells (DCs) are central for the induction of T cell immunity and tolerance. Fundamental for DCs to control the immune system is their differentiation from precursors into various DC subsets with distinct functions and locations in lymphoid organs and tissues. In contrast to the differentiation of epidermal Langerhans cells (LCs) and their seeding into the epidermis, LC maturation, turnover, and MHC class II Ag presentation capacities are strictly dependent on the presence of Dicer, which generates mature microRNAs (miRNAs). Absence of miRNAs caused a strongly disturbed steady-state homeostasis of LCs by increasing their turnover and apoptosis rate, leading to progressive ablation of LCs with age. The failure to maintain LCs populating the epidermis was accompanied by a proapoptotic gene expression signature. Dicer-deficient LCs showed largely increased cell sizes and reduced expression levels of the C-type lectin receptor Langerin, resulting in the lack of Birbeck granules. In addition, LCs failed to properly upregulate MHC class II, CD40, and CD86 surface molecules upon stimulation, which are critical hallmarks of functional DC maturation. This resulted in inefficient induction of CD4 T cell proliferation, whereas Dicer-deficient LCs could properly stimulate CD8 T cells. Taken together, Dicer-dependent generation of miRNAs affects homeostasis and function of epidermal LCs.
Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility
Authors: Solinas Graziella , Schiarea Silvia , Liguori Manuela , Fabbri Marco , Pesce Samantha , Zammataro Luca , Pasqualini Fabio , Nebuloni Manuela , Chiabrando Chiara , Mantovani Alberto , Allavena Paola
Published: June 2010

Tumor-associated macrophages (TAMs) are key orchestrators of the tumor microenvironment directly affecting neoplastic cell growth, neoangiogenesis, and extracellular matrix remodeling. In turn, the tumor milieu strongly influences maturation of TAMs and shapes several of their features. To address the early macrophage (Mϕ) differentiation phase in a malignant context, we mimicked a tumor microenvironment by in vitro coculturing human blood monocytes with conditioned media from different cancer cell lines. Only 2 out of 16 tumor cell lines induced Mϕ differentiation due to secreted M-CSF isoforms, including high molecular mass species. A global gene profiling of tumor-conditioned Mϕ was performed. Comparison with other datasets (polarized M1-Mϕ, M2-Mϕ, and TAMs isolated from human tumors) highlighted the upregulation of several genes also shared by TAM and M2-polarized Mϕ. The most expressed genes were selenoprotein 1, osteoactivin, osteopontin, and, interestingly, migration-stimulating factor (MSF), a poorly studied oncofoetal isoform of fibronectin. MSF (present in fetal/cancer epithelial and stromal cells but not in healthy tissues) was never identified in Mϕ. MSF production was confirmed by immunohistochemistry in human TAMs. MSF was induced by M-CSF, IL-4, and TGFβ but not by proinflammatory stimuli. RNA and protein analysis clearly demonstrated that it is specifically associated with the M2 polarization of Mϕ. Tumor-conditioned Mϕ-derived MSFs strongly stimulated tumor cell migration, thus contributing to the motile phenotype of neoplastic cells. In conclusion, MSF is a new molecule associated with the M2 polarization of Mϕ and expressed by TAMs. Its biological function may contribute to Mϕ-mediated promotion of cancer cell invasion and metastasis.
Intracellular Sequestration of the NKG2D Ligand ULBP3 by Human Cytomegalovirus
Authors: Bennett Neil J. , Ashiru Omodele , Morgan Fiona J. E. , Pang Yin , Okecha Georgina , Eagle Rob A. , Trowsdale John , Sissons J. G. Patrick , Wills Mark R.
Published: June 2010

Human CMV (HCMV) encodes multiple genes that control NK cell activation and cytotoxicity. Some of these HCMV-encoded gene products modulate NK cell activity as ligands expressed at the cell surface that engage inhibitory NK cell receptors, whereas others prevent the infected cell from upregulating ligands that bind to activating NK cell receptors. A major activating NKR is the homodimeric NKG2D receptor, which has eight distinct natural ligands in humans. It was shown that HCMV is able to prevent the surface expression of five of these ligands (MIC A/B and ULBP1, 2, and 6). In this article, we show that the HCMV gene product UL142 can prevent cell surface expression of ULBP3 during infection. We further show that UL142 interacts with ULBP3 and mediates its intracellular retention in a compartment that colocalizes with markers of the cis-Golgi complex. In doing so, UL142 prevents ULBP3 trafficking to the surface and protects transfected cells from NK-mediated cytotoxicity. This is the first description of a viral gene able to mediate downregulation of ULBP3.
A Toolbox for Predicting G‐Quadruplex Formation and Stability
Authors: Wong Han Min , Stegle Oliver , Rodgers Simon , Huppert Julian Leon
Published: June 2010

G‐quadruplexes are four stranded nucleic acid structures formed around a core of guanines, arranged in squares with mutual hydrogen bonding. Many of these structures are highly thermally stable, especially in the presence of monovalent cations, such as those found under physiological conditions. Understanding of their physiological roles is expanding rapidly, and they have been implicated in regulating gene transcription and translation among other functions. We have built a community‐focused website to act as a repository for the information that is now being developed. At its core, this site has a detailed database (QuadDB) of predicted G‐quadruplexes in the human and other genomes, together with the predictive algorithm used to identify them. We also provide a QuadPredict server, which predicts thermal stability and acts as a repository for experimental data from all researchers. There are also a number of other data sources with computational predictions. We anticipate that the wide availability of this information will be of use both to researchers already active in this exciting field and to those who wish to investigate a particular gene hypothesis.
Electrocardiographic Abnormalities of Takotsubo Cardiomyopathy in a Patient with Paced Ventricular Rhythm
Authors: Chauhan Krati , Sontineni Siva P. , Alla Venkata M. , Holmberg Mark J.
Published: June 2010

Takotsubo cardiomyopathy (TCM) is a unique cardiomyopathy characterized by chest pain, ECG, and regional wall motion abnormalities closely mimicking acute myocardial infarction, in the absence of significant coronary artery disease. Classic ECG changes of TCM include ST elevation or T wave inversion. However, ECG abnormalities of TCM in patients with paced ventricular rhythms have not been well characterized. Herein, we report the case of an 85-year-old pacemaker dependant female who was diagnosed with TCM four weeks following the demise of her husband. Abnormal negative T wave concordance in precordial leads and QT interval prolongation were the only new ECG findings and these reverted back to baseline on followup.
Stevens-Johnson syndrome/ erythema multiforme major and Chlamydia pneumoniae infection in young patients
Authors: Duarte Ana Filipa , João Cruz Maria , Moreira Elisabete , Baudrier Teresa , Mota Alberto , Azevedo Filomena
Published: June 2010

Erythema multiforme major (EMM) is an acute, self-limited mucocutaneous disease characterized by the abrupt onset of symmetrical fixed red papules evolving to target lesions. It is triggered mainly by infections, such as herpes simplex virus (HSV) and Mycoplasma pneumoniae, or drugs. In instances of extensive skin lesions with “giant” targets, prominent involvement of several mucous sites and fever, it may be difficult to distinguish from Stevens-Johnson syndrome (SJS), a rarer, life-threatening reaction which is mainly drug-induced. We report a 7-year old boy with SJS and Chlamydia pneumoniae infection and 3 patients with erythema multiforme (EM) and co-infection with Chlamydia pneumoniae: a 3-year old girl and a 29-year old man developed EMM lesions associated to Mycoplasma pneumoniae and Chlamydia pneumonia and a 20-year old woman with EMM associated to herpes simplex type 2 and Chlamydia pneumoniae infection. None of the 4 patients had history of drug intake in the last two months. Chlamydia pneumoniae is an intracellular bacteria responsible for respiratory infections. Despite the fact that its role in SJS/EMM has been rarely reported, our cases suggest that it may cause SJS and trigger EM when co-infecting a patient, either with Mycoplasma pneumoniae or herpes simplex. We conclude that infection by Chlamydia pneumoniae should be suspected and ruled out in every patient with SJS/EMM, especially in those with signs of respiratory infection.
High Lymphoid Enhancer-Binding Factor-1 Expression Is Associated with Disease Progression and Poor Prognosis in Chronic Lymphocytic Leukemia
Authors: Erdfelder Felix , Hertweck Magdalena , Filipovich Alexandra , Uhrmacher Sabrina , Kreuzer Karl-Anton
Published: June 2010

We determined lymphoid enhancer-binding factor-1 (LEF1) mRNA expression in 112 chronic lymphocytic leukemia (CLL) samples and assessed correlations with the prognostic markers ZAP70 and CD38, Binet stages, the percentage of lymphocytes in the peripheral blood, and fibromodulin (FMOD) transcripts. The mean LEF1 relative expression ratios (RER) were 53.72 and 37.10 in ZAP70-positive and ZAP70-negative patients, respectively (p = 0.004). However, we did not observe a significant difference in LEF1 expression between CD38-positive and CD38-negative patients. Moreover, patients requiring treatment showed a mean LEF1 RER of 85.61 whereas patients in recently diagnosed Binet A stage had a mean of only 22.01 (p < 0.001). We also found significant correl­ations of LEF1 with the percentage of lymphocytes and FMOD expression. Our results suggest that high LEF1 expression is associated with poor prognosis and disease progression. Thus, LEF1 might be involved in the process of disease progression and possibly can serve as a molecular parameter for risk assessment and/or monitoring of CLL.