bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid detection of carriers with BRCA1 and BRCA2mutations using high resolution melting analysis
Authors: Takano Elena A , Mitchell Gillian , Fox Stephen B , Dobrovic Alexander 
Published: March 2008

Abstract

Background
Germline inactivating mutations in BRCA1 and BRCA2 underlie a major proportion of the inherited predisposition to breast and ovarian cancer. These mutations are usually detected by DNA sequencing. Cost-effective and rapid methods to screen for these mutations would enable the extension of mutation testing to a broader population. High resolution melting (HRM) analysis is a rapid screening methodology with very low false negative rates. We therefore evaluated the use of HRM as a mutation scanning tool using, as a proof of principle, the three recurrent BRCA1 and BRCA2 founder mutations in the Ashkenazi Jewish population in addition to other mutations that occur in the same regions.

Methods
We designed PCR amplicons for HRM scanning of BRCA1 exons 2 and 20 (carrying the founder mutations185delAG and 5382insC respectively) and the part of the BRCA2 exon 11 carrying the 6174delT founder mutation. The analysis was performed on an HRM-enabled real time PCR machine.

Results
We tested DNA from the peripheral blood of 29 individuals heterozygous for known mutations. All the Ashkenazi founder mutations were readily identified. Other mutations in each region that were also readily detected included the recently identified Greek founder mutation 5331G>A in exon 20 of BRCA1. Each mutation had a reproducible melting profile.

Conclusion
HRM is a simple and rapid scanning method for known and unknown BRCA1 and BRCA2 germline mutations that can dramatically reduce the amount of sequencing required and reduce the turnaround time for mutation screening and testing. In some cases, such as tracking mutations through pedigrees, sequencing may only be necessary to confirm positive results. This methodology will allow for the economical screening of founder mutations not only in people of Ashkenazi Jewish ancestry but also in other populations with founder mutations such as Central and Eastern Europeans (BRCA1 5382insC) and Greek Europeans (BRCA1 5331G>A).
Beyond satisfaction: Using the Dynamics of Care assessment to better understand patients' experiences in care
Authors: Rapkin Bruce , Weiss Elisa , Chhabra Rosy , Ryniker Laura , Patel Shilpa , Carness Jason , Adsuar Roberto , Kahalas Wendy , DeLaMarter Carol , Feldman Ira , DeLorenzo Judy , Tanner Ellen 
Published: March 2008

Abstract

Background
Patient perceptions of and satisfaction with care have become important indicators of the quality of services and the relationship of services to treatment outcomes. However, assessment of these indicators continues to be plagued by measurement problems, particularly the lack of variance in satisfaction data. In this article, we present a new approach to better capture patient perceptions of experiences in care, the Dynamics of Care (DoC) assessment. It is an in-depth approach to defining and assessing patients' perspectives at different junctures in care, including their decisions about whether and where to seek care, the barriers encountered, and the treatments and services received.

Methods
The purpose of this article is to describe, validate, and discuss the benefits and limitations of the DoC, which was administered as part of a longitudinal study to evaluate the New York State HIV Special Needs Plan (SNP), a Medicaid managed care model for people living with HIV/AIDS. Data are from 426 study respondents across two time points.

Results
The results demonstrate the validity and value of the DoC. Help seeking decisions and satisfaction with care appear to be situation-specific, rather than person-specific. However, barriers to care appear to be more cross-situational for respondents, and may be associated with clients' living situations or care arrangements. Inventories in this assessment that were designed to identify potential deterrents to help seeking and difficulties encountered in care demonstrated clear principal component structures, and helped to explain satisfaction with care. The problem resolution index was found to be independent from satisfaction with care and the data were more normally distributed. DoC data were also associated with subsequent utilization and change in quality of life.

Conclusion
The DoC was designed to be a flexible, integrated measure to determine individuals' salient service needs, help seeking and experiences in care. One of the many strengths of the assessment is its focus on specific problems in context, thus providing a more sensitive and informative way to understand processes in care from the patient's perspective. This approach can be used to direct new programs and resources to the patients and situations that require them.
Exposure to diesel exhaust induces changes in EEG in human volunteers
Authors: Crüts Björn , van Etten Ludo , Törnqvist Håkan , Blomberg Anders , Sandström Thomas , Mills Nicholas L , Borm Paul JA 
Published: March 2008

Abstract

Background
Ambient particulate matter and nanoparticles have been shown to translocate to the brain, and potentially influence the central nervous system. No data are available whether this may lead to functional changes in the brain.

Methods
We exposed 10 human volunteers to dilute diesel exhaust (DE, 300 μg/m3) as a model for ambient PM exposure and filtered air for one hour using a double blind randomized crossover design. Brain activity was monitored during and for one hour following each exposure using quantitative electroencephalography (QEEG) at 8 different sites on the scalp. The frequency spectrum of the EEG signals was used to calculate the median power frequency (MPF) and specific frequency bands of the QEEG.

Results
Our data demonstrate a significant increase in MPF in response to DE in the frontal cortex within 30 min into exposure. The increase in MPF is primarily caused by an increase in fast wave activity (β2) and continues to rise during the 1 hour post-exposure interval.

Conclusion
This study is the first to show a functional effect of DE exposure in the human brain, indicating a general cortical stress response. Further studies are required to determine whether this effect is mediated by the nanoparticles in DE and to define the precise pathways involved.
Ethnophytotherapeutical research in the high Molise region (Central-Southern Italy)
Authors: Guarrera Paolo Maria , Lucchese Fernando , Medori Simone 
Published: March 2008

Abstract

Background
In the years 2003–2005 research was carried out concerning ethno-medicine in the high Molise (central- southern Italy), a region that has been the object of very little investigation from the ethnobotanical point of view. Upper Molise is a continuation of the mountain profiles of the Abruzzi Appenines: a series of hills, steep slopes and deep fluvial valleys making communications difficult. Primordial traditions (e.g. harvest feasts) are typical of the region.

Methods
Field data were collected through open interviews in the field. These were conducted on both an individual and group level, fresh plants gathered from surrounding areas being displayed. In other cases, individual interviews were conducted by accompanying the person involved to the places where they perform their activities (for example, in the woods with woodcutters, kitchen gardens and fields with housewives, pastures with shepherds, etc.). In total 54 individuals were interviewed.

Results
Data of 70 taxa belonging to 39 families were gathered. Among the species, 64 are used in human therapy, 5 as insect repellents, 11 in veterinary medicine, 1 to keep eggs and cheeses and 4 for magic purposes. The most important findings in ethno-medicine relate to the lichen Lobaria pulmonaria (L.) Hoffm. (wounds) and to some vascular plant species: Asplenium trichomanes L. and Ceterach officinarum Willd. (to regularize menstruation), Cyclamen hederifolium (chilblains), Centaurium erythraea Rafn. and Pulmonaria apennina Cristof. & Puppi (bruises), while in the ethno-veterinary field, we have Valeriana officinalis L. (wounds sustained by mules). Also worthy of note, given the isolation of the area, is the number of plants used to protect foodstuffs from parasites, among which Allium sativum L. and Capsicum frutescens L.

Conclusion
The research revealed a deep-rooted and widespread habit of husbanding the family's resources. Whilst isolation and snowfalls contributed to the widespread knowledge of means of conserving foodstuffs, they also led to the use of products easily available within each home. The values of E.I. (ethnobotanicity index) for the upper Molise region are considered amongst the highest in Italian areas. Nevertheless, like the values for other areas of Italy, they are lower than those of many Spanish areas, perhaps (and not only) because of the more rapid cultural erosion experienced in Italy.
Mannose-binding lectin deficiency is associated with early onset of polyarticular juvenile rheumatoid arthritis: a cohort study
Authors: Dolman Koert M , Brouwer Nannette , Frakking Florine NJ , Flatø Berit , Tak Paul P , Kuijpers Taco W , Førre Øystein , Smerdel-Ramoya Anna 
Published: March 2008

Abstract
Background
Mannose-binding lectin (MBL) is an innate immune protein. The aim of our study was to determine whether genetically determined MBL deficiency is associated with susceptibility to juvenile rheumatoid arthritis (JRA) and whether MBL2 genotypes are associated with JRA severity.

Methods
In a retrospective cohort study of 218 patients with polyarthritis (n = 67) and oligoarthritis (n = 151), clinical and laboratory disease variables were obtained by clinical examination and chart reviews. Healthy Caucasian adults (n = 194) served as control individuals. MBL2 gene mutations were determined by Taqman analysis to identify genotypes with high, medium and low expression of MBL. Functional MBL plasma concentrations were measured using enzyme-linked immunosorbent assay. Associations between clinical and laboratory variables and MBL2 genotypes were determined by Kruskal-Wallis and χ2 tests.

Results
MBL2 genotype frequencies were similar in polyarthritis and oligoarthritis patients as compared with control individuals. MBL plasma concentrations were associated with the high, medium and low MBL genotype expression groups (P < 0.01). In polyarthritis patients, the presence of low-expressing (deficient) MBL2 genotypes was associated with early age at onset of disease (P = 0.03). In oligoarthritis patients, patients with low-expressing MBL2 genotypes were more often in remission (81%) than patients in the medium (54%) and high (56%) genotype groups (P = 0.02). The remaining clinical and laboratory variables, such as arthritis severity index, presence of radiographic erosions and antinuclear antibody positivity, were not associated with MBL2 genotypes.

Conclusion
Genetically determined MBL deficiency does not increase susceptibility to JRA, but MBL deficiency is associated with a younger age at onset of juvenile polyarthritis. On the other hand, MBL-deficient children with juvenile oligoarthritis are more often in remission. Therefore, MBL appears to play a dual role in JRA.
Systems biology-defined NF-κB regulons, interacting signal pathways and networks are implicated in the malignant phenotype of head and neck cancer cell lines differing in p53 status
Authors: Yan Bin , Chen Guang , Saigal Kunal , Yang Xinping , Jensen Shane T , Van Waes Carter , Stoeckert Christian J , Chen Zhong 
Published: March 2008

Abstract
Background
Aberrant activation of the nuclear factor kappaB (NF-κB) pathway has been previously implicated as a crucial signal promoting tumorigenesis. However, how NF-κB acts as a key regulatory node to modulate global gene expression, and contributes to the malignant heterogeneity of head and neck cancer, is not well understood.

Results
To address this question, we used a newly developed computational strategy, COGRIM (Clustering Of Gene Regulons using Integrated Modeling), to identify NF-κB regulons (a set of genes under regulation of the same transcription factor) for 1,265 genes differentially expressed by head and neck cancer cell lines differing in p53 status. There were 748 NF-κB targets predicted and individually annotated for RELA, NFκB1 or cREL regulation, and a prevalence of RELA related genes was observed in over-expressed clusters in a tumor subset. Using Ingenuity Pathway Analysis, the NF-κB targets were reverse-engineered into annotated signature networks and pathways, revealing relationships broadly altered in cancer lines (activated proinflammatory and down-regulated Wnt/β-catenin and transforming growth factor-β pathways), or specifically defective in cancer subsets (growth factors, cytokines, integrins, receptors and intermediate kinases). Representatives of predicted NF-κB target genes were experimentally validated through modulation by tumor necrosis factor-α or small interfering RNA for RELA or NFκB1.

Conclusion
NF-κB globally regulates diverse gene programs that are organized in signal networks and pathways differing in cancer subsets with distinct p53 status. The concerted alterations in gene expression patterns reflect cross-talk among NF-κB and other pathways, which may provide a basis for molecular classifications and targeted therapeutics for heterogeneous subsets of head and neck or other cancers.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With Advanced Solid Tumors
Authors: O'Donnell Anne , Faivre Sandrine , Burris Howard A. , Rea Daniel , Papadimitrakopoulou Vassiliki , Shand Nicholas , Lane Heidi A. , Hazell Katharine , Zoellner Ulrike , Kovarik John M. , Brock Cathryn , Jones Suzanne , Raymond Eric , Judson Ian 
Published: March 2008

PurposeTo identify the optimal regimen and dosage of the oral mammalian target of rapamycin inhibitor everolimus (RAD001).MethodsWe performed a dose-escalation study in advanced cancer patients administering oral everolimus 5 to 30 mg/wk, with pharmacokinetic (PK) and pharmacodynamic (PD) studies. PD data prompted investigation of 50 and 70 mg weekly and daily dosing at 5 and 10 mg.ResultsNinety-two patients were treated. Dose-limiting toxicity was seen in one patient each at 50 mg/wk (stomatitis and fatigue) and 10 mg/d (hyperglycemia); hence, the maximum-tolerated dose was not reached. S6 kinase 1 activity in peripheral-blood mononuclear cells was inhibited for at least 7 days at doses ≥ 20 mg/wk. Area under the curve increased proportional to dose, but maximum serum concentration increased less than proportionally at doses ≥ 20 mg/wk. Terminal half-life was 30 hours (range, 26 to 38 hours). Partial responses were observed in four patients, and 12 patients remained progression free for ≥ 6 months, including five of 10 patients with renal cell carcinoma.ConclusionEverolimus was satisfactorily tolerated at dosages up to 70 mg/wk and 10 mg/d with predictable PK. Antitumor activity and PD in tumors require further clinical investigation. Doses of 20 mg/wk and 5 mg/d are recommended as appropriate starting doses for these studies.
Identifying Optimal Biologic Doses of Everolimus (RAD001) in Patients With Cancer Based on the Modeling of Preclinical and Clinical Pharmacokinetic and Pharmacodynamic Data
Authors: Tanaka Chiaki , O’Reilly Terence , Kovarik John M. , Shand Nicholas , Hazell Katharine , Judson Ian , Raymond Eric , Zumstein-Mecker Sabine , Stephan Christine , Boulay Anne , Hattenberger Marc , Thomas George , Lane Heidi A. 
Published: March 2008

PurposeTo use preclinical and clinical pharmacokinetic (PK)/pharmacodynamic (PD) modeling to predict optimal clinical regimens of everolimus, a novel oral mammalian target of rapamycin (mTOR) inhibitor, to carry forward to expanded phase I with tumor biopsy studies in cancer patients.Patients and MethodsInhibition of S6 kinase 1 (S6K1), a molecular marker of mTOR signaling, was selected for PD analysis in peripheral blood mononuclear cells (PBMCs) in a phase I clinical trial. PK and PD were measured up to 11 days after the fourth weekly dose. A PK/PD model was used to describe the relationship between everolimus concentrations and S6K1 inhibition in PBMCs of cancer patients and in PBMCs and tumors of everolimus-treated CA20948 pancreatic tumor-bearing rats.ResultsTime- and dose-dependent S6K1 inhibition was demonstrated in human PBMCs. In the rat model, a relationship was shown between S6K1 inhibition in tumors or PBMCs and antitumor effect. This allowed development of a direct-link PK/PD model that predicted PBMC S6K1 inhibition-time profiles in patients. Comparison of rat and human profiles simulated by the model suggested that a weekly 20- to 30-mg dose of everolimus would be associated with an antitumor effect in an everolimus-sensitive tumor and that daily administration would exert a greater effect than weekly administration at higher doses.ConclusionA direct-link PK/PD model predicting the time course of S6K1 inhibition during weekly and daily everolimus administration allowed extrapolation from preclinical studies and first clinical results to select optimal doses and regimens of everolimus to explore in future clinical trials.
„… sed vitae discimus“ Religionsunterricht zwischen Religiosität und christlicher Tradition – didaktische Orientierungen
Authors: Pohl-Patalong Uta 
Published: March 2008

Abstract
Religious education today is shaped by the tension between a vague “general religiousness” and an orientation in the Christian tradition. This tension should not be resolved on only one side, but should be shaped constructively. Therefore, the question of how the Christian tradition can serve life, is raised by the concept of general religiousness, should be considered. The most important task of Christian religious education in this perspective would be for pupils to experience the Christian tradition as serving their lives. This question should also be asked to other religions and forms of religiousness because these too are treated in religious education, which has an interreligious dimension. Christian religious education can thus show its ability for pluralism, without having a lack of position. This orientation has consequences for the training of the teachers.
New Wine and New Wineskins: Laity and a Liberative Future for the Church
Authors: Mannion Gerard 
Published: March 2008

Abstract
The purpose of this essay is to pose questions for practical theology concerning a liberative, community-based ecclesiology, and to pose questions for church leaders regarding the role of laity in shaping the future of the Roman Catholic Church. Identifying some critical issues before the church, the author proceeds to engage with liberative ecclesial visions, drawing particularly on the conceptual revisions advocated by Hermann Pottmeyer, the social and communitarian ecclesiologies of Latin American liberation theology (especially that of Leonardo Boff), and Paul Lakeland's work connecting liberation thinking with Euro-North American contexts. Mannion concludes with a vision for the future of the church, placed within a liberative ecclesiology and a vibrant lay ministry. He also suggests directions for practical theology. His intention throughout is to propose new wine (visions for the people of God) in new wineskins (ecclesial forms, policies, and structures) in which the new wine might mature.
A Study of Ministerial Identity and Theological reflection among Lay Ecclesial Ministers
Authors: O'Brien Maureen R 
Published: March 2008

Abstract
This essay explores ministerial identity and its formation in the context of theological reflection. In particular, it discusses theological premises, the values of narrative inquiry, and the results of a qualitative study of lay ministers participating in a university-based ministry education program. By engaging in a series of interviews, the author also gives a picture of the ambiguous and evolving nature of “lay ecclesial ministry” in the United States Catholic Church. This underscores the need of lay ministers for models of conversation-based theological reflection to aid their self-construction of ministerial identity. After an overview of the study's premises and methods, the essay presents key findings from analysis of the interviews. These findings focus on the construction of ministerial identity; the emergence of ministerial “touchstones”; the dynamics of informal and formal modes of theological reflection; and remaining questions and areas for continued research.
TRIPs, TRIPs-PLUS, Developing Countries and Public Health: The Case of Egypt
Authors: El Farag Mohamed Salem Abou 
Published: March 2008

AbstractThe article critically examines how Egyptian legislators made use of the degree of freedom left in the TRIPs Agreement for WTO Members to incorporate appropriate measures in their national laws aiming at meeting the public health needs and concerns, particularly access to quality health care and affordable pharmaceutical drugs. The article also explores and warns against the recent attempts made by a number of developed countries to impose TRIPs-plus obligations on several developing countries, including Egypt, for their detrimental effects on public health.
Take three cases: A reflection on the mission of applying law to human frailty
Authors: Levy Sharon 
Published: March 2008

AbstractThe birth in 1968 of Louise Brown, the first English test tube baby, was a beacon of hope to the estimated 1 in 7 couples who experience difficulty in conceiving a child. It was obvious that the process of assisted conception required regulation to deal with the legal and ethical ramifications of the developments science had given us and after much consultation and debate, The Human Fertilisation and Embryology Act 1990 was passed.
The shaping of Gorbachev: On framing in an interpreter-mediated talk-show interview
Authors: Wadensjö Cecilia 
Published: March 2008

AbstractThis paper examines a televised interview that BBC journalist and show host Clive Anderson conducted with the former head of state of the dissolved USSR, Mikhail Gorbachev, assisted by the interpreter Pavel Palazchenko. The paper explores this interview, focusing on its opening and closing, its local organization, and the involvement of the audience. Applying conversation analysis, the paper traces the generic belonging of current talk and looks into a variety of features that shaped the image of Gorbachev as a television personality in British TV. It demonstrates how Gorbachev and Anderson moved between and played with a ‘talk show interview’ and a ‘news interview’ framing of interaction. The analysis demonstrates how the encounter helped portray Gorbachev as a witty and adequate performer, irrespective of the fact that he did not speak English—the language of the broadcast and of the viewers. This was due to what he said, but no less to how he performed, and not least to his way of utilizing the assistance of the highly skilled interpreter, and also, I will argue, to the fact that the interview allowed him to take part in a shared game of entertainment, in a genuinely hybrid form of talk.
Fahrlässige Mittäterschaft in Japan
Authors: Utsumi Tomoko 
Published: March 2008

Abstract

I. Einleitung

Im 20. Jahrhundert hat die Entwicklung der Technik zur Zunahme der Produktivität und zur Erhöhung des Lebensstandards geführt. Unsere Gesellschaft ist jedoch andererseits einer erhöhten Gefahr von Rechtsgutverletzungen durch den Missbrauch von Technologien ausgesetzt. Es ist den Einzelnen unmöglich, sämtliche technischen Gefahren allein zu überwachen und Unfälle zu vermeiden. Daher ist es eine Aufgabe der Gesellschaft, die neuen Technologien für das Alltagsleben nützlich zu machen und ihre Gefahren angemessen zu kontrollieren. Es steht allerdings zu erwarten, dass Fälle zunehmen werden, in denen die Nachlässigkeit mehrerer Personen zusammenwirkt. Die wissenschaftliche Beschäftigung mit dieser Konstellation wird deshalb immer wichtiger.