bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drotrecogin alfa (activated): real-life use and outcomes for the UK
Authors: Rowan Kathryn M , Welch Catherine A , North Emma , Harrison David A 
Published: April 2008

Abstract
Introduction
In March 2001, the results of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study were published, which indicated a 6.1% absolute reduction in 28-day mortality. Drotrecogin alfa (activated; DrotAA) was subsequently approved for use in patients with severe sepsis.

Methods
In December 2002, critical care units in England, Wales and Northern Ireland were invited to participate in an audit of DrotAA. Data for each infusion of DrotAA were linked to case mix and outcome data from a national audit. Use of DrotAA was described and a nonrandomized comparison of effectiveness was conducted.

Results
1,292 infusions of DrotAA were recorded in 112 units; 61% commenced during the first 24 hours in the unit. The majority (77%) of patients had three or more organs failing; lung (42%) and abdomen (40%) were the most common primary sites of infection. Crude hospital mortality was high (45%); at 28 days, only 18% had left acute hospital and 19% were still in the unit. For 30%, the full 96-hour infusion was not completed; 24% of infusions were interrupted; 8.1% experienced one or more serious adverse events, of which 77% were serious bleeding events. Of eight relative risks estimated from individually-matched (0.75 to 0.85) and propensity-matched (0.82 to 0.90) controls, seven were consistent with the results of PROWESS. Restricting the analysis to patients receiving DrotAA during the first 24 hours resulted in larger treatment effects (relative risks 0.62 to 0.81). For all matches, similar patterns were seen across subgroups. No effect of DrotAA was seen for two organs failing or lower severity scores, compared with a significant mortality reduction for three or more organs failing or higher severity scores.

Conclusion
Use of DrotAA was approximately one in 16 for admissions meeting the definition for severe sepsis and with two or more organs failing. Patients receiving DrotAA were younger and more severely ill but were less likely to have serious conditions in their past medical history. Nonrandomized estimates for the effectiveness of DrotAA were consistent with the findings of PROWESS. DrotAA appeared not to be effective in patients with less severe disease.
Genomic context analysis in Archaea suggests previously unrecognized links between DNA replication and translation
Authors: Berthon Jonathan , Cortez Diego , Forterre Patrick 
Published: April 2008

Abstract
Background
Comparative analysis of genomes is valuable to explore evolution of genomes, deduce gene functions, or predict functional linking between proteins. Here, we have systematically analyzed the genomic environment of all known DNA replication genes in 27 archaeal genomes to infer new connections for DNA replication proteins from conserved genomic associations.

Results
Two distinct sets of DNA replication genes frequently co-localize in archaeal genomes: the first includes the genes for PCNA, the small subunit of the DNA primase (PriS), and Gins15; the second comprises the genes for MCM and Gins23. Other genomic associations of genes encoding proteins involved in informational processes that may be functionally relevant at the cellular level have also been noted; in particular, the association between the genes for PCNA, transcription factor S, and NudF. Surprisingly, a conserved cluster of genes coding for proteins involved in translation or ribosome biogenesis (S27E, L44E, aIF-2 alpha, Nop10) is almost systematically contiguous to the group of genes coding for PCNA, PriS, and Gins15. The functional relevance of this cluster encoding proteins conserved in Archaea and Eukarya is strongly supported by statistical analysis. Interestingly, the gene encoding the S27E protein, also known as metallopanstimulin 1 (MPS-1) in human, is overexpressed in multiple cancer cell lines.

Conclusion
Our genome context analysis suggests specific functional interactions for proteins involved in DNA replication between each other or with proteins involved in DNA repair or transcription. Furthermore, it suggests a previously unrecognized regulatory network coupling DNA replication and translation in Archaea that may also exist in Eukarya.
Type 1-polarized dendritic cells loaded with autologous tumor are a potent immunogen against chronic lymphocytic leukemia
Authors: Lee Je-Jung , Foon Kenneth A , Mailliard Robbie B , Muthuswamy Ravikumar , Kalinski Pawel 
Published: April 2008

AbstractInduction of active tumor-specific immunity in patients with chronic lymphocytic leukemia (CLL) and other hematologic malignancies is compromised by the deficit of endogenous dendritic cells (DCs). In attempt to develop improved vaccination strategies for patients with CLL and other tumors with poorly identified rejection antigens, we tested the ability of ex vivo-generated DCs to cross-present the antigens expressed by CLL cells and to induce CLL-specific, functional CTL responses. Monocyte-derived DCs from CLL patients were induced to mature using a “standard” cytokine cocktail (in IL-1β, TNF-α, IL-6, and PGE2) or using an α-type 1-polarized DC (αDC1) cocktail (in IL-1β, TNF-α, IFN-α, IFN-γ, and polyinosinic:polycytidylic acid) and were loaded with γ-irradiated, autologous CLL cells. αDC1 from CLL patients expressed substantially higher levels of multiple costimulatory molecules (CD83, CD86, CD80, CD11c, and CD40) than standard DCs (sDCs) and immature DCs, and their expression of CCR7 showed intermediate level. αDC1 secreted substantially higher (10–60 times) levels of IL-12p70 than sDCs. Although αDC1 and sDCs showed similar uptake of CLL cells, αDC1 induced much higher numbers (range, 2.4–38 times) of functional CD8+ T cells against CLL cells. The current demonstration that autologous tumor-loaded αDC1 are potent inducers of CLL-specific T cells helps to develop improved immunotherapies of CLL.
Mammography Before Diagnosis Among Women Age 80 Years and Older With Breast Cancer
Authors: Badgwell Brian D. , Giordano Sharon H. , Duan Zhigang Z. , Fang Shenying , Bedrosian Isabelle , Kuerer Henry M. , Singletary S. Eva , Hunt Kelly K. , Hortobagyi Gabriel N. , Babiera Gildy 
Published: April 2008

Purpose Screening mammography guidelines for patients age 80 years and older are variable. We determined the effect of mammography use on stage at breast cancer diagnosis and survival among women of this age range. Patients and Methods We used the linked Surveillance, Epidemiology, and End Results–Medicare database to evaluate 12,358 women ≥ 80 years of age diagnosed with breast cancer between 1996 and 2002. Patients were grouped according to number of mammograms during the 60 months before diagnosis: nonusers (0 mammograms), irregular users (one to two mammograms), and regular users (three or more mammograms). Effects of mammography on disease stage (I to IIa v IIb to IV) and survival were determined by logistic regression and Cox proportional hazards analyses. Results Percentages of women with nonuse, irregular use, and regular use of mammography during the 5 years preceding diagnosis were 49%, 29%, and 22%, respectively. On multivariate analysis, patients were 0.37 times less likely to present with late-stage cancer for each mammogram obtained (odds ratio, 0.63; 95% CI, 0.63 to 0.67). Breast cancer–specific 5-year survival among nonusers was 82%, that among irregular users was 88%, and that among regular users was 94%. However, survival from causes other than breast cancer was also associated with mammography use, suggesting a bias for healthier patients to undergo mammography. Conclusion Regular mammography among women ≥ 80 years of age was associated with earlier disease stage, although improved survival remains difficult to demonstrate. Health care providers should consider discussing the potential benefits of screening mammography with their older patients, particularly for those without significant comorbidity.
Granulocyte-Macrophage Colony-Stimulating Factor Potentiates Rituximab in Patients With Relapsed Follicular Lymphoma: Results of a Phase II Study
Authors: Cartron Guillaume , Zhao-Yang Lu , Baudard Marion , Kanouni Tarik , Rouillé Valérie , Quittet Philippe , Klein Bernard , Rossi Jean-Francois 
Published: April 2008

PurposeWe hypothesized that granulocyte-macrophage colony-stimulating factor (GM-CSF) could potentiate the clinical activity of rituximab given its individual and cooperative effects on FcγRIIa- and FcγRIIIa-expressing cells. A phase II clinical study combining GM-CSF and rituximab was initiated in patients with relapsed follicular lymphoma (FL) to determine the clinical and biologic responses, as well as safety of the combination.Patients and MethodsThirty three patients with relapsed FL were treated with GM-CSF 5 μg/kg/d on days 1 to 8 and rituximab 375 mg/m2on day 5 of each 21-day cycle for four cycles. Clinical response and tolerability were examined according to international criteria. Biologic monitoring included evaluation of immune cells involved in rituximab activity.ResultsOf 33 evaluated patients, a 70% overall response rate (complete response plus complete response unconfirmed, 45%) and a median progression-free survival (PFS) of 16.5 months were achieved. Outcome was influenced by the quality of response and the Follicular Lymphoma International Prognostic Index (FLIPI), where low- and intermediate-risk FLIPI groups were associated with significantly better PFS. After treatment there was a significant increase in granulocyte and monocyte counts. Examination of dendritic cell response showed an overall increase in plasmacytoid dendritic cells, especially in non-complete response patients, after treatment. Addition of GM-CSF did not impair tolerance to rituximab, and adverse events were rare and mild.DiscussionGM-CSF plus rituximab results in high response rates, along with a tolerable safety profile in patients with relapsed or progressive FL. The improved efficacy over rituximab monotherapy may be due to increases seen in monocyte, granulocyte, and dendritic cell populations.
HIV-Specific Differences in Outcome of Squamous Cell Carcinoma of the Anal Canal: A Multicentric Cohort Study of HIV-Positive Patients Receiving Highly Active Antiretroviral Therapy
Authors: Oehler-Jänne Christoph , Huguet Florence , Provencher Sawyna , Seifert Burkhardt , Negretti Laura , Riener Marc-Oliver , Bonet Marta , Allal Abdelkarim S. , Ciernik I. Frank 
Published: April 2008

Purpose To define clinical outcome after definitive chemoradiotherapy (CRT) of anal carcinoma in HIV-infected patients treated with highly active antiretroviral therapy (HAART). Patients and Methods A multicentric cohort comparison of 40 HIV-positive patients with HAART and 81 HIV-negative patients treated with radiotherapy (RT) or CRT was retrospectively performed. Local disease control (LC), relapse-free survival (RFS), overall survival (OS), cancer-specific survival (CSS), toxicity, and prognostic factors were investigated. Results HIV-positive patients were younger (mean age, 48 v 62 years; P < .0005), predominantly male (93% v 25%; P < .0005), and with early-stage (P = .06) and large-cell histology (90% v 67%; P = .005) disease. RT or CRT resulted in complete response in 92% (HIV positive) and 96% (HIV negative) of cases. Five-year OS was 61% (95% CI, 44% to 78%) in HIV-positive and 65% (95% CI, 53% to 77%) in HIV-negative patients (median follow-up, 36 months). Five-year LC was 38% (95% CI, 5% to 71%) in HIV-positive and 87% (95% CI, 79% to 95%) in HIV-negative patients (P = .008) compromising CSS and sphincter preservation. Grade 3/4 acute skin (35% v 17% [HIV negative]; P = .04) and hematologic (33% v 12% [HIV negative]; P = .08) toxicity together approximated 50% in HIV-positive patients. RFS in HIV-positive patients was associated with RT dose (P = .08) and severe acute skin toxicity (P = .04). Conclusion Long-term LC and acute toxicity represent major clinical challenges in HIV-positive patients with anal carcinoma. Even if fluoropyrimidine-based CRT is feasible and may result in similar response rates and OS as in HIV-negative patients, improved treatment strategies with better long-term outcome are warranted.
A simplified tumour model established via Epstein-Barr virus-encoded, nasopharyngeal carcinoma-derived oncogene latent membrane protein 1 in immunocompetent mice
Authors: Chow Kai-Ping N , Wu C C , Chang H Y , Chang C , Chang Y S 
Published: April 2008

Summary The expression and immune modulation of Epstein-Barr virus-encoded oncogene latent membrane protein 1 (N-LMP1) is essential in the pathogenesis of nasopharyngeal carcinoma. In previous studies, cell transformation has been induced by the expression of EBV-encoded N-LMP1 in non-tumour BALB/c-3T3 cells and these cells have then been used to form tumours in T-cell-deficient nude mice. However, studies using this model have been limited by the lack of a competent immune system. To facilitate the study of immune components in N-LMP1-driven oncogenesis, we herein developed a simplified N-LMP1-derived tumour model in immunocompetent mice. Cell transformation was induced by the expression of N-LMP1 in BALB/c-3T3 cells, and these transformants were used to induce oncogenesis in BALB/c mice. In contrast to the 100% successful tumour-induction rate in nude mice treated with monodispersed transformed cells, the tumour incidence in BALB/c mice was only 5–36%. However, the transplantation of tumour fragments into BALB/c mice yielded a reproducible tumour-induction rate of >85%, which is acceptable for most of the research needs. This novel model of N-LMP1-directed oncogenesis in an immunocompetent environment may serve as an important platform for the future assessment of N-LMP1-targeted tumour therapies.
Upgrading mouse health and welfare: direct benefits of a large-scale rederivation programme
Authors: Fray M D , Pickard A R , Harrison M , Cheeseman M T 
Published: April 2008

Summary We report the outcome of a 30-month programme to rederive 310 specific pathogen-free mouse strains to populate a new individually ventilated cage barrier facility at the Mary Lyon Centre (MLC), Medical Research Council (MRC) Harwell. The mice were rederived in a self-contained quarantine suite and embryo-recipient females were health-screened to assess microbiological status, before moving their offspring into the new facility. The MLC currently houses approximately 49,000 mice in about 9750 cages and we have 30 months of follow-up health screen data. Embryo rederivation and hysterectomy have high safety margins; however, the precaution of performing the programme in isolators facilitated the containment and decontamination of two mouse hepatitis virus (MHV) infection outbreaks. Rederivation of the colony has eliminated endemic MHV, mouse adenovirus type 2 (MAV-2), Theiler's murine encephalomyelitis virus, pinworms, intestinal protozoa, Pasteurella pneumotropica, Helicobacter spp. and mites. The improvements in microbiological status have had notable benefits for mouse health and welfare and the science at MRC Harwell. Previously important clinical entities such as sudden death associated with lactation ileus in C3H/HeH mice, early weight loss associated with inflammatory bowel disease in B6-TgN(HDexon1)61Gpb and B6-TgN(HD82Gln)81Dbo (Huntington) mice and early weight loss in male mice mutagenized with N-ethyl- N-nitrosourea have been markedly reduced or eliminated.
The effects on heart rate and temperature of mice and vas deferens responses to noradrenaline when their cage mates are subjected to daily restraint stress
Authors: Gilmore A J , Billing R L , Einstein R 
Published: April 2008

Summary Performing stressful procedures in view of cage mates may cause stress in observer animals. However, it is not known if stressful procedures performed in close proximity to, but not in view of cage mates are stressful for the (observer) cage mates. Radiotelemetry and postmortem in vitro studies of the vas deferens were used to determine the effects of stress on observers. Heart rate (HR) and core body temperature (cBT) were recorded for 1 h following weighing of a cage mate or 1 h during restraint of a cage mate and the hour following return of the restrained mouse to the cage. This procedure was repeated daily for 15 days. HR and cBT were increased in observers during both restraint and weighing of cage mates. Analysis of the area under the curve showed that HR and cBT in observers were significantly higher during restraint of a cage mate than after weighing of a cage mate. When mice were returned to the cage after weighing or restraint, HR and cBT were significantly higher in the cage mates of restrained animals. Comparison between days 1, 3, 7 and 14 found that, as the experiment progressed, HR and cBT were significantly reduced in the observer mice during the hour following return of the cage mates after restraint. Results from previous studies have shown that chronic stress causes the vas deferens to become hypersensitive to exogenous application of noradrenaline (NAd). In this study, vas deferens from observers of restraint had a significantly increased response to NAd. These results indicate that stressful procedures should be conducted in isolation from other mice.
Supervisor trainees' and their supervisors' perceptions of attainment of knowledge and skills: An empirical evaluation of a psychotherapy supervisor training programme
Authors: Sundin Eva C. , Ögren Marie‐Louise , Boëthius Siv Boalt 
Published: April 2008

ObjectivesThis study aimed to evaluate the success of a 2‐year, part‐time training programme for psychotherapy supervisors. A second aim was to examine factors that might contribute to perceived knowledge and skills attainment during the training course.DesignThis is a naturalistic, longitudinal study where several measures are used to examine group process and outcome.MethodsSupervisor trainees' (N = 21) and their facilitators' (N = 6) ratings of learning (knowledge and skills), relations to the supervisor and supervision group, usage of the group, and supervisor style were completed at three time points.ResultsThe findings suggested that both trainees and their supervisors perceived that the trainees attained a substantial amount of knowledge and skills during the course. In accordance with the literature and expectations, the regression analysis suggested a strong negative association between a strong focus on group processes in the initial and middle phases of the training and perceived knowledge and skills attainment in the final phase of the training. The expected, positive role of relations among trainees in the supervision group in the first half of the training and perceived knowledge and skills attainment in the final part of the training was obtained, whilst the hypothesized significance of the relationship between trainee and supervisor did not receive support.ConclusionsThe supervisory course seemed to provide a training that allowed trainees to attain knowledge and skills that are necessary for psychotherapy supervisors. The results of this pilot study also emphasize the need of more research on learning in the context of group supervision in psychotherapy.
Information Extraction from Interlaboratory Comparison in Testing—Temperature Measurement in the Black Test Corner
Authors: Beges Gaber , Jensen Hans Dalsgaard , Drnovsek Janko 
Published: April 2008

Abstract
This paper presents extraction of information from results of an interlaboratory comparison in testing, which was performed in the scope of the 5th Framework Program—INCOLAB (INitiative and CO-ordination to prepare LABoratories in Newly Associated States for full implementation of the (LVD) Low-Voltage Directive) project. The comparison covers all the requirements of classical proficiency testing, but also adds metrological aspects in order to improve the outcome of such tests, which is new in the field of interlaboratory comparisons in testing of electric safety. The objective was to show differences in methods and measurements in the black test corner (BTC, which is one of the tests required by the LVD directive standards), when performing the conformity assessment. A digital convection oven and a cooker were chosen as representative samples for comparison. Different shapes of samples were used to put forward understanding and application of the standard requirements. Additionally, the temperature artifact was used for comparison of the BTCs of different participating laboratories. All participating laboratories in this intercomparison were requested to follow the basic instructions given in the technical protocol, applying their everyday test procedure. Results showed a few problematic areas in safety testing. The entire intercomparison proved that in general, and for LVD in particular, better specification for BTCs as an example for a complex measuring instrument is required. Additional information about test samples was also obtained. The concern arising is that a product can be placed on the EU market with the conformity assessment activity support of testing laboratories with quite different measurement capabilities.
Retinol-binding protein-4 is not strongly associated with insulin sensitivity in normal pregnancies.
Authors: Ueland T , Dalsoren T , Voldner N , Godang K , Henriksen T , Bollerslev J 
Published: April 2008

ObjectiveRecently, experimental and clinical studies suggest that retinol-binding protein-4 (RBP4) may provide a link between obesity and insulin resistance. However, no previous studies have investigated the impact of circulating RBP4 on measures of insulin resistance in normal pregnant women, and the objective of this study is to measure serum RBP4 in early and late pregnancy and relate these to measures of insulin resistance and secretion controlling for changes in fat mass.Design and methodsSamples were obtained during oral glucose tolerance test (OGTT) from 44 normal pregnancies at weeks 14–16 and 30–32. Measures of fat mass were body mass index (BMI) and leptin while insulin sensitivity and secretion were predicted from OGTT. Leptin and RPB4 were measured by immunoassay.ResultsInsulin sensitivity decreased during the course of pregnancy. Insulin sensitivity and secretion were best explained by BMI and circulating leptin, but not RBP4, both in early and late pregnancy. However, a marked increase in fasting RBP4 from early to late pregnancy was observed, and this change was associated with a decline in insulin sensitivity. A marked increase in RBP4 was found during OGTT at weeks 14–16 with an opposite temporal course at weeks 30–32.ConclusionThe increased fat mass and insulin resistance during normal pregnancy was best explained by measures of fat mass. However, the increase in RBP4 from early to late pregnancy, associated with a decline in insulin sensitivity, potentially indicates interactions with glucose metabolism.