bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective Assessment of Discontinuation and Reinitiation of Erlotinib or Gefitinib in Patients with Acquired Resistance to Erlotinib or Gefitinib Followed by the Addition of Everolimus
Authors: Riely Gregory J. , Kris Mark G. , Zhao Binsheng , Akhurst Tim , Milton Daniel T. , Moore Erin , Tyson Leslie , Pao William , Rizvi Naiyer A. , Schwartz Lawrence H. , Miller Vincent A.
Published: September 2007

Purpose: Ten percent of U.S. patients with non–small cell lung cancer experience partial radiographic responses to erlotinib or gefitinib. Despite initial regressions, these patients develop acquired resistance to erlotinib or gefitinib. In these patients, we sought to assess changes in tumor metabolism and size after stopping and restarting erlotinib or gefitinib and to determine the effect of adding everolimus.

Experimental Design: Patients with non–small cell lung cancer and acquired resistance to erlotinib or gefitinib were eligible. Patients had 18-fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography and computed tomography scans at baseline, 3 weeks after stopping erlotinib or gefitinib, and 3 weeks after restarting erlotinib or gefitinib. Three weeks after restarting erlotinib or gefitinib, everolimus was added to treatment.

Results: Ten patients completed all four planned studies. Three weeks after stopping erlotinib or gefitinib, there was a median 18% increase in SUVmax and 9% increase in tumor diameter. Three weeks after restarting erlotinib or gefitinib, there was a median 4% decrease in SUVmax and 1% decrease in tumor diameter. No partial responses (0 of 10; 95% confidence interval, 0-31%) were seen with the addition of everolimus to erlotinib or gefitinib.

Conclusions: In patients who develop acquired resistance, stopping erlotinib or gefitinib results in symptomatic progression, increase in SUVmax, and increase in tumor size. Symptoms improve and SUVmax decreases after restarting erlotinib or gefitinib, suggesting that some tumor cells remain sensitive to epidermal growth factor receptor blockade. No responses were observed with combined everolimus and erlotinib or gefitinib. We recommend a randomized trial to assess the value of continuing erlotinib or gefitinib after development of acquired resistance.
Monocyte Chemotactic Protein-1 Secreted by Primary Breast Tumors Stimulates Migration of Mesenchymal Stem Cells
Authors: Dwyer R.M. , Potter-Beirne S.M. , Harrington K.A. , Lowery A.J. , Hennessy E. , Murphy J.M. , Barry F.P. , O'Brien T. , Kerin M.J.
Published: September 2007

Purpose: Major barriers to effective adenovirus-based gene therapy include induction of an immune response and tumor-specific targeting of vectors. The use of mesenchymal stem cells (MSC) as systemic delivery vehicles for therapeutic genes has been proposed as a result of their combined ability to home in on the tumor site and evade the host immune response. This study is aimed at investigating factors mediating homing of human MSCs to breast cancer primary cultures and cell lines in vitro and in vivo.

Experimental Design: Fluorescently labeled MSCs were given to mice bearing breast cancer xenografts, and tumor tissue was harvested to detect MSC engraftment. MSC migration in response to primary breast tumors in vitro was quantified, and chemokines secreted by tumor cells were identified. The role of monocyte chemotactic protein-1 (MCP-1) in cell migration was investigated using antibodies and standards of the chemokine. Serum MCP-1 was measured in 125 breast cancer patients and 86 healthy controls.

Results: Engrafted MSCs were detected in metastatic breast tumors in mice after systemic administration. There was a significant increase in MSC migration in response to primary breast tumor cells in vitro (6-fold to 11-fold increase). Tumor explants secreted a variety of chemokines including GROα, MCP-1, and stromal cell–derived factor-1α. An MCP-1 antibody caused a significant decrease (37-42%) in MSC migration to tumors. Serum MCP-1 levels were significantly higher in postmenopausal breast cancer patients than age-matched controls (P < 0.05).

Conclusions: These results highlight a role for tumor-secreted MCP-1 in stimulating MSC migration and support the potential of these cells as tumor-targeted delivery vehicles for therapeutic agents.
Radiation-Enhanced Vascular Targeting of Human Lung Cancers in Mice with a Monoclonal Antibody That Binds Anionic Phospholipids
Authors: He Jin , Luster Troy A. , Thorpe Philip E.
Published: September 2007

Purpose: New treatment strategies aimed at damaging tumor vasculature could potentially improve tumor response to radiation therapy. We recently showed that anionic phospholipids, principally phosphatidylserine, are specifically exposed on the luminal surface of tumor blood vessels. Here we tested the hypothesis that radiation therapy can increase phosphatidylserine exposure on lung tumor vasculature, thereby enhancing the antitumor properties of the anti-phosphatidylserine antibody 2aG4.

Experimental Design: The therapeutic efficacy of radiation therapy plus 2aG4 was tested in nude mice bearing radiation-resistant A549 human lung tumors. Radiation-induced phosphatidylserine exposure on endothelial cells and A549 tumor cells was analyzed by immunofluoresence staining. The mechanism of the enhanced antitumor effect was examined by histology and antibody-dependent cell-mediated cytotoxicity experiments.

Results: Focal irradiation of A549 human lung cancer xenografts increased the percentage of tumor vessels with exposed phosphatidylserine from 4% to 26%. Treatment of mice bearing A549 tumors with 2aG4 plus focal radiation therapy inhibited tumor growth by 80% and was superior to radiation therapy or 2aG4 alone (P < 0.01). Combination therapy reduced blood vessel density and enhanced monocyte infiltration into the tumor mass beyond that observed with individual treatments. In vitro, 2aG4 enhanced the ability of macrophages to kill endothelial cells with exposed phosphatidylserine in an Fc′-dependent manner.

Conclusion: These results suggest that 2aG4 enhances the antitumor effects of radiation therapy by increasing antibody-dependent cell-mediated cytotoxicity toward tumor vessels with externalized phosphatidylserine. Bavituximab, a chimeric version of 2aG4 in clinical trials, has the potential to enhance the therapeutic efficacy of radiation therapy in lung cancer patients.
CXCL12 G801A Polymorphism Is a Risk Factor for Sporadic Prostate Cancer Susceptibility
Authors: Hirata Hiroshi , Hinoda Yuji , Kikuno Nobuyuki , Kawamoto Ken , Dahiya Angela V. , Suehiro Yutaka , Tanaka Yuichiro , Dahiya Rajvir
Published: September 2007

Purpose: The chemokine CXCL12 and its receptor CXCR4 have been found to be associated with cancer metastasis. A single nucleotide polymorphism of CXCL12 G801A has been described and is regarded as a target for cis-acting factor that has the ability to up-regulate CXCL12 expression. Currently, there are no reports investigating the role of CXCL12 G801A polymorphism in prostate cancer (PC).

Experimental Design: We genotyped CXCL12 G801A and p53Arg72Pro in 167 PC patients and 167 age-matched healthy subjects. Genotyping was done with PCR-RFLP and confirmed by direct DNA sequencing. To investigate the effect of the CXCL12 G801A polymorphism on CXCL12 and CXCR4 expression, immunohistochemistry was done in genotyped PC tissues.

Results: A significant increase in the GA + AA genotype of the CXCL12 G801A polymorphism was observed in PC patients compared with healthy controls. The frequency of CXCL12 AA genotype was significantly higher in a group of patients with lymph node metastasis (23%) compared with those without metastasis (7%). The frequency of CXCL12 expression in AA + GA genotype carriers was significantly higher than that in GG genotype carriers. Among the carriers with CXCL12 GA + AA genotypes, CXCR4 expression was also significantly higher compared with those with the GG genotype. Moreover, among the groups with both CXCL12- and CXCR4-positive staining, the frequency of the CXCL12 GA + AA genotype was high. Although we did not find a significant relationship between the frequency of the Arg/Pro + Pro/Pro genotype of p53 Arg72Pro and susceptibility in PC, there was a combined effect of CXCL12 GA + AA genotype and the p53 72Arg/Pro + Pro/Pro genotype on the frequency of PC. These results indicate that the p53 codon 72 polymorphism may interact with CXCL12 G801A.

Conclusions: This is the first report showing that CXCL12 G801A polymorphism may be a risk factor for PC. Moreover, this study suggests that this polymorphism can be an important marker for detecting microinvasion and PC metastasis.
Inactivation of HOXA Genes by Hypermethylation in Myeloid and Lymphoid Malignancy is Frequent and Associated with Poor Prognosis
Authors: Strathdee Gordon , Holyoake Tessa L. , Sim Alyson , Parker Anton , Oscier David G. , Melo Junia V. , Meyer Stefan , Eden Tim , Dickinson Anne M. , Mountford Joanne C. , Jorgensen Heather G. , Soutar Richard , Brown Robert
Published: September 2007

Purpose: The HOX genes comprise a large family of homeodomain-containing transcription factors, present in four separate clusters, which are key regulators of embryonic development, hematopoietic differentiation, and leukemogenesis. We aimed to study the role of DNA methylation as an inducer of HOX gene silencing in leukemia.

Experimental Design: Three hundred and seventy-eight samples of myeloid and lymphoid leukemia were quantitatively analyzed (by COBRA analysis and pyrosequencing of bisulfite-modified DNA) for methylation of eight HOXA and HOXB cluster genes. The biological significance of the methylation identified was studied by expression analysis and through re-expression of HOXA5 in a chronic myeloid leukemia (CML) blast crisis cell line model.

Results: Here, we identify frequent hypermethylation and gene inactivation of HOXA and HOXB cluster genes in leukemia. In particular, hypermethylation of HOXA4 and HOXA5 was frequently observed (26-79%) in all types of leukemias studied. HOXA6 hypermethylation was predominantly restricted to lymphoid malignancies, whereas hypermethylation of other HOXA and HOXB genes was only observed in childhood leukemia. HOX gene methylation exhibited clear correlations with important clinical variables, most notably in CML, in which hypermethylation of both HOXA5 (P = 0.00002) and HOXA4 (P = 0.006) was strongly correlated with progression to blast crisis. Furthermore, re-expression of HOXA5 in CML blast crisis cells resulted in the induction of markers of granulocytic differentiation.

Conclusion: We propose that in addition to the oncogenic role of some HOX family members, other HOX genes are frequent targets for gene inactivation and normally play suppressor roles in leukemia development.
Is There a Human Homologue to the Murine Proteolysis-Inducing Factor?
Authors: Wieland Barbara M. , Stewart Grant D. , Skipworth Richard J.E. , Sangster Kathryn , Fearon Kenneth C.H. , Ross James A. , Reiman Tony J. , Easaw Jay , Mourtzakis Marina , Kumar Vishesh , Pak Brian J. , Calder Kathryn , Filippatos Gerasimos , Kremastinos Dimitris T. , Palcic Monica , Baracos Vickie E.
Published: September 2007

Purpose: A tumor-derived proteolysis-inducing factor (PIF) is suggested to be a potent catabolic factor in skeletal muscle of mice and humans. We aimed to establish the clinical significance of PIF in cancer patients and to elucidate its structural features.

Experimental Design: PIF was detected in human urine using a monoclonal antibody (mAb) and related to clinical outcomes. PIF immunoaffinity-purified using the mAb was purified/separated using reverse-phase high-performance liquid chromatography and two-dimensional electrophoresis. Ten human cancer cell lines were tested for expression of mRNA encoding PIF core peptide.

Results: PIF immunoreactivity was present in 160 of 262 patients with advanced cancers of the lung, esophagus/stomach, and other organs. In a Kaplan-Meier survival analysis of 181 lung cancer patients, PIF was unrelated to survival; PIF status was also unrelated to skeletal muscle loss confirmed by computed tomography imaging. PIF was seen in 16 of 24 patients with chronic heart failure and thus is not exclusive to malignant disease. In-gel digestion and mass spectrometric analysis of immunoaffinity purified PIF from cancer patients consistently identified human albumin and immunoglobulins. We showed nonspecific binding of purified albumin and immunoglobulins to the anti-PIF mAb, which is thus not a useful tool for PIF detection or purification in humans. Finally, the human PIF core peptide was detected in human cancer cell lines using reverse transcription-PCR and nucleotide sequencing; however, none of the amplified products had a site for the glycosylation critical to the proteolysis-inducing activity of murine PIF.

Conclusions: A putative human homologue of murine PIF and its role in human cancer cachexia cannot be verified.
Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative
Authors: Molinolo Alfredo A. , Hewitt Stephen M. , Amornphimoltham Panomwat , Keelawat Somboon , Rangdaeng Samraeung , Meneses García Abelardo , Raimondi Ana R. , Jufe Rafael , Itoiz María , Gao Yan , Saranath Dhananjaya , Kaleebi George S. , Yoo George H. , Leak Lee , Myers Ernest M. , Shintani Satoru , Wong David , Massey H. Davis , Yeudall W. Andrew , Lonardo Fulvio , Ensley John , Gutkind J. Silvio
Published: September 2007

Purpose: As an approach to evaluate the expression pattern and status of activation of signaling pathways in clinical specimens from head and neck squamous cell carcinoma (HNSCC) patients, we established the Head and Neck Cancer Tissue Array Initiative, an international consortium aimed at developing a high-density HNSCC tissue microarray, with a high representation of oral squamous cell carcinoma.

Experimental Design: These tissue arrays were constructed by acquiring cylindrical biopsies from multiple individual tumor tissues and transferring them into tissue microarray blocks. From a total of 1,300 cases, 547 cores, including controls, were selected and used to build the array.

Results: Emerging information by the use of phosphospecific antibodies detecting the activated state of signaling molecules indicates that the Akt-mammalian target of rapamycin (mTOR) pathway is frequently activated in HNSCC, but independently from the activation of epidermal growth factor receptor or the detection of mutant p53. Indeed, we identified a large group of tissue samples displaying active Akt and mTOR in the absence of epidermal growth factor receptor activation. Furthermore, we have also identified a small subgroup of patients in which the mTOR pathway is activated but not Akt, suggesting the existence of an Akt-independent signaling route stimulating mTOR.

Conclusions: These findings provide important information about the nature of the dysregulated signaling networks in HNSCC and may also provide the rationale for the future development of novel mechanism-based therapies for HNSCC patients.
Cyberdemocracy and Online Politics: A New Model of Interactivity
Authors: Ferber Paul , Foltz Franz , Pugliese Rudy
Published: September 2007

Building on McMillan's two-way model of interactivity, this study presents a three-way model of interactive communication, which is used to assess political Web sites' progress toward the ideals of cyberdemocracy and the fostering of public deliberation. Results of a 3-year study of state legislature Web sites, an analysis of the community networks, and a review of purely political sites such as MoveOn.org, RNC.org, and DNC.org are reported. Little deliberation was found on the legislature sites, but opportunities for such were greater on the other types of sites.
The Legal Landscape Following Technological Change: Paths to Adaptation
Authors: Moses Lyria Bennett
Published: September 2007

This article identifies the types of legal issues that result from technological change and discusses the different institutions involved in resolving those problems. It demonstrates that, despite the focus on political solutions, other institutions also have a role to play in solving legal dilemmas presented by technological change. Legislation may not always be necessary and can cause problems, especially where a technology is likely to evolve further. Even where legislative solutions are necessary, it is important to factor in the role played by other institutions when crafting legislation.
Putting the Community Back Into Community Networks: A Content Analysis
Authors: Horning Michael A.
Published: September 2007

This study examines the role that community networks can take in fulfilling McQuail's call for a more democratic-participant form of mass media. Community networks, which are online grassroots organizations designed to promote local community initiatives, increased their Internet presence in the 1990s. However, their number has declined in recent years. Earlier research has suggested that community networks fail because they lack a unified identity, have not determined their specific purpose on the Web, and do not provide relevant information to network members. Findings suggest that community networks wishing to achieve sustainability should concentrate their efforts on developing social capital and fostering strong democracy. This study examines the extent to which those existing community networks are working toward developing such content on their sites. Findings suggest that community networks are currently working toward developing content that promotes social capital but that far fewer networks are using their sites to promote strong democracy.
The Autonomy of Technology: Do Courts Control Technology or Do They Just Legitimize Its Social Acceptance?
Authors: Chandler Jennifer
Published: September 2007

This article draws on the suggestion that modern technology is “autonomous” in that our social control mechanisms are unable to control technology and instead merely adapt society to integrate new technologies. In this article, I suggest that common law judges tend systematically to support the integration of novel technologies into society. For example, courts sometimes require parties seeking compensation for serious injuries to submit to medical technologies to which the parties object for genuine reasons of fear or moral objection. Where a novel technology alters the environment in some way, courts sometimes legitimize that alteration by refusing to recognize harm and instead characterizing avoidance of the technology as self-imposed harm. The examples selected in this article were chosen to support the hypothesis in one way or another, and future work will aim to look for counter examples and to conduct a more complete assessment of the hypothesis.
STS Requires Changes in Teaching
Authors: Yager Robert E.
Published: September 2007

The major advantage of STS is the kind of teaching it allows and demands. Twelve middle school teachers who were enthused with STS teaching selected two sections for a research study. One section was the experimental STS section; the other followed the course syllabus and textbook closely. The major findings indicate the advantages for STS as a teaching approach.

Students at the STS approach learned as many science concepts as students who were taught such concepts directly. But the students in the STS sections were superior in all other aspects, including understanding and use of 14 process skills, use of creative thinking skills, development of more positive attitudes, better ability to apply and connect ideas and skills to other situations, and developing a better understanding of the nature and history of science.
Discourses of Authenticity Within a Pagan Community
Authors: Coco Angela , Woodward Ian
Published: September 2007

The commodification of the religious impulse finds its most overt expression in the New Age movement and its subculture neopaganism. This article examines discourses in the pagan community in an Australian state. Pagans, who have been characterized as individualist, eclectic, and diverse in their beliefs and practices, network through electronic mail discussion lists and chat forums as well as through local and national offline gatherings. We explore community building and boundary defining communications in these discourses. In particular, we examine interactions that reveal the mobilization of pagans' concern with authenticity in the context of late-capitalism, consumer lifestyles, and media representations of the “craft.” Our analysis highlights a series of tensions in pagans' representations of and engagement with consumer culture which are evident in everyday pagan discourse. These notions of in/authenticity are captured by invoking the “fluffy bunny” sanction.
The Purpose (and Perils) of Government-Nonprofit Partnership
Authors: Gazley Beth , Brudney Jeffrey L.
Published: September 2007

This study seeks to understand similarities and differences in why local governments and nonprofits choose to collaborate, particularly when those relationships are not governed by formal contracts or grants. Exchange, transaction, and resource dependence theories are used to understand the perceived advantages and disadvantages of collaboration as expressed by local government and nonprofit executives. Based on two large, comparable samples from Georgia, the analysis finds that the two sectors demonstrate a remarkable similarity in the benefits they seek from public-private partnerships, but with some key differences. The motivation to partner is driven by a desire to secure those resources most scarce for the respective sector: expertise and capacity for government, funding for nonprofits. Nonprofit executives generally exhibit a stronger undercurrent of negativity toward intersectoral partnership than do their public sector counterparts. This article discusses possible reasons for these similarities and differences and contributes to the scholarship linking capacity with organizational outcomes.
The Effects of Children and Employment Status on the Volunteer Work of American Women
Authors: Rotolo Thomas , Wilson John
Published: September 2007

Competing demands from work and family make it difficult for women to do volunteer work. An analysis of data from the Young Women's Cohort of the National Longitudinal Survey (1978-1991) shows that homemakers are more likely to volunteer than are full-time workers, followed by part-time workers. Mothers of school-age children are the most likely to volunteer, followed by childless women and mothers of young children. Mothers of school-age children are even more likely to volunteer if they are homemakers, and mothers of pre-school children are even less likely to volunteer if they work full-time.
High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation
Authors: Lee Stephanie J. , Klein John , Haagenson Michael , Baxter-Lowe Lee Ann , Confer Dennis L. , Eapen Mary , Fernandez-Vina Marcelo , Flomenberg Neal , Horowitz Mary , Hurley Carolyn K. , Noreen Harriet , Oudshoorn Machteld , Petersdorf Effie , Setterholm Michelle , Spellman Stephen , Weisdorf Daniel , Williams Thomas M. , Anasetti Claudio
Published: September 2007

The relative importance of various human leukocyte antigen (HLA) loci and the resolution level at which they are matched has not been fully defined for unrelated donor transplantation. To address this question, National Marrow Donor Program data from 3857 transplantations performed from 1988 to 2003 in the United States were analyzed. Patient-donor pairs were fully typed for HLA-A, -B, -C, -DRB1, -DQB1, -DQA1, -DPB1, and -DPA1 alleles. High-resolution DNA matching for HLA-A, -B, -C, and -DRB1 (8/8 match) was the minimum level of matching associated with the highest survival. A single mismatch detected by low- or high-resolution DNA testing at HLA-A, -B, -C or -DRB1 (7/8 match) was associated with higher mortality (relative risk, 1.25; 95% CI, 1.13-1.38; P < .001) and 1-year survival of 43% compared with 52% for 8/8 matched pairs. Single mismatches at HLA-B or HLA-C appear better tolerated than mismatches at HLA-A or HLA-DRB1. Mismatching at 2 or more loci compounded the risk. Mismatching at HLA-DP or -DQ loci and donor factors other than HLA type were not associated with survival. In multivariate modeling, patient age, race, disease stage, and cytomegalovirus status were as predictive of survival as donor HLA matching. High-resolution DNA matching for HLA-A, -B, -C, and -DRB1 alleles is associated with higher rates of survival.
The PreCardio-study protocol – a randomized clinical trial of a multidisciplinary electronic cardiovascular prevention programme
Authors: Claes Neree , Jacobs Nele
Published: September 2007

Background

Cardiovascular diseases (CVD) are the leading cause of death and the third cause of disability in Europe. Prevention programmes should include interventions aimed at a reduction of medical risk factors (hypertension, hypercholesterol, hyperglycemia, overweight and obesity) as well as behavioural risk factors (sedentary lifestyle, high fat intake and low fruit and vegetable intake, smoking). The aim of this study is to investigate the effects of a multifaceted, multidisciplinary electronic prevention programme on cardiovascular risk factors.

Methods/Design

In a randomized controlled trial, one group will receive a maximal intervention (= intervention group). The intervention group will be compared to the control group receiving a minimal intervention. An inclusion of 350 patients in total, with a follow-up of 3 years is foreseen. The inclusion criteria are age between 25–65 and insured by the Onderlinge Ziekenkas, insuring for guaranteed income in case of illness for self-employed. The maximal intervention group receives several prevention consultations by their general practitioner (GP) using a new type of cardiovascular risk calculator with personalised feedback on behavioural risk factors. These patients receive a follow-up with intensive support of health behaviour change via different methods, i.e. a tailored website and personal advice of a multidisciplinary team (psychologist, physiotherapist and dietician). The aim of this strategy is to reduce cardiovascular risk factors according to the guidelines. The primary outcome measures will be cardiovascular risk factors. The secondary outcome measures are cardiovascular events, quality of life, costs and incremental cost effectiveness ratios. The control group receives prevention consultations using a new type of cardiovascular risk calculator and general feedback.

Discussion

This trial incorporates interventions by GPs and other health professionals aiming at a reduction of medical and behavioural cardiovascular risk factors. An assessment of clinical, psychological and economical outcome measures will be performed.

Trial registration

ISRCTN23940498
Effect of oral lactulose on clinical and immunohistochemical parameters in patients with inflammatory bowel disease: a pilot study
Authors: Hafer Anne , Krämer Sigrid , Duncker Swantje , Krüger Martin , Manns Michael P , Bischoff Stephan C
Published: September 2007

Background

The prebiotic potential of lactulose is well established and preclinical studies demonstrated a protective effect of lactulose in murine models of colitis. The aim of the present study was to investigate the clinical and histological efficacy of lactulose in patients with inflammatory bowel disease (IBD), for which probiotic therapy yielded promising results.

Methods

Patients were treated with standard medication alone or combined with 10 g lactulose daily as adjuvant therapy for 4 months. Clinical efficacy of treatment was assessed using clinical activity indices, a quality of life index (IBDQ), endoscopic scores, defecation frequency and monitoring corticosteroid medication. Orsomucoid, alpha1-antitrypsin and other laboratory parameters were determined. In addition, in some participants colonic biopsies were analyzed with haematoxylin-eosin staining or with antibodies against HLA-DR, CD68, IgA and CD3, and evaluated systematically. All measurements were performed both at enrolment and at the end of the trial.

Results

14 patients presenting ulcerative colitis (UC) and 17 patients presenting Crohn's disease (CD), most of them in a clinically active state, were enrolled in this pilot study. After 4 month no significant improvement of clinical activity index, endoscopic score or immunohistochemical parameters was observed in CD or UC patients receiving lactulose in comparison to the control group. However, significant improvement of quality of life was observed in UC patients receiving lactulose compared to the control group (p = 0.04).

Conclusion

The findings of the present pilot study indicate that oral lactulose has no beneficial effects in IBD patients in particular with regard to clinical activity, endoscopic score or immunohistochemical parameters. The importance of the beneficial effect of lactulose in UC patients regarding the quality of life needs further evaluation in larger controlled clinical trials.

Trial registration

Current Controlled Trials ISRCTN92101486
Association between the BRCA2N372H variant and male breast cancer risk: a population-based case-control study in Tuscany, Central Italy
Authors: Palli Domenico , Falchetti Mario , Masala Giovanna , Lupi Ramona , Sera Francesco , Saieva Calogero , D'Amico Cristina , Ceroti Marco , Rizzolo Piera , Caligo Maria Adelaide , Zanna Ines , Ottini Laura
Published: September 2007

Background

Male breast cancer (MBC) is a rare disease and little is known about its aetiology. Germ-line mutations of BRCA2 and, at lower frequency, of BRCA1 are implicated in a relatively small proportion of MBC cases. Common polymorphic variants in BRCA1 and BRCA2 genes may represent breast cancer (BC) susceptibility alleles and could be associated with a modestly increased risk of MBC at population level. Considering the relevant role of BRCA2 in MBC, we investigated whether the BRCA2 N372H variant, representing the only common non-synonymous polymorphism in BRCA2, might modulate the risk of BC in male populations.

Methods

A case-control study was performed comparing a population-based series of 99 MBC cases, characterized for BRCA1 and BRCA2 mutations, with 261 male population controls, all residing in Tuscany, Central Italy. All MBC cases and controls were genotyped for the BRCA2 N372H allele by TaqMan allelic discrimination assays. To evaluate the genotype specific risk of the BRCA2 N372H variant, MBC carriers of germ-line BRCA1/2 mutations were excluded from the analyses.

Results

No association emerged in univariate and age-adjusted analyses. Age-specific analyses suggested an increased risk for the HH homozygous genotype in subjects younger than 60 years. A statistically significant interaction emerged between this genotype and age (p = 0.032). When analyses were restricted to MBC cases enrolled in the first 4 years following diagnosis, a recessive model showed a significantly increased risk of MBC in HH subjects younger than 60 years (OR = 5.63; 95% CI = 1.70;18.61).

Conclusion

Overall, our findings, although based on a relatively small series, suggest that the BRCA2 HH homozygous genotype might be positively associated with an increased risk of MBC in men younger than 60 years.
Measuring hospital-wide activity volume for patient safety and infection control: a multi-centre study in Japan
Authors: Hayashida Kenshi , Imanaka Yuichi , Fukuda Haruhisa
Published: September 2007

Background

In Japan, as in many other countries, several quality and safety assurance measures have been implemented since the 1990's. This has occurred in spite of cost containment efforts. Although government and hospital decision-makers demand comprehensive analysis of these activities at the hospital-wide level, there have been few studies that actually quantify them. Therefore, the aims of this study were to measure hospital-wide activities for patient safety and infection control through a systematic framework, and to identify the incremental volume of these activities implemented over the last five years.

Methods

Using the conceptual framework of incremental activity corresponding to incremental cost, we defined the scope of patient safety and infection control activities. We then drafted a questionnaire to analyze these realms. After implementing the questionnaire, we conducted several in-person interviews with managers and other staff in charge of patient safety and infection control in seven acute care teaching hospitals in Japan.

Results

At most hospitals, nurses and clerical employees acted as the main figures in patient safety practices. The annual amount of activity ranged from 14,557 to 72,996 person-hours (per 100 beds: 6,240; per 100 staff: 3,323) across participant hospitals. Pharmacists performed more incremental activities than their proportional share. With respect to infection control activities, the annual volume ranged from 3,015 to 12,196 person-hours (per 100 beds: 1,141; per 100 staff: 613). For infection control, medical doctors and nurses tended to perform somewhat more of the duties relative to their share.

Conclusion

We developed a systematic framework to quantify hospital-wide activities for patient safety and infection control. We also assessed the incremental volume of these activities in Japanese hospitals under the reimbursement containment policy. Government and hospital decision makers can benefit from this type of analytic framework and its empirical findings.
Genomic analysis reveals the major driving forces of bacterial life in the rhizosphere
Authors: Matilla Miguel A , Espinosa-Urgel Manuel , Rodríguez-Herva José J , Ramos Juan L , Ramos-González María Isabel
Published: September 2007

Background

Mutualistic interactions less well known than those between rhizobia and legumes are commonly found between plants and bacteria, frequently pseudomonads, which colonize roots and adjacent soil areas (the rhizosphere).

Results

A global analysis of Pseudomonas putida genes expressed during their interaction with maize roots revealed how a bacterial population adjusts its genetic program to this lifestyle. Differentially expressed genes were identified by comparing rhizosphere-colonizing populations with three distinct controls covering a variety of nutrients, growth phases and life styles (planktonic and sessile). Ninety rhizosphere up-regulated (rup) genes, which were induced relative to all three controls, were identified, whereas there was no repressed gene in common between the experiments. Genes involved in amino acid uptake and metabolism of aromatic compounds were preferentially expressed in the rhizosphere, which reflects the availability of particular nutrients in root exudates. The induction of efflux pumps and enzymes for glutathione metabolism indicates that adaptation to adverse conditions and stress (oxidative) response are crucial for bacterial life in this environment. The finding of a GGDEF/EAL domain response regulator among the induced genes suggests a role for the turnover of the secondary messenger c-diGMP in root colonization. Several mutants in rup genes showed reduced fitness in competitive root colonization.

Conclusion

Our results show the importance of two selective forces of different nature to colonize the rhizosphere: stress adaptation and availability of particular nutrients. We also identify new traits conferring bacterial survival in this niche and open a way to the characterization of specific signalling and regulatory processes governing the plant-Pseudomonas association.
L2 output, reformulation and noticing: Implications for IL development
Authors: Adams Rebecca
Published: September 2007

This study is a replication and extension of Swain and Lapkin's (in press) study of the developmental effects of learners noticing differences between their own and native speaker output. In their study, task repetition, noticing and participation in stimulated recalls were all factors that might have contributed to more targetlike usage in subsequent output. The current study separated the effects of each of these factors. Fifty-six L2 Spanish learners were randomly assigned to three groups: (1) Task repetition (participants repeated the tasks without additional treatment); (2) Noticing (participants repeated the task and compared their original output to NS reformulation); and (3) Noticing + SR (same as Noticing group with the addition of a stimulated recall session). Reformulations were traced throughout the learners’ output. Analysis of the data indicates that learners noticed differences between their own essays and the reformulated writing, and that there were quantitative differences in the output of participants from different treatment groups, with learners who participated in both noticing and stimulated recall incorporating significantly more targetlike forms in the post-treatment output than learners from the other groups.
Does manipulating foreknowledge of output tasks lead to differences in reading behaviour, text comprehension and noticing of language form?
Authors: Yoshimura Fumiko
Published: September 2007

This paper reports an experiment that addresses whether manipulating foreknowledge of output tasks leads to differences in reading behaviour, text comprehension and noticing of language form. Three tasks are used: reading for memorization, reading for retelling and reading for visualization. Reading for memorization and reading for retelling are different kinds of FL (foreign language) output tasks, while reading for visualization does not involve any FL output. The participants’ reading behaviour, text comprehension and noticing of language form were analysed using self-reports, comprehension test scores and retention or appropriate use of verb forms in the subsequent text production. The results suggest that foreknowledge of output tasks did influence reading behaviour: Participants used more translation into their L1, showed more matching between their interlanguage and target language, and paid more attention toward language form in the input. In addition, distinct reading behaviour and noticing of form were induced by different kinds of output tasks. Little difference was found in the text comprehension among the three groups. Implications from this study are (1) that language processing is affected by foreknowledge of output tasks - whether or not those output tasks are actually performed - and (2) different kinds of output tasks seem to cause different effects on language processing.
NKG2D and Natural Cytotoxicity Receptors Are Involved in Natural Killer Cell Interaction with Self‐Antigen Presenting Cells and Stromal Cells
Authors: POGGI ALESSANDRO , PREVOSTO CLAUDIA , ZANCOLLI MARTA , CANEVALI PAOLO , MUSSO ALESSANDRA , ZOCCHI MARIA RAFFAELLA
Published: September 2007

Abstract:  It is thought that human natural killer (NK) lymphocytes should not damage self‐tissues due to the inhibiting signal initiated by the engagement of one or another inhibitory receptor superfamily (IRS) members with self‐human histocompatibility antigen (HLA)‐I. During viral infection, the low expression of self‐HLA‐I on infected‐cells leads to a reduction of the inhibiting signal and thus NK cells kill self‐cells (missing self‐hypothesis). Here, we have analyzed human NK cell interaction with self‐cells as antigen‐presenting cells (APC) or stromal cells isolated from bone marrow or skin. Despite the expression of high levels of HLA‐I, APC and stromal cells are killed by interleukin (IL)‐2‐activated NK cells upon lymphocyte function antigen (LFA)1–(intracellular adhesion molecule) (ICAM)1 interaction. The natural cytotoxicity receptors NKp30 and NKp46 are responsible for the delivery of lethal hit to APC, whereas NKG2D‐activating receptor, the ligand of the major histocompatibility complex (MHC)‐related molecule MICA, and the UL16‐binding protein are involved in stromal cell killing. These events are dependent on the activation of phosphoinositol 3‐kinase and consequent release of perforins and granzymes. Both bone marrow stromal cells and skin fibroblasts inhibit T cell proliferation to alloantigen or triggering through CD3/T cell receptor complex. Importantly, NK cells can revert this veto effect. Altogether, these findings support the notion that NK cells can recognize self‐cells possibly affecting both APC function and interaction between lymphocytes and microenvironment leading to autoreactivity.
Human Proteinase 3 (PR3) and Its Binding Molecules
Authors: MÜLLER ANTJE , VOSWINKEL JAN , GOTTSCHLICH STEFAN , CSERNOK ELENA
Published: September 2007

Abstract:  Human proteinase 3 (PR3) is a multifunctional serine protease, mainly located in the azurophilic granules and on the cell surface of polymorphonuclear leukocytes (PMN). Cumulated data indicate that PR3, which is the main target autoantigen of antineutrophilic cytoplasmic antibodies (ANCA), interacts with several surface receptors and participates in the local inflammatory response. Herein, we summarize the efforts made to elucidate ANCA‐binding epitopes of PR3, extended by data derived from the use of a random peptide library. The inserts for 107 peptides were obtained by panning of a random peptide library with PR3‐ANCA+ immunoglobulins. Analysis of the amino acid sequences of the inserted peptides derived from isolated positive clones suggested that they do not belong to linear epitopes of PR03 and possess a high proportion of positively charged amino acids. Furthermore, this article focuses on immune functions of PR3 with respect to PR3 modulation of cell activation via cleavage of protease‐activated receptor‐2 (PAR‐2) and as binding protein for the proinflammatory cytokine IL‐32α. Altogether, there are a number of (auto)molecules that bind to PR3, some of them even competitive and each binding interaction seems to have specific implications.
Loss of Self‐Control in the Complement System and Innate Autoreactivity
Authors: MERI SEPPO
Published: September 2007

Abstract:  The complement system performs effective antimicrobial and clean‐up functions to keep the body clear from invading microbes and accumulating debris. From its about 35 components many regulate complement activity to prevent self‐attack. Our work has focused on regulator defects and dysfunctions that cause autoreactivity, that is, inflammation and damage against self‐tissues (“innate autoreactivity”). The major complement regulator, factor H (FH), protects host cells and keeps excessive amplification under control. Mutations and polymorphisms in FH predispose to four different diseases: membranoproliferative glomerulonephritis type II (MPGN II), partial lipodystrophy (PLD), recurrent atypical hemolytic uremic syndrome (aHUS), and age‐related macular degeneration (AMD). Loss of the complement regulatory activity (cofactor activity for C3b inactivation and decay accelerating activity) in the N terminus of FH leads to PLD and MPGN II, the latter of which is characterized by C3b and MAC deposition on the glomerular basement membranes of kidneys. Polymorphism in the SCR7‐domain in the middle part of FH predisposes to AMD, which is the most common cause of vision loss in elderly people. This polymorphism influences the ability of FH to bind to C‐reactive protein (CRP) and to target phagocytic clearance of debris (e.g., eye pigment) and control local inflammation. Finally, the loss of the ability of the FH C terminus to recognize C3b molecules deposited on self‐structures predisposes to aHUS, where blood cells, platelets, and endothelial cells, particularly in kidneys, become targets for repeated complement attacks and increased procoagulant activity. The pathogenetic mechanisms of these diseases are being increasingly understood, which in the future will help in designing new therapies.
Alterations of Th1/Th2 Reactivity by Heavy Metals
Authors: HEMDAN NASR Y. A. , EMMRICH FRANK , FABER SONYA , LEHMANN JOERG , SACK ULRICH
Published: September 2007

Abstract:  Heavy metal pollution still represents a primary concern regarding human health. Recently, it become evident that the contribution of heavy metals extends far beyond their accepted role in allergic diseases, and that they may play a more extensive role in a variety of other diseases. Several lines of evidence indicate that heavy metals have a key role in the induction or exacerbation of several autoimmune diseases (AD). Moreover, the association between exposure to heavy metals and the signs of autoimmunity are supported by some studies. The mechanisms by which heavy metals induce the development of AD are not yet fully understood. Our objective here is to highlight the association of exposure to some heavy metals and AD. In addition, we present recent results showing the possible alterations in Th1/Th2 reactivity by some heavy metals, which may constitute the trigger for the incidence of autoimmunity in susceptible individuals.
Effector Memory CD8+ T Cells Are Resistant to Apoptosis
Authors: GUPTA SUDHIR , GOLLAPUDI SASTRY
Published: September 2007

Abstract:  Based upon their migrating properties and effector functions, CD8+ T cells have been further classified into central memory (TCM) and two types of effector memory (TEM and TEMRA) cells. These memory cells display distinct replicative characteristics. Because apoptosis plays an important role in cellular homeostasis, we have examined the relative sensitivity of naïve (TN) and different memory CD8+ T cells to apoptosis. We show that both TEM and TEMRA CD8+ T cells are resistant to apoptosis, whereas TN and TCM CD8+ T cells are sensitive to apoptosis.
Autoimmune Reactions after Electro‐oxidation of IgG from Healthy Persons
Authors: BOŽIČ BORUT , ČUČNIK SAŠA , KVEDER TANJA , ROZMAN BLAŽ
Published: September 2007

Abstract:  Proteins, including immunoglobulins, can be modified by oxidation. Extensive oxidation of immunoglobulins leads to denaturation and loss of biological activity, while initial steps of oxidation may change their specificity due to chemical alteration of the paratope. Electro‐oxidation of the IgG fraction from healthy persons progress to auto‐immunoreactivity, as shown for several autoantibodies including anti‐β2‐glycoprotein I. Changes in immunoreactivity of IgG due to oxidative reactions highly depend on electric current and levels of serum antioxidants. Autoimmune reactions, leading to certain autoimmune diseases, may be partially a consequence of unbalanced antioxidative status of an individual.
Diagnosing Diseases by Measurement of Electrical Skin Impedance
Authors: WEITZEN RONY , EPSTEIN NAVA , SHOENFELD YEHUDA , ZIMLICHMAN EYAL
Published: September 2007

Abstract:  Recently, we have seen the development of diagnostic tools based on the rationale that the measurement of electrical impedance of specific dermal zones might reflect the occurrence of pathological states in corresponding internal organs. Studies published lately have shown the diagnostic potential of this technique. We set out to evaluate the accuracy of this tool in diagnosing cancer. Our study group was composed of cancer patients visiting the Oncology clinic for a routine follow‐up. All patients underwent conventional medical history and physical examination by a physician. We evaluated a device manufactured by Medex Screen Ltd. The device analysis was carried out by a physician who was blinded to the previous diagnosis. A third researcher compared the “conventional” diagnosis with the Medex device output using standard statistical analysis. Overall, 125 cancer patients were included in the study. When comparing Medex Screen diagnostic technique with the conventional methods of diagnosis for the various disorders we found a sensitivity of 76.2%, 78.7%, and 92.9% and a specificity of  95.0%, 90.7%, and 90.4% for lung, breast, and prostate cancer, respectively. Existence of metastatic disease or specific treatment did not affect the diagnostic properties of the described device. Although the exact mechanism is not entirely clear, measurement of electrical impedance of dermal–visceral zones has the potential to serve as a diagnostic and perhaps a screening tool for neoplastic pathologies. Further research should be conducted to create more evidence to support or dispute the use of this technique as a reliable diagnostic tool.