bluuebunny/crossref_metadata_2025 huggingface dataset:
Mathematics Anxiety and the Affective Drop in Performance
Authors: Ashcraft Mark H. , Moore Alex M.
Published: April 2009

The authors provide a brief review of the history and assessment of math anxiety, its relationship to personal and educational consequences, and its important impact on measures of performance. Overall, math anxiety causes an “affective drop,” a decline in performance when math is performed under timed, high-stakes conditions, both in laboratory tests as well as in educational settings. This means that math achievement and proficiency scores for math-anxious individuals are underestimates of true ability. The primary cognitive impact of math anxiety is on working memory, particularly problematic given the important role working memory plays in math performance. The authors conclude with a discussion of risk factors for math anxiety and some factors to be kept in mind when working with math-anxious students.
Relationship Between Parenting Stress and Ratings of Executive Functioning in Children With ADHD
Authors: Joyner Krystle B. , Silver Cheryl H. , Stavinoha Peter L.
Published: April 2009

Executive functioning is important to assess in children with attention deficit/hyperactivity disorder (ADHD). Parent report is used to obtain information about a child’s executive functioning; however, parent report can be influenced by many factors. This study’s hypothesis was that higher ratings of children’s executive dysfunction are associated with parenting stress. Parents of 32 children (ages 8-12 years) with ADHD completed the Parenting Stress Index and two executive function rating scales, the BRIEF and CEFS. Stress produced by child and family system characteristics was significantly correlated with composite scores and subscales from the executive function rating scales. Findings suggest that parent ratings of their children’s executive functioning appear related to the stress they experience being parents, particularly with regard to their children’s challenging behaviors.
Approximate Method for Buckling of Symmetric Composite Laminates under Thermal Loading
Authors: Barton Oscar
Published: April 2009

In this paper, an approximate closed-form solution is presented to compute the thermal buckling response of a symmetric angle-ply laminates that are clamped in one edge and free along the other edge. For this boundary condition, no exact solution is available and, in order to compute the critical buckling temperatures, numerical methods such as the Rayleigh—Ritz or finite element method must be used. Approximate closed-form solutions bridge the void between exact and approximate numerical solutions and can readily be employed in design optimization. The environment corresponds to a steady state condition providing a uniform temperature distribution for the laminate. The laminate consists of four layers [θ/-θ]s constructed of low, moderate, and high stiffness ratio materials. Comparative results using the Rayleigh—Ritz method provides a means of assessing the accuracy of the expression. For certain laminate architectures, several modes must be computed using the approximate quadratic expression to ascertain the lowest buckling mode, and once identified, provides an excellent approximation for the mode computed using the Rayleigh—Ritz method.
Foster Parent Intervention Engagement Moderating Child Behavior Problems and Placement Disruption
Authors: DeGarmo David S. , Chamberlain Patricia , Leve Leslie D. , Price Joe
Published: April 2009

Objective: The authors conduct a within intervention group analysis to test whether caregiver engagement (e.g., participation, homework completion, openness to ideas, apparent satisfaction) in a group-based intervention moderates risk factors for foster child outcomes in a state-supported randomized trial of caregiver parent training. Methods: The intervention is delivered in 16 weekly sessions by trained leaders. Outcomes are pre—post change in problem behaviors and negative placements. Results: Analysis of 337 caregivers nested within 59 parent groups show caregiver engagement moderates number of prior placements on increases in child problem behaviors, and moderates risk of negative placement disruption for Hispanics. Conclusions: Variance in parent group process affects program effectiveness. Implications for practice and increasing effective engagement are discussed.
An Evaluation of the Factor Structure of the Change Assessment Inventory for Domestic Violence among Korean Batterers
Authors: Jae Yop Kim  , Ah Young Song
Published: April 2009

Objective: Results of testing the original four-factor structure of the URICA—DV as well as two three-factor structures in prior researches is presented to investigate alternative structures suitable for Korean batterers. Method: This study developed the URICA—DV Korean Version and sought the most appropriate structure for a Korean context. The sample is 293 batterers either referred by the courts, by prosecution, or who participated voluntarily. Results: The original four-factor model and the two three-factor models are demonstrated as possessing poor model fit index and fail to be accepted as apt models for a Korean context. The suggested three-factor model is a better fit according to confirmatory factor analysis. Conclusion: Findings and further discussion for practical implications and research are presented.
The Effects of Cognitive—Behavioral Therapy on Trait Anger and Paranoid Ideation
Authors: González-Prendes A. Antonio , Jozefowicz-Simbeni Debra M. Hernández
Published: April 2009

Objective: This study evaluates a cognitive—behavioral anger treatment approach to reduce anger and paranoid ideation on men ( n = 32) in treatment for anger problems and compares levels of paranoid ideation with a sample of men ( n = 27) who sought mental health treatment for non-anger issues. Method: A pre- and posttest design is used to evaluate within- and between-groups differences on anger and paranoid ideation. Results: At pretest, the anger group has significantly higher scores on paranoid ideation than the non-anger group. Significant reductions in trait anger and paranoid ideation are recorded from pre- to posttreatment for the anger group. Conclusions: Cognitive—behavioral therapy for anger helps reduce anger and paranoid ideation. Limitations of the study are discussed.
Southeast Asian Parents Raising a Child With Autism: A Qualitative Investigation of Coping Styles
Authors: Luong June , Yoder Marian K. , Canham Daryl
Published: April 2009

Autism is a developmental disability increasing in incidence over the past decade. Parents of children with autism experience prolonged levels of stress and isolation. Using qualitative research design, nine parents of children with autism participated in this study that focused on the effect of autism on the family, coping styles, and support systems. The target population was first-generation Southeast Asian American parents. Results revealed nine coping style patterns: (a) denial/passive coping, (b) empowerment, (c) redirecting energy, (d) shifting of focus, (e) rearranging life and relationships, (f) changed expectations, (g) social withdrawal, (h) spiritual coping, and (i) acceptance. The school was considered the primary supportive entity. Although findings may not be unique to the Southeast Asian group, the research provides an in-depth perspective on their lived experience, their struggles, and strengths. Insight gained from this investigation can help school nurses better understand the affect of autism on families, identify specific needs, and address these needs by advocating for appropriate supportive programs.
The Relationship between Defense Spending and Economic Growth in the United States
Authors: Heo Uk
Published: April 2009

Recent increases in U.S. defense spending have renewed interest in the defense—growth nexus. The Feder-Ram—based models have traditionally been used in examining this relationship, but Dunn, Smith, and Willenbockel recommend the augmented Solow model because of several weaknesses inherent in the Feder-Ram model (including its static nature, simultaneity bias, and multicollinearity issues). The augmented Solow model addresses these issues, but it has weaknesses too. Thus, by employing both the Feder-Ram and augmented Solow models, the author tests the defense—growth nexus in the United States for 1954 through 2005. The results indicate that defense spending does not significantly affect the U.S. economy.
Diagnosing Attention-Deficit Hyperactivity Disorder in College Students
Authors: Katz Nolan , Petscher Yaacov , Welles Theresa
Published: April 2009

Objective: Formal criteria for the use informant-ratings of adult ADHD symptoms have not been established yet they are commonplace in standard assessment batteries. Method: The current study explores the relationship between self- and informant-ratings and the impact of requiring interrater agreement in a sample comprised of 190 self-referred college students. Results: Participants self-reported higher childhood and current symptoms scores and current impairment scores than informants. Similarities were evident between diagnostic groups who met ADHD criteria by self-report only and by both sources when considering the number of self-reported settings of impairment. Diagnostic groups who met criteria by informant-report only and by both sources were similar when considering informant-reported settings of impairment. Conclusion: Participants who meet criteria for ADHD based on one source endorse a similar number of settings of impairment as participants who meet criteria for ADHD by both sources. The implications for the use of informant-ratings are presented. (J. of Att. Dis. 2009; 13(3) 277-283)
The Role of Policy Advocacy in Assuring Comprehensive Family Life Education in California
Authors: Brindis Claire D. , Geierstanger Sara P. , Faxio Adrienne
Published: April 2009

As part of their 10-year $60 million Teenage Pregnancy Prevention Initiative, The California Wellness Foundation funded 18 state and local organizations to conduct policy advocacy to strengthen teen pregnancy prevention policies. This article describes how some of these grantees accomplished noteworthy goals, including the passage of the California Comprehensive Sexual Health and HIV/AIDS Prevention Education Act (SB71), the prevention of the state’s pursuit of federal “abstinence-only-until-marriage” funding, and the passage of a local school district FLE policy. Grantee progress is presented through a five-stage policy change framework: Institutional Capacity and Leadership Building, Policy Issue Recognition, Policy Prioritization, Policy Adoption, and Policy Maintenance. Implications are shared for advocates, policy makers, and funders who are developing initiatives aimed at improving the health of adolescents.
Anti-dialogic Positioning in Change Stories: Bank Robbers, Saviours and Peons
Authors: Beech Nic , MacPhail Stacy A. , Coupland Christine
Published: April 2009

Stories people tell of going through change incorporate and react to others around them. Positions can be taken in stories that tend towards the monological, having a singular perspective and being somewhat sealed off from others. Alternatively, stories can tend towards the dialogical, a multiple, less certain and more interactive mode. We explore multiple stories of an organizational change and analyse a paradoxical situation that emerges. We argue that although the stories may have the appearance of being dialogical, they can be seen as co-existing but self-sealing, or anti-dialogic. We introduce an interruption to the story and discuss a possibility for challenging anti-dialogic positioning in change stories.
A prognostic model for amputation in critical lower limb ischemia
Authors: Klomp HM , Steyerberg EW , Wittens CHA , van Urk H , Habbema JDF ,   For the ESES study group
Published: April 2009

Abstract

In a (negative) multicenter randomized trial on management for inoperable critical lower limb ischemia, comparing spinal cord stimulation and best medical treatment, a number of pre-defined factors were analyzed for prognostic value. We included a radiological arterial disease score, modified from the SVS/ISCVS runoff score. The purpose of this analysis was to evaluate clinical factors and commonly used circulatory measurements for prognostic modeling in patients with critical lower limb ischemia. We determined the incidence of amputation and its relation to various pre-defined risk factors. A total of 120 patients with critical limb ischemia were included in the study. The integrity of circulation in the affected limb was evaluated on five levels: suprainguinal, infrainguinal, popliteal, infrapopliteal and pedal. A total radiological arterial disease score was calculated from 1 (full integrity of circulation) to 20 (maximally compromised state). We used Cox regression analysis to quantify prognostic effects and differential treatment (predictive) effects. Major amputation occurred in 33% of the patients at 6 months and in 51% at 2 years. The presence of ischemic skin lesions and the radiological arterial disease score were independent prognostic factors for amputation. Patients with ulcerations or gangrene had a higher amputation risk (hazard ratio 2.38, p = 0.018 and 2.30, p = 0.036 respectively) as well as patients with a higher radiological arterial disease score (hazard ratio 1.17 per increment, p = 0.003). We did not observe significant interactions between prognostic factors and the effect of spinal cord stimulation. In conclusion, in patients with critical lower limb ischemia, the presence of ischemic skin lesions and the described radiological arterial disease score can be used to estimate amputation risk.
Short series of emergency stent-graft repair of symptomatic penetrating thoracic aortic ulcers (PTAU)
Authors: Girn HRS , McPherson S , Nicholson T , Mavor AID , Homer-Vanniasinkam S , Gough MJ
Published: April 2009

Abstract

Acute penetrating thoracic aortic ulcers (PTAU) are associated with vessel rupture, particularly when intramural haematoma (IMH) is present. Although surgical repair is the treatment of choice for PTAU in the aortic arch, definitive treatment of PTAU in other locations of the thoracic aorta remains controversial, particularly in this frail cohort of patients. Recent series of elective and semi-elective endovascular stent-graft repair of PTAU of the descending thoracic aorta show comparable results with the previously advocated best medical management. We report our results from a retrospective, observational study of acute stent-graft repair of symptomatic PTAU. Between 2000 and 2005, 11 patients (seven male, four female; median age 71 years) presented with acute PTAU. CT scans demonstrated an associated IMH in six, a contained leak in three or rupture in four unstable patients. All were covered by a single endovascular stent [Gore (5), Talent (5), Zenith (1); 10 inserted via the groin and one via iliac conduit within 1 week of presentation (five < 24 h). Technical success was 90.90% (10/11) and 3/11 (27%) died within 30 days (two ARDS, one a persistent leak and rupture at 48 h). One patient developed transient paraplegia; three haemothoraces required chest drains, one of which subsequently required empyema drainage. In survivors, CT scans were satisfactory, with no further intervention required at 32.5 (6–66) months of median follow-up. In conclusion, endovascular management of acute PTAU appears effective and durable with mortality rates that are likely to be better than for open surgery. However, haemodynamic compromise at presentation remains a robust denominator of over-all survival.
Whose body is it anyway? Verbalization, embodiment, and the creation of narratives
Authors: Antelius Eleonor
Published: April 2009

This article examines the creation of narratives between people with severe disabilities and the personnel working with them. It shows that although a co-created narrative of what it means to be severely disabled ( the story of dependence) seems to prevail, another narrative ( the story of autonomy ) is also told, where the story of dependence is rejected by the person with disabilities. However, this story of autonomy only becomes clear if we recognize three central claims: (1) there is a connection between where the physical body of the person with disabilities is positioned in space and what he or she is allowed or able to be and do; (2) since the body is a communicative tool, the moving of the body could be interpreted as a narrative, told through the embodiment of space; and (3) the embodied story can challenge existing social structures. The article highlights the inherent struggle for power within narrations and how the creation of alternative narratives can contest existing social structures.
New directions for civil renewal in Britain
Authors: Message Kylie
Published: April 2009

• As with most migration-related issues, it is cities that are on the front lines of the social cohesion debate. Museums — important as sites that represent nations and cities and their populations — have been positioned by national governments as strategic players in the debate, with the result that they are increasingly held accountable to claims that they are, or have the potential to become, central to the wellbeing of community life. This article explores the reasons that the public policy initiatives of cultural diversity, cultural cohesion, cultural capital and cultural industries have come to rely on museums as institutions that collect and create culture, in all its diverse forms, experiences and understandings. •
`deepthroatfucker' and `Discerning Adonis'
Authors: Attwood Feona
Published: April 2009

• This article uses interviews with male cybersex participants to examine their experiences of cybersex and considers constructions of `self' and `sex' in their discussions. It asks how the adoption of a cybersex persona is understood by participants and how they characterize their cybersexual practices in order to develop a clearer picture of the ways in which new forms of communication technology are implicated in producing new forms of sexual practice and how these relate to contemporary perceptions of what sex is. •
Questions, questioning, and institutional practices: an introduction
Authors: Tracy Karen , Robles Jessica
Published: April 2009

This article introduces the special issue on questions, questioning, and institutional practices. We begin by considering how questioning as a discursive practice is a central vehicle for constructing social worlds and reflecting existing ones. Then we describe the different ways questions and question(ing) have been defined, typologized, and critiqued, in general and within seven institutions including policing, the courts, medicine, therapy, research interviews, education, and mediated political exchanges. The introduction concludes with a preview of the articles in the special issue.
Review: Durable glycaemia — the promised land
Authors: Campbell Ian W
Published: April 2009

Patients with type 2 diabetes experience progressive loss of glycaemic control and require intensification of glucose-lowering therapies. Durable glycaemic control has been shown to reduce microvascular and macrovascular complications in patients with type 1 diabetes or type 2 diabetes. The range of available glucose-lowering agents has been expanded with the addition of the thiazolidinediones (TZDs) pioglitazone androsiglitazone and, more recently, dipeptidyl peptidase-4 inhibitors and the glucagon-like peptide-1 analogue exenatide. In clinical trials, the TZDs have provided sustained glycaemic control, both in monotherapy and in combination with metformin and sulphonylureas. Pioglitazone has also been associated with improvements in the long-term cardiovascular morbidity and mortality of patients with type 2 diabetes. Br J Diabetes Vasc Dis 2009;9:53—63
Prevalence of HTLV-1 infection in type 2 diabetic patients in Mashhad, northeastern Iran
Authors: Taghavi Morteza , Fatemi Seddigheh
Published: April 2009

Objective The aim of this study was to evaluate the prevalence of human T cell leukaemia virus type 1 (HTLV-1) infection among patients with type 2 diabetes mellitus in Mashhad in northeastern Iran.

Methods A total of 266 consecutive type 2 diabetic patients (mean age 54.36±11.58 years) attending our unit were compared with 60,892 non-diabetic blood donors for the presence of HTLV-1 infection. Serological testing for HTLV-1 was undertaken using an enzyme-linked immunosorbent assay, and a polymerase chain reaction (PCR) was performed in positive HTLV-1 samples.

Results PCR confirmed HTLV-1 infection in ten patients. The prevalence of HTLV-1 infection was more than five-fold higher in the diabetic patients than the blood donor group (3.75 vs. 0.663%; p<0.001). There was no apparent association between HTLV-1 infection and age, sex, body mass index, diabetes duration or glycaemic control.

Conclusions A higher prevalence of HTLV-1 infection was detected in diabetic patients and this should be borne in mind when treating type 2 diabetic patients in regions where HTLV-1 infection is endemic. Br J Diabetes Vasc Dis 2009; 9:81—83
Prescribing errors in diabetes
Authors: Cox Anthony R , Ferner Robin E
Published: April 2009

Prescribing errors in diabetes have the potential to cause serious adverse effects. Antidiabetic agents are a significant cause of admission to hospital. Prescribing errors can be caused by poor handwriting, failure to communicate clearly, and by the use of inappropriate abbreviations. Serious errors involving insulin have been reported in the UK media. While education and training may reduce the number of errors, experience shows that errors will continue to occur without changes to systems. Br J Diabetes Vasc Dis 2009;9:84—88
The Development and Reform of School Administration in Greece
Authors: Saiti Anna
Published: April 2009

The purpose of this article is to present and investigate the current situation in Greece regarding the management of primary schools and to underline the need for reforms in the field of school administration. The coordination of the relationship between the state and schools is an issue vital for both: primarily for schools, as they require a degree of independence to do their work on behalf of society, justly and properly; and for the state, which wishes to assure itself that the schools are adequately serving the needs of society and providing an efficient and comprehensive system of education. This article assesses the Greek primary school system in terms of avoidable bureaucratic processes and recommends strategies for improving the efficiency of school administration.
Apology, historical obligations and the ethics of memory
Authors: Thompson Janna
Published: April 2009

This article defends a conception of citizenship and political solidarity that encompasses an ethics of memory and the recognition of obligations that come from history. It claims that citizens ought to remember the deeds of their predecessors and to apologize and make recompense for historical injustices. To establish that such obligations exist it is necessary to contend with a tradition of liberal philosophical thought that regards history as irrelevant to the duties of citizens and their relationship as members of a political society. `Ahistorical liberalism' not only fails to appreciate the importance to people of historical memories. It also faces serious philosophical and moral difficulties. The obligations and rights of citizens are best understood in the framework of a relationship of intergenerational cooperation that gives citizens duties in respect to the past as well as the future.
Anatomical Study of the Palmar Intermetacarpal Perforator Flap
Authors: PELISSIER P. , GARDET H. , SAWAYA E. , PINSOLLE V. , CASOLI V.
Published: April 2009

The authors present an anatomical study of a small flap that may be harvested from any of the palmar intermetacarpal spaces while performing fasciectomy in Dupuytren’s contracture. The flap is diamond-shaped, vascularised by two perforating branches originating from the underlying true digital arteries and may be rotated through 90° to 180° in either direction to provide skin cover and subcutaneous padding over the distal palm and/or the base of the finger.
A human polymorphism affects NEDD4L subcellular targeting by leading to two isoforms that contain or lack a C2 domain
Authors: Garrone Nicholas F , Blazer-Yost Bonnie L , Weiss Robert B , Lalouel Jean-Marc , Rohrwasser Andreas
Published: April 2009

Background

Ubiquitination serves multiple cellular functions, including proteasomal degradation and the control of stability, function, and intracellular localization of a wide variety of proteins. NEDD4L is a member of the HECT class of E3 ubiquitin ligases. A defining feature of NEDD4L protein isoforms is the presence or absence of an amino-terminal C2 domain, a class of subcellular, calcium-dependent targeting domains. We previously identified a common variant in human NEDD4L that generates isoforms that contain or lack a C2 domain.

Results

To address the potential functional significance of the NEDD4L common variant on NEDD4L subcellular localization, NEDD4L isoforms that either contained or lacked a C2 domain were tagged with enhanced green fluorescent protein, transfected into Xenopus laevis kidney epithelial cells, and imaged by performing confocal microscopy on live cells. We report that the presence or absence of this C2 domain exerts differential effects on the subcellular distribution of NEDD4L, the ability of C2 containing and lacking NEDD4L isoforms to mobilize in response to a calcium stimulus, and the intracellular transport of subunits of the NEDD4L substrate, ENaC. Furthermore, the ability of the C2-containing isoform to influence β-ENaC mobilization from intracellular pools involves the NEDD4L active site for ubiquitination. We propose a model to account for the potential impact of this common genetic variant on protein function at the cellular level.

Conclusion

NEDD4L isoforms that contain or lack a C2 domain target different intracellular locations. Additionally, whereas the C2-containing NEDD4L isoform is capable of shuttling between the plasma membrane and intracellular compartments in response to calcium stimulus the C2-lacking isoform can not. The C2-containing isoform differentially affects the mobilization of ENaC subunits from intracellular pools and this trafficking step requires NEDD4L ubiquitin ligase activity. This observation suggests a new mechanism for the requirement for the PY motif in cAMP-mediated exocytosis of ENaC. We have elucidated how a common genetic variant can underlie significant functional diversity in NEDD4L at the cellular level. We propose a model that describes how that functional variation may influence blood pressure. Moreover, our observations regarding differential function of the NEDD4L isoforms may impact other aspects of physiology that involve this ubiquitin ligase.
Reverse transcription-quantitative polymerase chain reaction: description of a RIN-based algorithm for accurate data normalization
Authors: Ho-Pun-Cheung Alexandre , Bascoul-Mollevi Caroline , Assenat Eric , Boissière-Michot Florence , Bibeau Frédéric , Cellier Dominic , Ychou Marc , Lopez-Crapez Evelyne
Published: April 2009

Background

Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is the gold standard technique for mRNA quantification, but appropriate normalization is required to obtain reliable data. Normalization to accurately quantitated RNA has been proposed as the most reliable method for in vivo biopsies. However, this approach does not correct differences in RNA integrity.

Results

In this study, we evaluated the effect of RNA degradation on the quantification of the relative expression of nine genes (18S, ACTB, ATUB, B2M, GAPDH, HPRT, POLR2L, PSMB6 and RPLP0) that cover a wide expression spectrum. Our results show that RNA degradation could introduce up to 100% error in gene expression measurements when RT-qPCR data were normalized to total RNA. To achieve greater resolution of small differences in transcript levels in degraded samples, we improved this normalization method by developing a corrective algorithm that compensates for the loss of RNA integrity. This approach allowed us to achieve higher accuracy, since the average error for quantitative measurements was reduced to 8%. Finally, we applied our normalization strategy to the quantification of EGFR, HER2 and HER3 in 104 rectal cancer biopsies. Taken together, our data show that normalization of gene expression measurements by taking into account also RNA degradation allows much more reliable sample comparison.

Conclusion

We developed a new normalization method of RT-qPCR data that compensates for loss of RNA integrity and therefore allows accurate gene expression quantification in human biopsies.
Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models
Authors: Lee Nancy , Woodrum Chelsey L , Nobil Alison M , Rauktys Aubrey E , Messina Michael P , Dabora Sandra L
Published: April 2009

Background

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome, characterized by hamartomatous growths in the brain, skin, kidneys, lungs, and heart, which lead to significant morbidity. TSC is caused by mutations in theTSC1orTSC2genes, whose products, hamartin and tuberin, form a tumor suppressor complex that regulates the PI3K/Akt/mTOR pathway. Early clinical trials show that TSC-related kidney tumors (angiomyolipomas) regress when treated with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (also known as sirolimus). Although side effects are tolerable, responses are incomplete, and tumor regrowth is common when rapamycin is stopped. Strategies for future clinical trials may include the investigation of longer treatment duration and combination therapy of other effective drug classes.

Results

Here, we examine the efficacy of a prolonged maintenance dose of rapamycin inTsc2+/-mice with TSC-related kidney tumors. Cohorts were treated with rapamycin alone or in combination with interferon-gamma (IFN-g). The schedule of rapamycin included one month of daily doses before and after five months of weekly doses. We observed a 94.5% reduction in kidney tumor burden inTsc2+/-mice treated (part one) daily with rapamycin (8 mg/kg) at 6 months ≤ age < 7 months, (part 2) weekly with rapamycin (16 mg/kg) at 7 months ≤ age < 12 months, and (part 3) daily with rapamycin (8 mg/kg) at 12 months ≤ age < 13 months; but we did not observe any improvement with combination IFN-g plus rapamycin in this study. We also used aTsc2-/-subcutaneous tumor model to evaluate other classes of drugs including sorafenib, atorvastatin, and doxycycline. These drugs were tested as single agents and in combination with rapamycin. Our results demonstrate that the combination of rapamycin and sorafenib increased survival and may decrease tumor volume as compared to rapamycin treatment alone while sorafenib as a single agent was no different than control. Atorvastatin and doxycycline, either as single agents or in combination with rapamycin, did not improve outcomes as compared with controls.

Conclusion

Our results indicate that prolonged treatment with low doses of mTOR inhibitors may result in more complete and durable TSC-related tumor responses, and it would be reasonable to evaluate this strategy in a clinical trial. Targeting the Raf/Mek/Erk and/or VEGF pathways in combination with inhibiting the mTOR pathway may be another useful strategy for the treatment of TSC-related tumors.
Locating sex-specific evidence on clinical questions in MEDLINE: a search filter for use on OvidSP™
Authors: Moerman Clara J , Deurenberg Rikie , Haafkens Joke A
Published: April 2009

Background

Many recently published clinical studies report sex-specific data. This information may help to improve clinical decision-making for both sexes, but it is not easily accessible in MEDLINE. The aim of this project was to develop and validate a search filter that would facilitate the retrieval of studies reporting high quality sex-specific data on clinical questions.

Methods

A filter was developed by screening titles, abstracts and Medical Subject Headings (MeSH) in a set of 80 high quality and relevant papers, 75 of which were identified through a review of clinical guidelines and five through other means. The filter, for use on OvidSP™, consists of nine command lines for searching free text words in the title, abstract and MeSH of a paper. It was able to identify 74/80 (92.5%) of the articles from which it was derived. The filter was evaluated in a set of 622 recently published original studies on Alzheimer's disease and on asthma. It was validated against a reference of 98 studies from this set, which provided high quality, clinically relevant, sex-specific evidence. Recall and precision were used as performance measures.

Results

The filter demonstrated 81/98 (83%) recall and 81/125 (65%) precision in retrieving relevant articles on Alzheimer's disease and on asthma. In comparison, only 30/98 (31%) recall would have been achieved if sex-specific MeSH terms only had been used.

Conclusion

This sex-specific search filter performs well in retrieving relevant papers, while its precision rate is good. It performs better than a search with sex-specific MeSH. The filter can be useful to anyone seeking sex-specific clinical evidence (e.g., guideline organizations, researchers, medical educators, clinicians).
Contribution of type 2 diabetes associated loci in the Arabic population from Tunisia: a case-control study
Authors: Ezzidi Intissar , Mtiraoui Nabil , Cauchi Stéphane , Vaillant Emmanuel , Dechaume Aurélie , Chaieb Molka , Kacem Maha , Almawi Wassim Y , Froguel Philippe , Mahjoub Touhami , Vaxillaire Martine
Published: April 2009

Background

Candidate gene and genome-wide association studies have both reproducibly identified several common Single Nucleotide Polymorphisms (SNPs) that confer type 2 diabetes (T2D) risk in European populations. Our aim was to evaluate the contribution to T2D of five of these established T2D-associated loci in the Arabic population from Tunisia.

Methods

A case-control design comprising 884 type 2 diabetic patients and 513 control subjects living in the East-Center of Tunisia was used to analyze the contribution to T2D of the following SNPs: E23K in KCNJ11/Kir6.2, K121Q in ENPP1, the -30G/A variant in the pancreatic β-cell specific promoter of Glucokinase, rs7903146 in TCF7L2 encoding transcription factor 7-like2, and rs7923837 in HHEX encoding the homeobox, hematopoietically expressed transcription factor.

Results

TCF7L2-rs7903146 T allele increased susceptibility to T2D (OR = 1.25 [1.06–1.47], P = 0.006) in our study population. This risk was 56% higher among subjects carrying the TT genotype in comparison to those carrying the CC genotype (OR = 1.56 [1.13–2.16], P = 0.002). No allelic or genotypic association with T2D was detected for the other studied polymorphisms.

Conclusion

In the Tunisian population, TCF7L2-rs7903146 T allele confers an increased risk of developing T2D as previously reported in the European population and many other ethnic groups. In contrast, none of the other tested SNPs that influence T2D risk in the European population was associated with T2D in the Tunisian Arabic population. An insufficient power to detect minor allelic contributions or genetic heterogeneity of T2D between different ethnic groups can explain these findings.
Anti-metastatic effects of viral and non-viral mediated Nk4 delivery to tumours
Authors: Buhles Alexandra , Collins Sara A , van Pijkeren Jan P , Rajendran Simon , Miles Michelle , O'Sullivan Gerald C , O'Hanlon Deirdre M , Tangney Mark
Published: April 2009

The most common cause of death of cancer sufferers is through the occurrence of metastases. The metastatic behaviour of tumour cells is regulated by extracellular growth factors such as hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, and aberrant expression/activation of the c-Met receptor is closely associated with metastatic progression. Nk4 (also known as Interleukin (IL)32b) is a competitive antagonist of the HGF c-Met system and inhibits c-Met signalling and tumour metastasis. Nk4 has an additional anti-angiogenic activity independent of its HGF-antagonist function. Angiogenesis-inhibitory as well as cancer-specific apoptosis inducing effects make the Nk4 sequence an attractive candidate for gene therapy of cancer. This study investigates the inhibition of tumour metasasis by gene therapy mediated production of Nk4 by the primary tumour. Optimal delivery of anti-cancer genes is vital in order to achieve the highest therapeutic responses. Non-viral plasmid delivery methods have the advantage of safety and ease of production, providing immediate transgene expression, albeit short-lived in most tumours. Sustained presence of anti-angiogenic molecules is preferable with anti-angiogenic therapies, and the long-term expression mediated by Adeno-associated Virus (AAV) might represent a more appropriate delivery in this respect. However, the incubation time required by AAV vectors to reach appropriate gene expression levels hampers efficacy in many fast-growing murine tumour models. Here, we describe murine trials assessing the effects of Nk4 on the spontaneously metastatic Lewis Lung Carcinoma (LLC) model when delivered to primary tumour via plasmid lipofection or AAV2 vector. Intratumoural AAV-Nk4 administration produced the highest therapeutic response with significant reduction in both primary tumour growth and incidence of lung metastases. Plasmid-mediated therapy also significantly reduced metastatic growth, but with moderate reduction in primary subcutaneous tumour growth. Overall, this study demonstrates the potential for Nk4 gene therapy of metastatic tumours, when delivered by AAV or non-viral methods.
Analysis of transcribed human endogenous retrovirus W env loci clarifies the origin of multiple sclerosis-associated retrovirus envsequences
Authors: Laufer Georg , Mayer Jens , Mueller Benedikt F , Mueller-Lantzsch Nikolaus , Ruprecht Klemens
Published: April 2009

Background

Multiple sclerosis-associated retrovirus (MSRV) RNA sequences have been detected in patients with multiple sclerosis (MS) and are related to the multi-copy human endogenous retrovirus family type W (HERV-W). Only one HERV-W locus (ERVWE1) codes for a complete HERV-W Env protein (Syncytin-1). Syncytin-1 and the putative MSRV Env protein have been involved in the pathogenesis of MS. The origin of MSRV and its precise relation to HERV-W were hitherto unknown.

Results

By mapping HERV-WenvcDNA sequences (n = 332) from peripheral blood mononuclear cells of patients with MS and healthy controls onto individual genomic HERV-Wenvelements, we identified seven transcribed HERV-Wenvloci in these cells, including ERVWE1. Transcriptional activity of individual HERV-Wenvelements did not significantly differ between patients with MS and controls. Remarkably, almost 30% of HERV-WenvcDNAs were recombined sequences that most likely arosein vitrobetween transcripts from different HERV-Wenvelements. Re-analysis of published MSRVenvsequences revealed that all of them can be explained as originating from genomic HERV-Wenvloci or recombinations among them. In particular, a MSRVenvclone previously used for the generation of monoclonal antibody 6A2B2, detecting an antigen in MS brain lesions, appears to be derived from a HERV-Wenvlocus on chromosome Xq22.3. This locus harbors a long open reading frame for an N-terminally truncated HERV-W Env protein.

Conclusion

Our data clarify the origin of MSRVenvsequences, have important implications for the status of MSRV, and open the possibility that a protein encoded by a HERV-Wenvelement on chromosome Xq22.3 may be expressed in MS brain lesions.
Screening for Alpha 1 antitrypsin deficiency in Tunisian subjects with obstructive lung disease: a feasibility report
Authors: Denden Sabri , Zorzetto Michele , Amri Fethi , Knani Jalel , Ottaviani Stefania , Scabini Roberta , Gorrini Marina , Ferrarotti Ilaria , Campo Ilaria , Chibani Jemni Ben , Khelil Amel Haj , Luisetti Maurizio
Published: April 2009

Background

AATD is one of the most common inherited disorders in the World. However, it is generally accepted that AATD in North African populations is not a risk factor for lung and/or liver disease, based on a number of small studies. We therefore planned a screening study for detection of AATD in patients with OLD in a cohort of patients from Kairouan in central Tunisia. Methods: One hundred twenty patients with OLD (asthma, emphysema, COPD) were enrolled in the screening programme. Laboratory diagnosis for AATD was performed according to current diagnostic standards.

Results

We found that 6/120 OLD patients carried an AAT deficient allele, 1 PI*MZ, 1 PI*MPlowel, 3 PI*MMmalton, 1 PI*MMwurzburg.

Conclusion

this pilot study demonstrated that alleles related to deficiency of AAT are not absent in the Tunisian population, and that rare AATD variants prevailed over commonest PI*Z variant. These results would support a larger scale screening for AATD in Tunisia.
BMP-2 signaling in ovarian cancer and its association with poor prognosis
Authors: Le Page Cécile , Puiffe Marie-Line , Meunier Liliane , Zietarska Magdalena , de Ladurantaye Manon , Tonin Patricia N , Provencher Diane , Mes-Masson Anne-Marie
Published: April 2009

Background

We previously observed the over-expression of BMP-2 in primary cultures of epithelial ovarian cancer (EOC) cells as compared to normal epithelial cells based on Affymetrix microarray profiling [1]. Here we investigate the effect of BMP-2 on several parameters of ovarian cancer tumorigenesis using the TOV-2223, TOV-1946 and TOV-112D EOC cell lines.

Methods

We treated each EOC cell line with recombinant BMP-2 and assayed various parameters associated with tumorigenesis. More specifically, cell signaling events induced by BMP-2 treatment were investigated by western-blot using anti-phosphospecific antibodies. Induction of Id1, Snail and Smad6 mRNA expression was investigated by real time RT-PCR. The ability of cells to migrate was tested using the scratch assay. Cell-cell adhesion was analyzed by the ability of cells to form spheroids. We also investigated BMP-2 expression in tissue samples from a series of EOC patients.

Results

Treatment of these cell lines with recombinant BMP-2 induced a rapid phosphorylation of Smad1/5/8 and Erk MAPKs. Increased expression of Id1, Smad6 and Snail mRNAs was also observed. Only in the TOV-2223 cell line were these signaling events accompanied by an alteration in cell proliferation. We also observed that BMP-2 efficiently increased the motility of all three cell lines. In contrast, BMP-2 treatment decreased the ability of TOV-1946 and TOV-112D cell lines to form spheroids indicating an inhibition of cell-cell adhesion. The expression of BMP-2 in tumor tissues from patients was inversely correlated with survival.

Conclusion

These results suggest that EOC cell secretion of BMP-2 in the tumor environment contributes to a modification of tumor cell behavior through a change in motility and adherence. We also show that BMP-2 expression in tumor tissues is associated with a poorer prognosis for ovarian cancer patients.
Treating patients with fibromyalgia in primary care settings under routine medical practice: a claim database cost and burden of illness study
Authors: Sicras-Mainar Antoni , Rejas Javier , Navarro Ruth , Blanca Milagrosa , Morcillo Ángela , Larios Raquel , Velasco Soledad , Villarroya Carme
Published: April 2009

Introduction

The objective of this study was to analyze health care and non-health care resource utilization under routine medical practice in a primary care setting claims database and to estimate the incremental average cost per patient per year of fibromyalgia syndrome (FMS) compared with a reference population.

Methods

A 12-month cross-sectional and retrospective study was completed using computerized medical records from a health provider database. Analyses were conducted from the perspective of the provider and from the viewpoint of society. Health care and non-health care resource utilization included drugs, complementary tests, all types of medical visits, referrals, hospitalizations, sick leave, and early retirement because of disability due to FMS. Patients with a diagnosis of FMS in accordance with ICD-10 (International Statistical Classification of Diseases and Related Health Problems, 10th revision) criteria were included in the analysis if they had at least one claim for FMS during the 12 months prior to the end of May 2007. A non-FMS comparison group was also created with the remaining subjects.

Results

Of the 63,526 patients recruited for the study, 1,081 (1.7%) (96.7% of whom were women, 54.2 [10.1] years old) met the criteria for FMS. After an adjustment for age and gender, FMS subjects used significantly more health care resources than the reference population and had more sick leave and the percentage of subjects with premature retirement was also significantly higher (P < 0.001 in all cases). As a result, FMS subjects showed an incremental adjusted per-patient per-year total cost of €5,010 (95% confidence interval [CI] 3,494 to 6,076, +153%, P < 0.001) on average compared with non-FMS subjects. Significantly higher differences were observed in both health care and non-health care adjusted costs: €614 (404 to 823, +66%) and €4,394 (3,373 to 5,420, +189%), respectively (P < 0.001 in both cases). Annual drug expenditure per patient on average was considerably higher in FMS patients, €230 (124 to 335, +64%, P < 0.001), than the reference group.

Conclusions

Under routine medical practice, patients with FMS were associated with considerably higher annual total costs in the primary care setting compared with the reference population.
The transferome of metabolic genes explored: analysis of the horizontal transfer of enzyme encoding genes in unicellular eukaryotes
Authors: Whitaker John W , McConkey Glenn A , Westhead David R
Published: April 2009

Background

Metabolic networks are responsible for many essential cellular processes, and exhibit a high level of evolutionary conservation from bacteria to eukaryotes. If genes encoding metabolic enzymes are horizontally transferred and are advantageous, they are likely to become fixed. Horizontal gene transfer (HGT) has played a key role in prokaryotic evolution and its importance in eukaryotes is increasingly evident. High levels of endosymbiotic gene transfer (EGT) accompanied the establishment of plastids and mitochondria, and more recent events have allowed further acquisition of bacterial genes. Here, we present the first comprehensive multi-species analysis of E/HGT of genes encoding metabolic enzymes from bacteria to unicellular eukaryotes.

Results

The phylogenetic trees of 2,257 metabolic enzymes were used to make E/HGT assertions in ten groups of unicellular eukaryotes, revealing the sources and metabolic processes of the transferred genes. Analyses revealed a preference for enzymes encoded by genes gained through horizontal and endosymbiotic transfers to be connected in the metabolic network. Enrichment in particular functional classes was particularly revealing: alongside plastid related processes and carbohydrate metabolism, this highlighted a number of pathways in eukaryotic parasites that are rich in enzymes encoded by transferred genes, and potentially key to pathogenicity. The plant parasites Phytophthora were discovered to have a potential pathway for lipopolysaccharide biosynthesis of E/HGT origin not seen before in eukaryotes outside the Plantae.

Conclusions

The number of enzymes encoded by genes gained through E/HGT has been established, providing insight into functional gain during the evolution of unicellular eukaryotes. In eukaryotic parasites, genes encoding enzymes that have been gained through horizontal transfer may be attractive drug targets if they are part of processes not present in the host, or are significantly diverged from equivalent host enzymes.