bluuebunny/crossref_metadata_2025 huggingface dataset:
Sarcopenia as a Determinant of Chemotherapy Toxicity and Time to Tumor Progression in Metastatic Breast Cancer Patients Receiving Capecitabine Treatment
Authors: Prado Carla M.M. , Baracos Vickie E. , McCargar Linda J. , Reiman Tony , Mourtzakis Marina , Tonkin Katia , Mackey John R. , Koski Sheryl , Pituskin Edith , Sawyer Michael B.
Published: April 2009

Purpose: Body composition has emerged as an important prognostic factor in cancer patients. Severe depletion of skeletal muscle (sarcopenia) and, hence, of overall lean body mass may represent an occult condition in individuals with normal or even high body weight. Sarcopenia has been associated with poor performance status, 5-fluorouracil toxicity, and shortened survival in cancer patients. Here, we prospectively studied patients with metastatic breast cancer receiving capecitabine treatment in order to determine if sarcopenia was associated with a higher incidence of toxicity and a shorter time to tumor progression (TTP).

Experimental Design: Fifty-five women with metastatic breast cancer resistant to anthracycline and/or taxane treatment were included. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1 of treatment, and TTP was determined prospectively.

Results: Approximately 25% of patients were classified as sarcopenic, and this feature was seen in normal weight, overweight, and obese individuals. Toxicity was present in 50% of sarcopenic patients, compared with only 20% of nonsarcopenic patients (P = 0.03), and TTP was shorter in sarcopenic patients (101.4 days; confidence interval, 59.8-142.9) versus nonsarcopenic patients (173.3 days; confidence interval, 126.1-220.5; P = 0.05).

Conclusion: Sarcopenia is a significant predictor of toxicity and TTP in metastatic breast cancer patients treated with capecitabine. Our results raise the potential use of body composition assessment to predict toxicity and individualize chemotherapy dosing.
Overexpression and Mislocalization of the Chromosomal Segregation Protein Separase in Multiple Human Cancers
Authors: Meyer Rene , Fofanov Viacheslav , Panigrahi AnilK. , Merchant Fatima , Zhang Nenggang , Pati Debananda
Published: April 2009

Purpose: Separase, an endopeptidase, plays a pivotal role in chromosomal segregation by separating sister chromatids during the metaphase to anaphase transition. Using a mouse mammary tumor model we have recently shown that overexpression of Separase induces aneuploidy and tumorigenesis (Zhang et al., Proc Natl Acad Sci 2008;105:13033). In the present study, we have investigated the expression level of Separase across a wide range of human tumors.

Experimental Design: To examine the expression levels and localization of Separase in human tumors, we have performed immunofluorescence microscopy using human Separase antibody and tumor tissue arrays from osteosarcoma, colorectal, breast, and prostate cancers with appropriate normal controls.

Results: We show that Separase is significantly overexpressed in osteosarcoma, breast, and prostate tumor specimens. There is a strong correlation of tumor status with the localization of Separase into the nucleus throughout all stages of the cell cycle. Unlike the normal control tissues, where Separase localization is exclusively cytoplasmic in nondividing cells, human tumor samples show significantly higher number of resting cells with a strong nuclear Separase staining. Additionally, overexpression of Separase transcript strongly correlates with high incidence of relapse, metastasis, and lower 5-year overall survival rate in breast and prostate cancer patients.

Conclusion: These results further strengthen our hypothesis that Separase might be an oncogene, whose overexpression induces tumorigenesis, and indicates that Separase overexpression and aberrant nuclear localization are common in many tumor types and may predict outcome in some human cancers.
MicroRNA Expression Ratio Is Predictive of Head and Neck Squamous Cell Carcinoma
Authors: Avissar Michele , Christensen Brock C. , Kelsey Karl T. , Marsit Carmen J.
Published: April 2009

Purpose: The involvement of microRNAs in cancer and their potential as biomarkers of diagnosis and prognosis are becoming increasingly appreciated. We sought to identify microRNAs altered in head and neck squamous cell carcinoma (HNSCC) and to determine whether microRNA expression is predictive of disease.

Experimental Design: RNA isolated from fresh-frozen primary tumors, fresh-frozen nondiseased head and neck epithelial tissues, and HNSCC cell lines was profiled for the expression of 662 microRNAs by microarray. The microRNAs that were both differentially expressed on the array and by quantitative reverse transcription-PCR were subsequently validated by quantitative reverse transcription-PCR using a total of 99 HNSCC samples and 14 normal epithelia.

Results: A marked difference in microRNA expression pattern was observed between tumors and cell lines. Eighteen microRNAs were significantly altered in their expression between normal tissues and tumors. Four of these microRNAs were validated in the larger sample series, and each showed significant differential expression (P < 0.0001). Furthermore, an expression ratio of miR-221:miR-375 showed a high sensitivity (0.92) and specificity (0.93) for disease prediction.

Conclusions: These data suggest that cultured tumor cell lines are inappropriate for microRNA biomarker identification and that the pattern of microRNA expression in primary head and neck tissues is reflective of disease status, with certain microRNAs exhibiting strong predictive potential. These results indicate that miR-221 and miR-375 should be evaluated further as diagnostic biomarkers because they may hold utility in defining broadly responsive prevention and treatment strategies for HNSCC.
Environmental and Individual Factors Associated with Nail Fluoride Concentration
Authors: Fukushima R. , Rigolizzo D.S. , Maia L.P. , Sampaio F.C. , Lauris J.R.P. , Buzalaf M.A.R.
Published: April 2009

Nails have been suggested as suitable biomarkers of exposure to F, with the advantage of being easily obtained. The effect of water F concentration, age, gender, nail growth rate and geographical area on the F concentration in the fingernail and toenail clippings were evaluated. Volunteers (n = 300) aged 3–7, 14–20, 30–40 and 50–60 years from five Brazilian communities (A–E) participated. Drinking water and nail samples were collected and F concentration was analyzed with the electrode. A reference mark was made on each nail and growth rates were calculated. Data were analyzed by ANOVA and linear regression (α = 0.05). Mean water F concentrations (± SE, mg/l) were 0.09 ± 0.01, 0.15 ± 0.01, 0.66 ± 0.01, 0.72 ± 0.02, and 1.68 ± 0.08 for A–E, respectively. Mean F concentrations (± SE, mg/kg) ranged between 1.38 ± 0.14 (A, 50–60 years) and 10.20 ± 2.35 (D, 50–60 years) for fingernails, and between 0.92 ± 0.08 (A, 14–20 years) and 7.35 ± 0.80 (E, 50–60 years) for toenails. Among the tested factors, geographical area and water F concentration exerted the most influence on finger- and toenail F concentrations. Subjects of older age groups (30–40 and 50–60 years) from D and E showed higher nail F concentrations than the others. Females presented higher nail F concentration than males. Water F concentration, age, gender and geographical area influenced the F concentration of finger- and toenails, and hence should be taken into account when using this biomarker of exposure to predict risk for dental fluorosis.
Modeling the Impact of Sex on How Exercise Is Associated with Cognitive Changes and Death in Older Canadians
Authors: Fallah Nader , Mitnitski Arnold , Middleton Laura , Rockwood Kenneth
Published: April 2009

Background: Exercise improves cognition and lessens the risk of death in older adults. Cognition and mortality are each also affected by biological sex, which might modify the effect of exercise. We investigated how sex mediates the impact of exercise on mortality and 5-year changes in cognition. Methods: In the Canadian Study of Health and Aging (n = 8,403, 60.7% women), cognitive states were defined as errors in the Modified Mini-Mental State Examination. Improvement and declines were modeled using a 4-parameter truncated Poisson distribution. Results: Men and women showed similar levels of improvement or stabilization (34.1%, 95% CI = 32.1–35.9 in women and 30.2%, 95% CI = 28.2–32.4 in men). In unadjusted analysis, more men died (34%, 95% CI = 32.3–36.3) than did women (30.3%, 95% CI = 28.4–32.2). Higher education was beneficial for cognitive function in both sexes, but did not impact survival when other factors were considered. The effect of exercise differed by sex: women had a survival advantage compared with men, but men most benefited in cognitive functioning. Conclusions: Exercise is strongly associated with cognitive improvement and stabilization in men, and with better survival in women. In contrast to conventional approaches, our model allows us to analyze how different risk factors affect cognition to any degree, and simultaneously to assess their impact on survival.
FOXP1 Expression Predicts Polymorphic Histology and Poor Prognosis in Gastric Mucosa-Associated Lymphoid Tissue Lymphomas
Authors: Han Shao-liang , Wu Xiu-ling , Wan Li , Zeng Qi-qiang , Li Jun-lin , Liu Zhi
Published: April 2009

Rationale/Hypothesis: Forkhead box protein P1 (FOXP1) is one member of the forkhead box protein P (FOXP) subfamily, which are transcription factors that mediate signaling and affect gene regulation, and elevated expression of FOXP1 has been reported to correlate with poor prognosis of diffuse large B-cell lymphoma (DLBCL). Recently, it was also found that FOXP1 expression occurs in mucosa-associated lymphoid tissue (MALT) lymphomas. Objective: FOXP1 expression and its relationship to morphology and prognosis in a series of 43 gastric MALT lymphomas were investigated retrospectively. Findings: The FOXP1 nuclear expression (44.2%, 19/43) of tumors between mono- and polymorphic histology (4 of 26 [15.4%] vs. 15 of 17 [88.2%]) was significantly different (p < 0.001). All 14 relapsed tumors after operation featured strong nuclear FOXP1 positivity. A significantly shorter cumulative 10-year survival (52.6%,10/19) was found in high FOXP1 expression patients, compared with patients with negative expression (83.3%, 20/24) (p < 0.01). Also, the cumulative 10-year survival rate (30.8%, 4/13) for stage IIE+IV was significantly shorter than that (83.3%, 25/30) in stage I+II (p < 0.01). Moreover, high FOXP1 expression and advanced stage IIE+IV were independent prognostic factors in multivariate Cox regression analysis. Conclusions: Our results show that FOXP1 expression is correlated with morphic histology, and FOXP1 and clinical staging appear to be independent prognostic factors in gastric MALT lymphomas.
Compromising Postural Balance in the Elderly
Authors: Swanenburg Jaap , de Bruin Eling D. , Uebelhart Daniel , Mulder Theo
Published: April 2009

Background: Additional tasks that are assumed to disturb standing postural control can be divided in added motor or added cognitive tasks. It is unknown which type of task causes the most disturbances of postural control in elderly. Objective: The aim of this study was to determine whether the dual tasking disturbance of postural control in elderly is caused by vocal articulation or by limited attentional resources. Methods: 39 elderly (81 ± 7 years) were tested on a force plate in a two-legged standing position. Seven balance variables were assessed: maximum displacement and standard deviation amplitude in the medial-lateral (ML, SDML) and anterior-posterior (AP, SDAP) direction, average speed of displacement (V) and the area of the 95th percentile ellipse (AoE) and sway path (PL) per given time. The following task combinations were tested: no secondary task, repeating a number aloud (articulation), counting backwards aloud (articulation and attention), and counting backwards silently (attention). All tasks were tested with and without vision. Results: A factorial ANOVA revealed main effects of additional tasks in PL, ML, SDML, AP, AoE and V. Bonferroni post-hoc analysis in a vision situation showed significant difference between no task and counting backwards aloud task in balance variables ML (p = 0.006), SDML (p = 0.002), AP (p = 0.020) and V (p = 0.003), respectively. All no-vision situations showed no significant difference between the different tasks. Conclusion: The findings suggest that the combined articulation and attention-demanding secondary task stressed the attentional system of elderly to such an extent that it compromised the performance of the primary task (quiet standing). The counting backwards aloud task may be used as dual task for clinical balance assessment in at-risk populations. This task was best able to disturb postural control.
Reliability Based Finite Element Analysis of Mechanical Components
Authors: Hojjati M.H , Sadighi A.
Published: April 2009

In a conventional finite element analysis, material properties, dimensions and applied loads are usually defined as deterministic quantities. This simplifying assumption however, is not true in practical applications. Using statistics in engineering problems enables us to consider the effects of the input variables dispersion on the output parameters in an analysis. This provides a powerful tool for better decision making for more reliable design. In this paper, a probabilistic based design is presented which evaluates the sensitivity of a mechanical model to random input variables. To illustrate the effectiveness of this method, a simple bracket is analyzed for stress‐strain behavior using commercially available finite element software. Young’s modulus, applied pressure and dimensions are considered as random variables with Gaussian distribution and their effects on maximum stress and displacement is evaluated. The finite element results are compared with reliability based theoretical results which show very good agreement. This demonstrates the capability of commercially available software to handle probabilistic approach design.
Democratization as Deliberative Capacity Building
Authors: Dryzek John S.
Published: April 2009

Effective deliberation is central to democracy and so should enter any definition of democratization. However, the deliberative aspect now ubiquitous in the theory, practice, and promotion of democracy is generally missing in comparative studies of democratization. Deliberation capacity can be distributed in variable ways in the deliberative systems of states and other polities. A framework is described for locating and analyzing the contributions of its components and so evaluating the degree to which a polity’s deliberative system is authentic, inclusive, and consequential. An emphasis on deliberation reveals important determinants of democratic transition and consolidation, thereby providing substantial explanatory as well as evaluative and normative purchase.
Mental Disorder and Violent Victimization
Authors: Teasdale Brent
Published: April 2009

Much research has focused on violence committed by individuals with mental disorders, but their victimization experiences have received less attention. This literature indicates that individuals with mental disorders are at a significantly higher risk of violent victimization than are individuals with no such diagnosis, but few studies have attempted to provide or test a theoretical explanation for these differences. This study analyzes data from the MacArthur Violence Risk Assessment Study, a longitudinal study of individuals released from three psychiatric hospitals, to test the effects of theoretically derived risk factors for victimization. Based on multilevel growth curve models, the author finds that symptomatology, homelessness, and alcohol abuse significantly increase the risk of victimization for persons with major mental disorders. In addition, stress and gender interact, predicting victimization, suggesting that—for men—stress increases the odds of victimization. The implications of these findings for research and practice are discussed.
Jurors' Responses To Unusual Inadmissible Evidence
Authors: Pickel Kerri L. , Karam Tanya J. , Warner Todd C.
Published: April 2009

Two experiments investigated jurors' ability to disregard unusual inadmissible evidence. Participants listened to an audio recording of a theft trial. Those in four experimental conditions heard critical testimony favoring the prosecution, which was ruled either admissible or inadmissible and which contained either neutral details or details that were unusual in terms of semantic content (Experiment 1) or form (Experiment 2). Control jurors received no critical evidence. Exposure to unusual rather than neutral evidence led jurors to see the defendant as more guilty but only if that evidence was inadmissible instead of admissible. Additionally, jurors remembered unusual evidence better than neutral evidence. The results are consistent with Wegner's ironic-process theory and suggest that attempts at thought suppression are less successful if the forbidden information is especially memorable.
The supportive and palliative care needs of Australian families of children who die from cancer
Authors: Monterosso L , Kristjanson LJ , Phillips MB
Published: April 2009

Objective

To identify the perceptions of parents of children who died from cancer regarding the palliative and supportive care they received in hospital and in community settings.

Method

Face-to-face or telephone questionnaires. Setting Tertiary paediatric oncology centres in Western Australia, New South Wales, Queensland and Victoria.

Participants

69 parents.

Results

Parents indicated the need for clear and honest information about their child’s condition and prognosis throughout the trajectory of illness. Parents also required access to, and advice from, multidisciplinary health professionals when caring for their child at home. Parents preferred to care for their child at home wherever possible throughout the palliative care trajectory of their child’s cancer and were well supported by immediate and extended family and friends. However, many families were affected emotionally and financially by the burden of caring for their child with incurable cancer. Families required financial and practical assistance with providing care from their child. Parents wanted and needed more practical resources and information to assist with the management of their child’s nutrition and pain, as well as for the support of their other children.

Conclusion

Care for children and their families should be coordinated by a multidisciplinary team in consultation with children and their families, and should be linked and integrated with the treating hospital in collaboration with community services.
NMDA receptor antagonists augment antidepressant-like effects of lithium in the mouse forced swimming test
Authors: Ghasemi M. , Raza M. , Dehpour AR
Published: April 2009

Although there is evidence of the involvement of N-methyl-D-aspartate receptors (NMDAR) in the action of lithium, its role in the antidepressant effects of lithium in a behavioural model remains unclear. In this study, we evaluated the effects of NMDAR antagonists on the antidepressant-like effects of lithium in the mouse forced swimming test. Lithium (30 and 100 mg/kg, i.p.) significantly (P < 0.01) reduced the immobility times of mice, whereas at lower doses (5 and 10 mg/kg) had no effect. NMDA antagonists ketamine (2 and 5 mg/kg, i.p.), MK-801 (0.1 and 0.25 mg/kg, i.p.) and ifenprodil (1 and 3 mg/kg, i.p.) significantly (P < 0.05) decreased the immobility time. Lower doses of ketamine (0.5 and 1 mg/kg), MK-801 (0.01 and 0.05 mg/kg) and ifenprodil (0.1 and 0.5 mg/kg) had no effect. Combined treatment of subeffective doses of lithium (10 mg/kg) and ketamine (1 mg/kg), MK-801 (0.05 mg/kg) or ifenprodil (0.5 mg/kg) robustly (P < 0.001) exerted an antidepressant-like effect. The noneffective dose of a NMDA agonist (NMDA, 75 mg/kg, i.p.) prevented the antidepressant-like effect of lithium (30 mg/kg). None of the drugs at subactive doses or in combination with lithium had significant effect on the locomotor activity in the open field test. We for the first time suggested a role for NMDAR signalling in the antidepressant-like effects of lithium, providing a new approach for treatment of depression.
Delayed stress-induced differences in locomotor and depression-related behaviour in female neuropeptide-Y Y1 receptor knockout mice
Authors: Painsipp E. , Sperk G. , Herzog H. , Holzer P.
Published: April 2009

Neuropeptide-Y acting through Y1 receptors reduces anxiety and stress sensitivity in rodents. In Y1 receptor knockout (Y1−/−) mice, however, anxiety-related behaviour is altered only in a context-dependent manner. Here, we investigated whether stress causes a delayed change in the emotional-affective behaviour of female Y1−/−mice. Locomotor and anxiety-related behaviour was assessed with the elevated plus-maze (EPM) test and depression-like behaviour with the forced swim test (FST). These behavioural tests were also used as experimental stress paradigms. Locomotion and anxiety-like behaviour did not differ between naïve control and Y1−/−mice. One week after the FST, locomotion was reduced in control animals but unchanged in Y1−/−mice, whereas anxiety-like behaviour remained unaltered in both genotypes. Depression-like behaviour (immobility) was identical in naïve control and Y1− /−mice but, 1 week after the EPM test, was attenuated in Y1−/−mice relative to control animals. Our data show that naïve female Y1−/−mice do not grossly differ from female control animals in their locomotor and depression-like behaviour. Exposure to the stress associated with behavioural testing, however, leads to delayed genotype-dependent differences in locomotion and depression-like behaviour. These findings attest to a role of Y1 receptor signalling in the control of stress coping and/or adaptation.
Evaluating Video Models of Evidence-Based Instructional Practices to Enhance Teacher Learning
Authors: Dieker Lisa A. , Lane Holly B. , Allsopp David H. , O'Brien Chris , Butler Tyran Wright , Kyger Maggie , Lovin LouAnn , Fenty Nicole S.
Published: April 2009

A process was developed to create Web-based video models of effective instructional practices for use in teacher education settings. Three video models, created at three university sites, demonstrated exemplary implementation of specific, evidence-based strategies in reading, math, and science. Video models of strategies were field tested with preservice and practicing teachers working with diverse student populations. The authors provide an explanation of the video development process and present field-test data that demonstrate the influence of video modeling on teacher learning.
Recruiting for representation in public deliberation on the ethics of biobanks
Authors: Longstaff Holly , Burgess Michael M.
Published: April 2009

This paper addresses the dilemmas of participant sampling and recruitment for deliberative science policy projects. Results are drawn from a deliberative public event that was held in April and May, 2007. The research objective of The BC Biobank Deliberation was to assess deliberative democracy as an approach to legitimate policy advice from a subset of British Columbians concerning the secondary use of human tissues for prospective genomic and genetic research. The overall goal was to have participants identify key values that should guide a biobank in British Columbia. This paper assesses our team’s group decision-making processes concerning participant sampling for the 2007 event. Results presented here should allow the reader to critically examine our team’s choices and could also be used to assist advocates of deliberative democracy and others who may wish to propose similar events in the future.
Scientific controversies in museums: notes from a semi-peripheral country
Authors: Delicado Ana
Published: April 2009

This research note discusses the representation of scientific controversies in museums in a particular national context, Portugal. Despite the recent development of the national scientific system and the field of science museums, the connection between science and society has remained weak. The description of the content of scientific exhibitions, namely about controversial issues, shows that science is still portrayed as beyond dispute and unequivocally beneficial and the public is dismissed as irrational and in need of enlightenment. The role of museums as forums for debate and exchange of ideas is yet to be fulfilled.
Publics performing publics: of PiGs, PiPs and politics
Authors: Michael Mike
Published: April 2009

This theoretical paper considers the ways in which the “publics” of public understanding of science and public engagement with science perform themselves not only in relation to science knowledge and scientific institutions, but also in relation to other publics. Specifically, through a survey of the literature, there is an exploration of the processes of differentiation and identification amongst publics. Two broad rhetorical categories of public are identified: Publics-in-General (PiGs) and Publics-in-Particular (PiPs). The means by which they are variously differentiated, and the performative uses to which these can be put are considered. Implications for both the implementation of public engagement processes, and the critique of such engagement, are discussed.
Weight Perception and Dieting Behavior Among Korean Adolescents
Authors: Lee Gyuyoung , Ha Yeongmi , Vann Julie Jacobson , Choi Eunsook
Published: April 2009

This study examines relationships among weight status, weight perceptions, and dieting behaviors in South Korean adolescents. As perceptions of an ideal body for teens in Korea have changed over time, it is important for school nurses to understand these relationships to help students achieve health. A cross-sectional survey of 3,191 8th and 2,252 11th-grade students from 21 middle and high schools across Korea completed a self-administered questionnaire. The prevalence of overweight among adolescents was 17.5% in males and 6.0% in females. Overall, 65.9% of students perceived their weight status accurately. Females overestimated their weight status 2.3 times more often than males. Male students underestimated their weight status 2.7 times more frequently than females. Approximately one third of participants misperceived their weight status, with variations existing between males and females. Study results suggest the need to develop male- and female-specific interventions to promote healthy body images and body weight.
Structural and Functional Characterization of Low-molecular-weight Heparins: Impact on the Development of Guidelines for Generic Products
Authors: Adiguzel Cafer , Jeske Walter P. , Hoppensteadt Debra , Walenga Jeanine M. , Bansal Vinod , Fareed Jawed
Published: April 2009

Low-molecular-weight heparins (LMWHs) are poly-pharmacologic drugs used to treat thrombotic and cardiovascular disorders. Recently, several generic versions of branded LMWHs have been introduced. Although generic versions of LMWHs exhibit similar profiles, marked differences in their biological and pharmacologic properties have been demonstrated. Several studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs and also underscore the importance of further pharmacologic studies involving animal and human clinical trials. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) are currently developing guidelines for the acceptance of complex biological drugs including LMWHs. The US FDA considers these drugs as follow-on agents whereas the EMEA classifies these drugs as biosimilar agents. Until clear guidelines are developed, generic interchange of LMWHs may not be feasible.
Remaining Skeptical: Bridling for and with One Another
Authors: Vagle Mark D. , Hughes Hilary E. , Durbin Diana J.
Published: April 2009

In this article, we argue that being our own best critics is a process by which we commit to interrogating what we know (or think we know) as we design a study. We situate the idea of bridling within the philosophical and methodological conversation of a more traditional notion in phenomenological research, bracketing, and then within Macbeth’s three expressions of reflexivity in qualitative research. Based on our analysis of some of our methodological decisions, we articulate four pivotal issues we faced. We close by making specific suggestions for faculty and graduate students individually and as research teams to consider as they strive to be their own best critics in their research.
Transabdominal Duplex Ultrasonography for Bedside Inferior Vena Cava Filter Placement: Examples, Technique, and Review
Authors: Amankwah Kwame S. , Seymour Keri , Costanza Michael , Berger Jeremy , Gahtan Vivian
Published: April 2009

Pulmonary embolism remains an endemic challenge for public health care. The first line of treatment for venous thromboembolic disorder has been anticoagulation; however, in the absence of appropriate pharmacologic treatment, because of failure or contraindication, caval filter placement has been widely performed in the prevention of pulmonary embolism. Initially an open surgical procedure, technological advancements have allowed filter placement to be done percutaneously. Bedside filter placement in the intensive care unit with ultrasonographic imaging has been reported to be safe, effective, and reliable. In this report, we present an example, discuss our technique, and review the literature.
High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder
Authors: Preudhomme Claude , Renneville Aline , Bourdon Violaine , Philippe Nathalie , Roche-Lestienne Catherine , Boissel Nicolas , Dhedin Nathalie , André Jean-Marie , Cornillet-Lefebvre Pascale , Baruchel André , Mozziconacci Marie-Joelle , Sobol Hagay
Published: April 2009

Familial platelet disorder (FPD), a rare autosomal dominant disorder characterized by quantitative and qualitative platelet abnormalities, is considered as a model of genetic predisposition to acute myeloid leukemia (AML). So far, monoallelic RUNX1 germline mutations have been found in 19 of 20 families with reported FPD, and the analysis of blast cells from only 5 patients at acute leukemia (AL) stage has shown no additional RUNX1 abnormality. Here, we performed RUNX1 analysis at constitutional and somatic levels in 8 persons with FPD who developed AL from 4 independent families. In addition to the germline RUNX1 mutation, we identified a second RUNX1 alteration in 6 AML cases (acquired point mutations in 4 cases and duplication of the altered RUNX1 allele associated with acquired trisomy 21 in 2 other cases). Although haploinsufficiency of RUNX1 causes FPD, our findings suggest that a second genetic event involving RUNX1 is often associated with progression to AML.
Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome
Authors: Bosticardo Marita , Marangoni Francesco , Aiuti Alessandro , Villa Anna , Grazia Roncarolo Maria
Published: April 2009

Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency caused by mutations in the gene encoding for WASP, a key regulator of signaling and cytoskeletal reorganization in hematopoietic cells. Mutations in WASP result in a wide spectrum of clinical manifestations ranging from the relatively mild X-linked thrombocytopenia to the classic full-blown WAS phenotype characterized by thrombocytopenia, immunodeficiency, eczema, and high susceptibility to developing tumors and autoimmune manifestations. The life expectancy of patients affected by severe WAS is reduced, unless they are successfully cured by bone marrow transplantation from related identical or matched unrelated donors. Because many patients lack a compatible bone marrow donor, the administration of WAS gene–corrected autologous hematopoietic stem cells could represent an alternative therapeutic approach. In the present review, we focus on recent progress in understanding the molecular and cellular mechanisms contributing to the pathophysiology of WAS. Although molecular and cellular studies have extensively analyzed the mechanisms leading to defects in T, B, and dendritic cells, the basis of autoimmunity and thrombocytopenia still remains poorly understood. A full understanding of these mechanisms is still needed to further implement new therapeutic strategies for this peculiar immunodeficiency.
Regulation of Hoxb4 induction after neurulation by somite signal and neural competence
Authors: Amirthalingam Gayana S , Howard Sara , Alvarez Susana , de Lera Angel R , Itasaki Nobue
Published: April 2009

Background

While the body axis is largely patterned along the anterior-posterior (A-P) axis during gastrulation, the central nervous system (CNS) shows dynamic changes in the expression pattern of Hox genes during neurulation, suggesting that the CNS refines the A-P pattern continuously after neural tube formation. This study aims at clarifying the role of somites in up-regulating Hoxb4 expression to eventually establish its final pattern and how the neural tube develops a competence to respond to extrinsic signals.

Results

We show that somites are required for the up-regulation of Hoxb4 in the neural tube at the level of somites 1 to 5, the anterior-most domain of expression. However, each somite immediately adjacent to the neural tube is not sufficient at each level; planar signaling is additionally required particularly at the anterior-most segments of the expression domain. We also show that the dorsal side of the neural tube has a greater susceptibility to expressing Hoxb4 than the ventral region, a feature associated with dorsalization of the neural tube by BMP signals. BMP4 is additionally able to up-regulate Hoxb4 ventrally, but the effect is restricted to the axial levels at which Hoxb4 is normally expressed, and only in the presence of retinoic acid (RA) or somites, suggesting a role for BMP in rendering the neural tube competent to express Hoxb4 in response to RA or somite signals.

Conclusion

In identifying the collaboration between somites and neural tube competence in the induction of Hoxb4, this study demonstrates interplay between A-P and dorsal-ventral (D-V) patterning systems, whereby a specific feature of D-V polarity may be a prerequisite for proper A-P patterning by Hox genes.
Adenomatous polyposis coli-mediated control of β-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors
Authors: Miclea Razvan L , Karperien Marcel , Bosch Cathy AJ , van der Horst Geertje , van der Valk Martin A , Kobayashi Tatsuya , Kronenberg Henry M , Rawadi Georges , Akçakaya Pinar , Löwik Clemens WGM , Fodde Riccardo , Wit Jan Maarten , Robanus-Maandag Els C
Published: April 2009

Background

During skeletogenesis, protein levels of β-catenin in the canonical Wnt signaling pathway determine lineage commitment of skeletal precursor cells to osteoblasts and chondrocytes. Adenomatous polyposis coli (Apc) is a key controller of β-catenin turnover by down-regulating intracellular levels of β-catenin.

Results

To investigate whether Apc is involved in lineage commitment of skeletal precursor cells, we generated conditional knockout mice lacking functionalApcinCol2a1-expressing cells. In contrast to other models in which an oncogenic variant of β-catenin was used, our approach resulted in the accumulation of wild type β-catenin protein due to functional loss of Apc. Conditional homozygousApcmutant mice died perinatally showing greatly impaired skeletogenesis. All endochondral bones were misshaped and lacked structural integrity. Lack of functional Apc resulted in a pleiotropic skeletal cell phenotype. The majority of the precursor cells lackingApcfailed to differentiate into chondrocytes or osteoblasts. However, skeletal precursor cells in the proximal ribs were able to escape the noxious effect of functional loss of Apc resulting in formation of highly active osteoblasts. Inactivation of Apc in chondrocytes was associated with dedifferentiation of these cells.

Conclusion

Our data indicate that a tight Apc-mediated control of β-catenin levels is essential for differentiation of skeletal precursors as well as for the maintenance of a chondrocytic phenotype in a spatio-temporal regulated manner.
Immunostaining with D2–40 improves evaluation of lymphovascular invasion, but may not predict sentinel lymph node status in early breast cancer
Authors: Britto Anna V , Schenka André A , Moraes-Schenka Natália G , Alvarenga Marcelo , Shinzato Júlia Y , Vassallo José , Ward Laura S
Published: April 2009

Background

Sentinel lymph node (SLN) biopsy is a widely used diagnostic procedure in the management of early breast cancer. When SLN is free of metastasis, complete axillary dissection may be skipped for staging in clinically N0 patients, allowing a more conservative procedure. Histological tumor features that could reliably predict SLN status have not yet been established. Since the degree of tumor lymphangiogenesis and vascularization may theoretically be related to the risk of lymph node metastasis, we sought to evaluate the relationship between lymph vessel invasion (LVI), lymphatic microvascular density (LVD), microvascular density (MVD) and VEGF-A expression, with SLN status and other known adverse clinical risk factors.

Methods

Protein expression of D2–40, CD34, and VEGF-A was assessed by immunohistochemistry on paraffin-embedded sections of primary breast cancer specimens from 92 patients submitted to SLN investigation. The presence of LVI, the highest number of micro vessels stained for D2–40 and CD34, and the protein expression of VEGF-A were compared to SLN status, clinicopathological features and risk groups.

Results

LVI was detected in higher ratios by immunostaining with D2–40 (p < 0.0001), what would have changed the risk category from low to intermediate in four cases (4.3%). There was no association between LVI and other angiogenic parameters determined by immunohistochemistry with SLN macrometastases, clinical features or risk categories.

Conclusion

Assessment of LVI in breast carcinoma may be significantly increased by immunostaining with D2–40, but the clinical relevance of altering the risk category using this parameter may not be advocated according to our results, neither can the use of LVI and LVD as predictors of SLN macrometastasis in early breast cancer.
Identification and characterization of Ca2+-activated K+ channels in granulosa cells of the human ovary
Authors: Traut Matthias H , Berg Dieter , Berg Ulrike , Mayerhofer Artur , Kunz Lars
Published: April 2009

Background

Granulosa cells (GCs) represent a major endocrine compartment of the ovary producing sex steroid hormones. Recently, we identified in human GCs a Ca2+-activated K+ channel (KCa) of big conductance (BKCa), which is involved in steroidogenesis. This channel is activated by intraovarian signalling molecules (e.g. acetylcholine) via raised intracellular Ca2+ levels. In this study, we aimed at characterizing 1. expression and functions of KCa channels (including BKCa beta-subunits), and 2. biophysical properties of BKCa channels.

Methods

GCs were obtained from in vitro-fertilization patients and cultured. Expression of mRNA was determined by standard RT-PCR and protein expression in human ovarian slices was detected by immunohistochemistry. Progesterone production was measured in cell culture supernatants using ELISAs. Single channels were recorded in the inside-out configuration of the patch-clamp technique.

Results

We identified two KCa types in human GCs, the intermediate- (IK) and the small-conductance KCa (SK). Their functionality was concluded from attenuation of human chorionic gonadotropin-stimulated progesterone production by KCa blockers (TRAM-34, apamin). Functional IK channels were also demonstrated by electrophysiological recording of single KCa channels with distinctive features. Both, IK and BKCa channels were found to be simultaneously active in individual GCs. In agreement with functional data, we identified mRNAs encoding IK, SK1, SK2 and SK3 in human GCs and proteins of IK and SK2 in corresponding human ovarian cells. Molecular characterization of the BKCa channel revealed the presence of mRNAs encoding several BKCa beta-subunits (beta2, beta3, beta4) in human GCs. The multitude of beta-subunits detected might contribute to variations in Ca2+ dependence of individual BKCa channels which we observed in electrophysiological recordings.

Conclusion

Functional and molecular studies indicate the presence of active IK and SK channels in human GCs. Considering the already described BKCa, they express all three KCa types known. We suggest that the plurality and co-expression of different KCa channels and BKCa beta-subunits might allow differentiated responses to Ca2+ signals over a wide range caused by various intraovarian signalling molecules (e.g. acetylcholine, ATP, dopamine). The knowledge of ovarian KCa channel properties and functions should help to understand the link between endocrine and paracrine/autocrine control in the human ovary.
A controlled trial of value-based insurance design – The MHealthy: Focus on Diabetes (FOD) trial
Authors: Spaulding Alicen , Fendrick A Mark , Herman William H , Stevenson James G , Smith Dean G , Chernew Michael E , Parsons Dawn M , Bruhnsen Keith , Rosen Allison B
Published: April 2009

Background

Diabetes affects over 20 million Americans, resulting in substantial morbidity, mortality, and costs. While medications are the cornerstone of secondary prevention, many evidence-based therapies are underutilized, and patients often cite out-of-pocket costs as the reason. Value-based insurance design (VBID) is a 'clinically sensitive' refinement to benefit design which links patient cost-sharing to therapy value; the more clinically beneficial (and valuable) a therapy is for a patient, the lower that patient's cost-sharing should be. We describe the design and implementation of MHealthy: Focus on Diabetes (FOD), a prospective, controlled trial of targeted co-payment reductions for high value, underutilized therapies for individuals with diabetes.

Methods

The FOD trial includes 2,507 employees and dependents with diabetes insured by one large employer. Approximately 81% are enrolled in a single independent-practice association model health maintenance organization. The control group includes 8,637 patients with diabetes covered by other employers and enrolled in the same managed care organization. Both groups received written materials about the importance of adherence to secondary prevention therapies, while only the intervention group received targeted co-payment reductions for glycemic agents, antihypertensives, lipid-lowering agents, antidepressants, and diabetic eye exams. Primary outcomes include medication uptake and adherence. Secondary outcomes include health care utilization and expenditures. An interrupted time series, control group design will allow rigorous assessment of the intervention's impact, while controlling for unrelated temporal trends. Individual patient-level baseline data are presented.

Discussion

To our knowledge, this is the first prospective controlled trial of co-payment reductions targeted to high-value services for high-risk patients. It will provide important information on feasibility of implementation and effectiveness of VBID in a real-world setting. This program has the potential for broad dissemination to other employers and insurers wishing to improve the value of their health care spending.
Persistence with anti-tumour necrosis factor therapies in patients with psoriatic arthritis: observational study from the British Society of Rheumatology Biologics Register
Authors: Saad Amr A , Ashcroft Darren M , Watson Kath D , Hyrich Kimme L , Noyce Peter R , Symmons Deborah PM ,   the British Society for Rheumatology Biologics Register
Published: April 2009

Introduction

Anti-TNF therapies represent a breakthrough in the treatment of severe psoriatic arthritis. However, little is known about long-term drug persistence with these treatments in patients with psoriatic arthritis in routine clinical practice. The aim of this study was to assess persistence with first-course and second-course treatment with anti-TNF agents in a prospective cohort of psoriatic arthritis patients and to identify factors associated with and reasons for drug discontinuation.

Methods

A total of 566 patients with psoriatic arthritis were registered with the British Society for Rheumatology Biologics Register (first anti-TNF agent: etanercept, n = 316; infliximab, n = 162; and adalimumab, n = 88). Treating physicians completed 6-monthly follow-up questionnaires detailing changes to anti-TNF therapies. Persistence with treatment was examined using Kaplan–Meier survival analysis. Reasons for withdrawal were classified as due to inefficacy, adverse events or other reasons. Univariate and multivariate Cox proportional hazard models were developed to examine potential predictors of withdrawals due to inefficacy or adverse events, using a range of demographic, baseline disease-specific and therapeutic variables.

Results

At baseline, the mean (standard deviation) age of patients was 45.7 (11.1) years, 53% were female and the mean disease duration was 12.4 (8.7) years. Persistence data were available for a mean (standard deviation) follow-up of 2.3 (0.9) person-years. In total, 422 patients had completed at least 12 months of follow-up, 75.5% of whom remained on their first anti-TNF drug while 9.5% discontinued due to inefficacy, 10.0% due to adverse events and 5.0% due to other reasons. During the period of follow-up, 178 patients received a second anti-TNF therapy. The survivor function on second anti-TNF for switchers was 74% at 12 months.

Conclusions

Psoriatic arthritis patients show high persistence rates with both initial and second anti-TNF therapies.
A nucleolar protein allows viability in the absence of the essential ER-residing molecular chaperone calnexin
Authors: Beauregard Pascale B. , Guérin Renée , Turcotte Cynthia , Lindquist Susan , Rokeach Luis A.
Published: April 2009

In fission yeast, the ER-residing molecular chaperone calnexin is normally essential for viability. However, a specific mutant of calnexin that is devoid of chaperone function (Δhcd_Cnx1p) induces an epigenetic state that allows growth of Schizosaccharomyces pombe without calnexin. This calnexin-independent (Cin) state was previously shown to be mediated via a non-chromosomal element exhibiting some prion-like features. Here, we report the identification of a gene whose overexpression induces the appearance of stable Cin cells. This gene, here named cif1+ for calnexin-independence factor 1, encodes an uncharacterized nucleolar protein. The Cin cells arising from cif1+ overexpression (Cincif1 cells) are genetically and phenotypically distinct from the previously characterized CinΔhcd_cnx1 cells, which spontaneously appear in the presence of the Δhcd_Cnx1p mutant. Moreover, cif1+ is not required for the induction or maintenance of the CinΔhcd_cnx1 state. These observations argue for different pathways of induction and/or maintenance of the state of calnexin independence. Nucleolar localization of Cif1p is required to induce the Cincif1 state, thus suggesting an unexpected interaction between the vital cellular role of calnexin and a function of the nucleolus.