bluuebunny/crossref_metadata_2025 huggingface dataset:
The cost effectiveness of telephone counselling to aid smoking cessation in Denmark: A modelling study
Authors: Rasmussen Susanne Reindahl
Published: November 2012

Aim: To assess the cost-effectiveness of the Danish smoking cessation telephone service “quitline”. Methods: The study was based on the number of quitline callers in 2005. The outcome was measured as costs per life year saved (LYS) based on the assessment in 2001 of continued abstinence over a 12-month period (19.0%) and point prevalence of abstinence at 12 months of follow up (29.7%), respectively. The costs per LYS are estimated as the annual running costs of reactive telephone counselling service divided by the total number of LYS, which has been estimated as the difference between current smokers’ and ex-smokers’ life expectancies according to age group and gender based on Danish smoking proportions, relative risks of smoking-related mortality of all causes, and standard life tables. Results: A total of 511 ex-smokers have been estimated to gain 2172 life years based on continued abstinence over 12 months. Using the point prevalence abstinence at 12 months, 799 ex-smokers are estimated to gain 3394 life years. Discounting LYS at 3% p.a., the costs per LYS are €213 for ex-smokers with continued abstinence and €137 for ex-smokers with point prevalence abstinence. The sensitivity analysis for a worst-case scenario indicates that the costs per LYS are €1199. For comparison the average costs per LYS of smoking cessation interventions in other Danish settings are €1592 (95% CI €1547-1636). Conclusions: The Danish reactive telephone counselling to aid smoking cessation appears to be cost-effective in comparison with other Danish smoking cessation interventions.
Antenatal betamethasone exposure alters renal responses to angiotensin-(1–7) in uninephrectomized adult male sheep
Authors: Bi Jianli , Contag Stephen A , Carey Luke C , Tang Lijun , Valego Nancy K , Chappell Mark C , Rose James C
Published: November 2012

Antenatal corticosteroid exposure reduces renal function and alters the intrarenal renin-angiotensin system to favor angiotensin activation of angiotensin type 1 receptor (AT1R) mediated responses in ovine offspring. This study aimed to assess whether antenatal steroid exposure would affect renal responses to the direct intrarenal infusion of angiotensin-(1–7) in rams and the angiotensin receptors involved in mediating responses to the peptide.

Adult, uninephrectomized rams exposed to either betamethasone or vehicle before birth received intrarenal angiotensin-(1–7) infusions (1 ng/kg/min) alone or in combination with antagonists to angiotensin receptors for 3 h. Basal sodium excretion (UNa) was significantly lower and mean arterial pressure was significantly higher in betamethasone- compared to the vehicle-treated sheep. Angiotensin-(1–7) decreased UNa more in betamethasone- than in vehicle-treated sheep. Candesartan reversed the response to angiotensin-(1–7) but D-Ala7-angiotensin-(1–7) did not. Angiotensin-(1–7) infusion decreased effective renal plasma flow in both groups to a similar extent and the response was reversed by candesartan, but was not blocked by D-Ala7-angiotensin-(1–7). Glomerular filtration rate increased significantly in both groups after 3 h infusion of angiotensin-(1–7) plus candesartan. These results suggest that antenatal exposure to a clinically relevant dose of betamethasone impairs renal function in rams. Moreover, angiotensin-(1–7) appears capable of activating the AT1R in uninephrectomized rams.
MDR-1 C3435T polymorphism may affect blood pressure in resistant hypertensive patients independently of its effects on aldosterone release
Authors: Lacchini Riccardo , Figueiredo Valéria N , Demacq Caroline , Coeli-Lacchini Fernanda B , Martins Luís C , Yugar-Toledo Juan , Coca Antonio , Tanus-Santos Jose E , Moreno Heitor
Published: November 2012

Aldosterone increases plasma volume and may be involved with resistant hypertension. P-glycoprotein is a transporter involved in the distribution and disposition of aldosterone, and is encoded by the MDR-1 gene. MDR-1 has functional polymorphisms that may affect P-glycoprotein expression. We hypothesized that the C3435T polymorphism in MDR-1 could be associated with resistant hypertension and with changes in hypertension-related parameters. We studied 105 healthy volunteers, 137 hypertensive patients responsive to treatment, and 83 resistant hypertensive patients. While we found no association of C3435T genotypes with resistance to treatment ( p = 0.31), C allele was associated with hypertension ( p = 0.03). Furthermore, the CC genotype was associated with higher systolic blood pressure ( p < 0.01 for both daytime and nighttime, respectively) and diastolic blood pressure ( p < 0.01 for both daytime and nighttime, respectively). This effect was probably independent of aldosterone, as we found no differences in aldosterone plasma levels, nor in pulse wave velocity (PVW) between the genotypes groups ( p = 0.77 and p = 0.48, respectively). Our results show an association of C3435T with hypertension and with blood pressure levels in resistant hypertensive subjects.
Imidapril provides a protective effect on pulmonary hypertension induced by low ambient temperature in broiler chickens
Authors: Hao Xue-Qin , Zhang Shou-Yan , Li Meng , Yang Zhen , Niu Ming-Fu , Sun Tong-Wen , Yang Dan-Li , Kong Tao , Li Jian
Published: November 2012

Objective:

The objective of this article is to explore the role of imidapril on pulmonary hypertension induced by low ambient temperature in broiler chickens.

Materials and methods:

Ninety chickens were randomly divided into three groups ( n = 30): a control group, a low-temperature group and an imidapril group. Chickens in the low-temperature group and imidapril group were exposed to low ambient temperature from 14 days of age until 45 days of age; chickens in the imidapril group were gavaged with imidapril 3 mg/kg once daily for 30 days. The pulmonary arterial pressure, main pulmonary arterial diameter and pulmonary arterial wall thickness were measured, and lung tissue ACE, ACE2 mRNA expression, proliferating cell nuclear antigen (PCNA)-positive cells and Ang II, Ang (1-7) concentration were evaluated.

Results:

The pulmonary arterial pressure was higher, the main pulmonary arterial diameter was wider and the pulmonary arterial wall was thicker in the low-temperature group than those in the control group and the imidapril group. ACE mRNA and PCNA-positive cells increased significantly in the low-temperature group compared with the control group and imidapril group; lung tissue Ang II concentration in the low-temperature group was higher, but Ang (1-7) content was lower than that in the control group and imidapril group.

Conclusion:

Imidapril provides a protective effect on pulmonary hypertension induced by low ambient temperature in broiler chickens.
Analysis of wave performance through pile–rock breakwaters
Authors: Liu Yong , Li Hua-jun
Published: November 2012

This study gives an analytical solution of wave interaction with a new-type pile–rock breakwater in the context of linear potential theory. The pile–rock breakwater consists of two rows of closely spaced piles and a rock core between them. The matched eigenfunction expansion method is used to obtain the analytical solution. The analytical solution is confirmed by other solutions for several limiting cases of the present structure. The solution is also validated by a multi-domain boundary element method solution. The reflection coefficient, the transmission coefficient and the energy loss coefficient of the pile–rock breakwater are examined. Their significance for practical engineering is discussed.
Impaired response to exercise intervention in the vasculature in metabolic syndrome
Authors: Knaub Leslie A , McCune Sylvia , Chicco Adam J , Miller Matthew , Moore Russell L , Birdsey Nicholas , Lloyd Monique I , Villarreal Juan , Keller Amy C , Watson Peter A , Reusch Jane EB
Published: November 2012

Physical activity decreases risk for diabetes and cardiovascular disease morbidity and mortality; however, the specific impact of exercise on the diabetic vasculature is unexamined. We hypothesized that an acute, moderate exercise intervention in diabetic and hypertensive rats would induce mitochondrial biogenesis and mitochondrial antioxidant defence to improve vascular resilience. SHHF/ Mcc-facp lean (hypertensive) and obese (hypertensive, insulin resistant), as well as Sprague Dawley (SD) control rats were run on a treadmill for 8 days. In aortic lysates from SD rats, we observed a significant increase in subunit proteins from oxidative phosphorylation (OxPhos) complexes I–III, with no changes in the lean or obese SHHF rats. Exercise also increased the expression of mitochondrial antioxidant defence uncoupling protein 3 (UCP3) ( p < 0.05) in SHHF lean rats, whereas no changes were observed in the SD or SHHF obese rats with exercise. We evaluated upstream signalling pathways for mitochondrial biogenesis, and only peroxisome proliferators–activated receptor gamma coactivator 1α (PGC-1α) significantly decreased in SHHF lean rats ( p < 0.05) with exercise. In these experiments, we demonstrate absent mitochondrial induction with exercise exposure in models of chronic vascular disease. These findings suggest that chronic vascular stress results in decreased sensitivity of vasculature to the adaptive mitochondrial responses normally induced by exercise.
How Can Both the Intervention and Its Evaluation Fulfill Health Promotion Principles? An Example From a Professional Development Program
Authors: Tremblay Marie-Claude , Richard Lucie , Brousselle Astrid , Beaudet Nicole
Published: November 2012

The emergence over the past 20 years of health promotion discourse poses a specific challenge to public health professionals, who must come to terms with new roles and new intervention strategies. Professional development is, among other things, a lever for action to be emphasized in order to meet these challenges. To respond to the specific training needs of public health professionals, a team from the Direction de santé publique de Montréal (Montreal Public Health Department) in Quebec, Canada, established in 2009 the Health Promotion Laboratory, an innovative professional development project. An evaluative component, which supports the project’s implementation by providing feedback, is also integrated into the project. This article seeks to demonstrate that it is possible to integrate the basic principles of health promotion into a professional development program and its evaluation. To this end, it presents an analytical reading of both the intervention and its evaluation component in light of the cardinal principles in this field. Initiatives such as the Health Promotion Laboratory and its evaluation are essential to consolidate the foundations of professional development and its assessment by concretely integrating health promotion discourse into these practices.
An Applied Research Intervention
Authors: Doughty Michele J.
Published: November 2012

Introduction. The Surveillance Epidemiology and End Results Program 2000-2006 data reported that African American women experienced a higher incidence of early-onset invasive breast cancer and in situ breast cancer in comparison with other racial/ethnic groups. Of the total of 25,100 cases reported; in situ breast cancer represented 6,460 cases and invasive breast cancer represented 18,640 cases. This intervention focused on women younger than 40 years to increase understanding and the utilization of preventive services. Method. Over a course of 10 months, the researcher designed, implemented, and evaluated an evidence-based breast cancer course intervention integrating the health belief model. The methodology was implemented in 4-week cohorts through in-class and asynchronous learning-centered environments tailored to African American women aged 20 to 39 years at 2-year and 4-year postsecondary schools and culturally relevant community-based organizations. Results. The intervention was statistically significant, improving understanding of breast cancer in African American women in a classroom environment, p < .039, and in an online environment, p < .05. The study compared ages 20 to 29 and 30 to 39, finding high agreement and no statistically significance difference related to age about the use of preventive services, importance of preventive services, and tailoring preventive service for younger women. Conclusions. The intervention demonstrated the implementation of an evidence-based breast cancer intervention that improved understanding of breast cancer in this race/ethnicity. Additionally, there is a strong need to improve preventive services through the integration of evidence-based educational interventions targeting women of African American prior to age 40.
The New Zealand Nurse Specialist Framework
Authors: Holloway Kathryn
Published: November 2012

Maximizing the contribution that nurses can make to the health care outcomes is the focus of health workforce planners and funders worldwide. New Zealand, along with many other countries, faces significant taxonomical challenges in developing specialist nursing workforce as nurse specialists and specialty areas of practice are inconsistently defined. Clearly defining and capturing data on current workforces is a challenge shared by many countries impacting on the ability to understand current supply and plan for anticipated increased demand. This article presents an overview of the New Zealand Nurse Specialist Framework (NZNSF) developed through a consensus approach as part of a doctoral study. The NZSNF has already been adopted by some national nursing groups in New Zealand and provides an overarching structure to support coherence, clarity and consistency for nurse specialists. The framework aims to support workforce policy makers in planning effective utilization of the nurse specialist in health care delivery.
Adjudicatory Oversight and Judicial Decision Making in Executive Branch Agencies
Authors: Boyd Christina L. , Driscoll Amanda
Published: November 2012

Adjudications are an important, though understudied, means through which administrative agencies create policies that have a lasting impact. We argue that executive branch agency heads utilize their oversight of agency adjudications to advance agency goals. Relying on an original data set of adjudications appealed to the U.S. Department of Agriculture’s agency head’s adjudication delegee, our empirical results indicate a substantial positive effect on the probability that the agency head will reverse an administrative law judge (ALJ) when he receives the appeal of an antiagency ALJ decision. However, the agency’s adjudication oversight is conditional on political constraints, including partisanship differences between an agency and the litigated law and whether the case is being heard during a time of presidential transition. These results have clear implications for the use and effectiveness of agency adjudications as a political tool.
Conscious Attention, Meditation, and Bilateral Information Transfer
Authors: Bob Petr , Zimmerman Elizabeth M. , Hamilton Elizabeth A. , Sheftel Jenna G. , Bajo Stephanie D. , Raboch Jiri , Golla Megan , Konopka Lukasz M.
Published: November 2012

Recent findings indicate that conscious attention is related to large-scale information integration of various brain regions, including both hemispheres, that enables integration of parallel distributed modalities of processed information. There is also evidence that the level of information transference related to integration or splitting among brain regions, and between hemispheres, establishes a certain level of efficiency of the information processing. The level of information transference also may have modulatory influences on attentional capacity that are closely linked to the emotional arousal and autonomic response related to a stimulus. These findings suggest a hypothesis that changes in conscious attention, specifically during meditation could be reflected in the autonomic activity as the left–right information transference calculated from bilateral electrodermal activity (EDA). With the aim to compare conscious attention during meditation with other attentional states (resting state, Stroop task, and memory task), we performed bilateral EDA measurement in 7 healthy persons during resting state, Stroop task, neurofeedback memory test, and meditation. The results indicate that the information transference (ie, transinformation) is able to distinguish those attentional states, and that the highest level of the transinformation has been found during attentional processing related to meditation, indicating higher level of connectivity between left and right sides. Calculations other than pointwise transinformation (PTI) performed on EDA records, such as mean skin conductance level or laterality index, were not able to distinguish attentional states. The results suggest that PTI may present an interesting method useful for the assessment of information flow, related to neural functioning, that in the case of meditation may reflect typical integrative changes in the autonomic nervous system related to brain functions and focused attentional processing.
Male Peer Influence on African American Men’s Motivation for Physical Activity
Authors: Griffith Derek M. , King Andrea , Ober Allen Julie
Published: November 2012

Thematic analysis of data from nine exploratory focus groups conducted with 71 middle-aged and older African American men and eight focus groups with 77 key women in their lives revealed how social norms and modeling of physical activity influenced men’s motivation to exercise. Both men and women identified male peers as an important source of ideas, encouragement, and support to initiate and sustain physical activity, yet sedentary peers also could contribute to men being less motivated to be active. The primary difference in men’s and women’s perspectives was that men attributed their decline in activity levels to difficulties in finding time for physical activity, whereas women attributed sedentary lifestyles to an increase in men’s physical illnesses and ailments. Men’s participation in team sports and overall activity levels diminished with age. Peer social support can be critical for interventions to help African American men engage in and sustain physical activity.
Development of the Stanford Expectations of Treatment Scale (SETS): A tool for measuring patient outcome expectancy in clinical trials
Authors: Younger Jarred , Gandhi Vanisha , Hubbard Emily , Mackey Sean
Published: November 2012

Background

A patient’s response to treatment may be influenced by the expectations that the patient has before initiating treatment. In the context of clinical trials, the influence of participant expectancy may blur the distinction between real and sham treatments, reducing statistical power to detect specific treatment effects. There is therefore a need for a tool that prospectively predicts expectancy effects on treatment outcomes across a wide range of treatment modalities.

Purpose

To help assess expectancy effects, we created the Stanford Expectations of Treatment Scale (SETS): an instrument for measuring positive and negative treatment expectancies. Internal reliability of the instrument was tested in Study 1. Criterion validity of the instrument (convergent, discriminant, and predictive) was assessed in Studies 2 and 3.

Methods

The instrument was developed using 200 participants in Study 1. Reliability and validity assessments were made with an additional 423 participants in Studies 2 and 3.

Results

The final six-item SETS contains two subscales: positive expectancy (α = 0.81–0.88) and negative expectancy (α = 0.81–0.86). The subscales predict a significant amount of outcome variance (between 12% and 18%) in patients receiving surgical and pain interventions. The SETS is simple to administer, score, and interpret.

Conclusion

The SETS may be used in clinical trials to improve statistical sensitivity for detecting treatment differences or in clinical settings to identify patients with poor treatment expectancies.
Measurement of the convective moisture transfer coefficient from porous building material surfaces applying a wind tunnel method
Authors: Talev Goce , Jelle Bjørn Petter , Næss Erling , Gustavsen Arild , Thue Jan Vincent
Published: November 2012

This article presents results for the average convective moisture transfer coefficients of several porous building material samples exposed to airflow. The experimental measurements explore the effect of the various air velocities, air temperatures and local positions on the average convective moisture transfer coefficients. Selected building materials were soaked in distilled water at least 2 weeks before the measurements. A thin building specimen with moisture content close to the saturation point was mounted in level with the bottom wind tunnel surface. A stable airflow regime was measured over the thin samples placed in the specimen holder. Water from the sample holder was absorbed from the bottom side of the building materials and evaporated from the upper side of the specimen during the airflow exposure. Two different membranes were fixed over the water cup as reference materials for comparison. The measurements were carried out at a relative humidity of 50% ± 3%, air temperatures of 23.6°C ± 0.5°C, 26.5°C ± 0.5°C and 30.0°C ± 0.5°C, and air velocities of 1.1, 3.0 and 5.5 m/s. The experimental data show that the convective moisture transfer coefficient is a function of velocity, temperature difference between the ambient air and material surface, local position as well as of the material type. The experimental results from water surfaces were compared to the expressions for the convective moisture transfer coefficients from the literature.
Antimicrobial peptide elicitors: New hope for the post-antibiotic era
Authors: de Oca Ernesto Prado Montes
Published: November 2012

Antimicrobial peptides or host defense peptides are fundamental components of human innate immunity. Recent and growing evidence suggests they have a role in a broad range of diseases, including cancer, allergies and susceptibility to infection, including HIV/AIDS. Antimicrobial peptide elicitors (APEs) are physical, biological or chemical agents that boost human antimicrobial peptide expression. The current knowledge of APEs and their potential use in the treatment of human infectious diseases are reviewed, and a classification system for APEs is proposed. The efficient use of APEs in clinical practice could mark the beginning of the urgently needed post-antibiotic era, but further trials assessing their efficacy and safety are required.
Granulocytic myeloid-derived suppressor cells are cryosensitive and their frequency does not correlate with serum concentrations of colony-stimulating factors in head and neck cancer
Authors: Trellakis Sokratis , Bruderek Kirsten , Hütte Jan , Elian Motaz , Hoffmann Thomas K , Lang Stephan , Brandau Sven
Published: November 2012

Granulocytic myeloid-derived suppressor cells (MDSC) are a MDSC subset expanded in various cancer types. As many clinical studies rely on the use of stored collections of frozen blood samples, we first tested the influence of freezing/thawing procedures on immunophenotyping and enumeration of granulocytic MDSC (G-MDSC). To identify factors involved in expansion of human G-MDSC, we then analyzed correlations between G-MDSC frequencies, clinical parameters and granulocyte-related factors in the peripheral blood of head and neck cancer patients. HLA-DR, CD14, CD33 and CD66b allowed a clear discrimination of G-MDSC from monocytic MDSC and immature myeloid cells. MDSC subsets were sensitive to cryopreservation with immature G-MDSC showing the highest sensitivity. G-MDSC frequencies were increased in advanced disease stage and associated with the level of CCL4 and CXCL8, but not with colony-stimulating factors, IL-6, S100A8/9, CXCL1 and other cytokines. Our results indicate that the frequency of MDSC, in particular G–MDSC, may be underestimated in retrospective clinical analyses using frozen blood samples. Increased G-MDSC frequencies correlate with advanced disease and increased concentrations of CXCL8, but, unexpectedly, not with growth factors (such as granulocyte colony-stimulating factor), IL-6 and CXCL1. Our data suggest that CXCL8 promotes accumulation of G-MDSC in cancer patients independent of classical colony-stimulating factors.
Bactericidal/permeability increasing protein: A multifaceted protein with functions beyond LPS neutralization
Authors: Balakrishnan Arjun , Marathe Sandhya A , Joglekar Madhura , Chakravortty Dipshikha
Published: November 2012

Bactericidal permeability increasing protein (BPI), a 55–60 kDa protein, first reported in 1975, has gone a long way as a protein with multifunctional roles. Its classical role in neutralizing endotoxin (LPS) raised high hopes among septic shock patients. Today, BPI is not just a LPS-neutralizing protein, but a protein with diverse functions. These functions can be as varied as inhibition of endothelial cell growth and inhibition of dendritic cell maturation, or as an anti-angiogenic, chemoattractant or opsonization agent. Though the literature available is extremely limited, it is fascinating to look into how BPI is gaining major importance as a signalling molecule. In this review, we briefly summarize the recent research focused on the multiple roles of BPI and its use as a therapeutic.
Bevacizumab and ovarian cancer
Authors: Garcia Agustin , Singh Harpreet
Published: November 2012

Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor-A, and is indicated in the treatment of various tumors (colon, lung, renal, and glioblastoma). It has been recently approved for the treatment of ovarian cancer in various countries. This review summarizes the activity and toxicity of bevacizumab in the treatment of ovarian cancer, both as single-agent drug and in combination with cytotoxic chemotherapy. As a single-agent drug, it has shown response rates of 16–21% in the treatment of recurrent ovarian cancer. Two phase III randomized trials have been published evaluating the addition of bevacizumab to standard chemotherapy as front-line treatment of advanced ovarian cancer. In addition, trials evaluating the combination with chemotherapy in recurrent ovarian cancer (platinum-sensitive and platinum-resistant disease) have also been reported. All these trials showed a statistically significant improvement in progression-free survival although no improvement in overall survival has been reported. The main adverse event is hypertension. Other serious, but uncommon adverse events include gastrointestinal perforation as well as renal and central nervous system toxicity.
Ventilatory Management and Extubation Criteria of the Neurological/Neurosurgical Patient
Authors: Souter M. J. , Manno Edward M.
Published: November 2012

Approximately 200 000 patients per year will require mechanical ventilation secondary to neurological injury or disease. The associated mortality, morbidity, and costs are significant. The neurological patient presents a unique set of challenges to airway management, mechanical ventilation, and defining extubation readiness. Neurological injury and disease can directly or indirectly involve the process involved with respiration or airway control. This article will review the basics of airway management and mechanical ventilation in the neurological patient. The current state of the literature evaluating extubation criteria in the neurological patient will also be reviewed.
Using Evidence-Based Practice in the School Health Room
Authors: Bultas Margaret W. , McLaughlin Laura
Published: November 2012

School nurses should be engaging in evidence-based practice (EBP) in their health room settings as supported by the initiatives of the Institute of Medicine. EBP is a set of skills that health professionals can use in order to ensure high quality and current clinical care is provided. School nurses are faced with a diverse and complex population of children and often work in isolation from nursing peers, which can lead to limited professional peer discussions about recent changes or outdated clinical practices. EBP combines the use of evidence from the literature, expert guidelines, clinician expertise, and client preferences in order to provide optimum care. This article leads the school nurse through the process and use of EBP in the school setting.
Detecting Suicidality From Facial Appearance
Authors: Kleiman Sela , Rule Nicholas O.
Published: November 2012

Suicide is a pervasive problem worldwide. In this investigation, we show that individuals can perceive suicidality from facial appearance with accuracy that is significantly greater than chance guessing. Inferences of expected or obvious cues, such as how depressed a person seems, did not lead to accurate judgments. Rather, perceptions of how impulsive an individual appears differentiated suicide victims from living controls. Teasing apart various forms of impulsivity revealed that perceptions of impulsive aggression, distinct from other forms of impulsive behavior (e.g., impulsive buying), distinguished suicide victims from controls. Finally, experienced mental health clinicians did not perform significantly better than laypersons at judging suicidality. Facial appearance may therefore hold cues to suicidality, expanding what is known about the expression and perception of social cues from the face and providing new insights into the relationship between mental health and nonverbal cues.
Canonical Wnt signaling in megakaryocytes regulates proplatelet formation
Authors: Macaulay Iain C. , Thon Jonathan N. , Tijssen Marloes R. , Steele Brian M. , MacDonald Bryan T. , Meade Gerardene , Burns Philippa , Rendon Augusto , Salunkhe Vishal , Murphy Ronan P. , Bennett Cavan , Watkins Nicholas A. , He Xi , Fitzgerald Desmond J. , Italiano Joseph E. , Maguire Patricia B.
Published: November 2012

Wnt signaling is involved in numerous aspects of vertebrate development and homeostasis, including the formation and function of blood cells. Here, we show that canonical and noncanonical Wnt signaling pathways are present and functional in megakaryocytes (MKs), with several Wnt effectors displaying MK-restricted expression. Using the CHRF288-11 cell line as a model for human MKs, the canonical Wnt3a signal was found to induce a time and dose-dependent increase in β-catenin expression. β-catenin accumulation was inhibited by the canonical antagonist dickkopf-1 (DKK1) and by the noncanonical agonist Wnt5a. Whole genome expression analysis demonstrated that Wnt3a and Wnt5a regulated distinct patterns of gene expression in MKs, and revealed a further interplay between canonical and noncanonical Wnt pathways. Fetal liver cells derived from low-density-lipoprotein receptor-related protein 6-deficient mice (LRP6−/−), generated dramatically reduced numbers of MKs in culture of lower ploidy (2N and 4N) than wild-type controls, implicating LRP6-dependent Wnt signaling in MK proliferation and maturation. Finally, in wild-type mature murine fetal liver-derived MKs, Wnt3a potently induced proplatelet formation, an effect that could be completely abrogated by DKK1. These data identify novel extrinsic regulators of proplatelet formation, and reveal a profound role for Wnt signaling in platelet production.
WT1-specific T-cell responses in high-risk multiple myeloma patients undergoing allogeneic T cell–depleted hematopoietic stem cell transplantation and donor lymphocyte infusions
Authors: Tyler Eleanor M. , Jungbluth Achim A. , O'Reilly Richard J. , Koehne Guenther
Published: November 2012

While the emergence of WT1-specific cytotoxic T lymphocytes (WT1-CTL) has been correlated with better relapse-free survival after allogeneic stem cell transplantation in patients with myeloid leukemias, little is known about the role of these cells in multiple myeloma (MM). We examined the significance of WT1-CTL responses in patients with relapsed MM and high-risk cytogenetics who were undergoing allogeneic T cell–depleted hematopoietic stem cell transplantation (alloTCD-HSCT) followed by donor lymphocyte infusions. Of 24 patients evaluated, all exhibited WT1-CTL responses before allogeneic transplantation. These T-cell frequencies were universally correlated with pretransplantation disease load. Ten patients received low-dose donor lymphocyte infusions beginning 5 months after transplantation. All patients subsequently developed increments of WT1-CTL frequencies that were associated with reduction in specific myeloma markers, in the absence of graft-versus-host disease. Immunohistochemical analyses of WT1 and CD138 in bone marrow specimens demonstrated consistent coexpression within malignant plasma cells. WT1 expression in the bone marrow correlated with disease outcome. Our results suggest an association between the emergence of WT1-CTL and graft-versus-myeloma effect in patients treated for relapsed MM after alloTCD-HSCT and donor lymphocyte infusions, supporting the development of adoptive immunotherapeutic approaches using WT1-CTL in the treatment of MM (registered at http://clinicaltrials.gov, ID: NCT01131169).
inv(16)/t(16;16) acute myeloid leukemia with non–type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations
Authors: Schwind Sebastian , Edwards Colin G. , Nicolet Deedra , Mrózek Krzysztof , Maharry Kati , Wu Yue-Zhong , Paschka Peter , Eisfeld Ann-Kathrin , Hoellerbauer Pia , Becker Heiko , Metzeler Klaus H. , Curfman John , Kohlschmidt Jessica , Prior Thomas W. , Kolitz Jonathan E. , Blum William , Pettenati Mark J. , Dal Cin Paola , Carroll Andrew J. , Caligiuri Michael A. , Larson Richard A. , Volinia Stefano , Marcucci Guido , Bloomfield Clara D.
Published: November 2012

The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n = 182; 87%) and non–type A (n = 26; 13%) patients. At diagnosis, non–type A patients had lower white blood counts (P = .007), and more often trisomies of chromosomes 8 (P = .01) and 21 (P < .001) and less often trisomy 22 (P = .02). No patient with non–type A fusion carried a KIT mutation, whereas 27% of type A patients did (P = .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non–type A and type A patients with wild-type KIT were similar. We also derived a fusion-type–associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealed—among others—an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non–type A patients. We conclude that non–type A fusions associate with distinctclinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile.
Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms
Authors: Cazzola Mario , Rossi Marianna , Malcovati Luca
Published: November 2012

Precursor mRNA splicing is catalyzed by the spliceosome, a macromolecule composed of small nuclear RNAs associated with proteins. The SF3B1 gene encodes subunit 1 of the splicing factor 3b, which is important for anchoring the spliceosome to precursor mRNA. In 2011, whole-exome sequencing studies showed recurrent somatic mutations of SF3B1 and other genes of the RNA splicing machinery in patients with myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm. SF3B1 mutations had a particularly high frequency among conditions characterized by ring sideroblasts, which is consistent with a causal relationship. SF3B1 mutants were also detected at a lower frequency in a variety of other tumor types. In chronic lymphocytic leukemia, SF3B1 was found to be the second most frequently mutated gene. In myelodysplastic syndromes, SF3B1 mutations appear to be founding genetic lesions and are associated with a low risk of leukemic evolution. In contrast, SF3B1 mutations have a lower incidence in early stages of chronic lymphocytic leukemia, are more common in advanced disease, and tend to be associated with poor prognosis, suggesting that they occur during clonal evolution of the disease. The assessment of SF3B1 mutation status may become innovative diagnostic and prognostic tools and the availability of spliceosome modulators opens novel therapeutic prospects.
Gene expression analysis of a murine model with pulmonary vascular remodeling compared to end-stage IPAH lungs
Authors: Shimodaira Kayoko , Okubo Yoichiro , Ochiai Eri , Nakayama Haruo , Katano Harutaka , Wakayama Megumi , Shinozaki Minoru , Ishiwatari Takao , Sasai Daisuke , Tochigi Naobumi , Nemoto Tetsuo , Saji Tsutomu , Kamei Katsuhiko , Shibuya Kazutoshi
Published: November 2012

Background

Idiopathic pulmonary arterial hypertension (IPAH) continues to be one of the most serious intractable diseases that might start with activation of several triggers representing the genetic susceptibility of a patient. To elucidate what essentially contributes to the onset and progression of IPAH, we investigated factors playing an important role in IPAH by searching discrepant or controversial expression patterns between our murine model and those previously published for human IPAH. We employed the mouse model, which induced muscularization of pulmonary artery leading to hypertension by repeated intratracheal injection of Stachybotrys chartarum, a member of nonpathogenic and ubiquitous fungus in our envelopment.

Methods

Microarray assays with ontology and pathway analyses were performed with the lungs of mice. A comparison was made of the expression patterns of biological pathways between our model and those published for IPAH.

Results

Some pathways in our model showed the same expression patterns in IPAH, which included bone morphogenetic protein (BMP) signaling with down-regulation of BMP receptor type 2, activin-like kinase type 1, and endoglin. On the other hand, both Wnt/planar cell polarity (PCP) signaling and its downstream Rho/ROCK signaling were found alone to be activated in IPAH and not in our model.

Conclusions

Activation of Wnt/PCP signaling, in upstream positions of the pathway, found alone in lungs from end stage IPAH may play essential roles in the pathogenesis of the disease.
Copy Number Variation detection from 1000 Genomes project exon capture sequencing data
Authors: Wu Jiantao , Grzeda Krzysztof R , Stewart Chip , Grubert Fabian , Urban Alexander E , Snyder Michael P , Marth Gabor T
Published: November 2012

Background

DNA capture technologies combined with high-throughput sequencing now enable cost-effective, deep-coverage, targeted sequencing of complete exomes. This is well suited for SNP discovery and genotyping. However there has been little attention devoted to Copy Number Variation (CNV) detection from exome capture datasets despite the potentially high impact of CNVs in exonic regions on protein function.

Results

As members of the 1000 Genomes Project analysis effort, we investigated 697 samples in which 931 genes were targeted and sampled with 454 or Illumina paired-end sequencing. We developed a rigorous Bayesian method to detect CNVs in the genes, based on read depth within target regions. Despite substantial variability in read coverage across samples and targeted exons, we were able to identify 107 heterozygous deletions in the dataset. The experimentally determined false discovery rate (FDR) of the cleanest dataset from the Wellcome Trust Sanger Institute is 12.5%. We were able to substantially improve the FDR in a subset of gene deletion candidates that were adjacent to another gene deletion call (17 calls). The estimated sensitivity of our call-set was 45%.

Conclusions

This study demonstrates that exonic sequencing datasets, collected both in population based and medical sequencing projects, will be a useful substrate for detecting genic CNV events, particularly deletions. Based on the number of events we found and the sensitivity of the methods in the present dataset, we estimate on average 16 genic heterozygous deletions per individual genome. Our power analysis informs ongoing and future projects about sequencing depth and uniformity of read coverage required for efficient detection.
Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects
Authors: van Eijk Kristel R , de Jong Simone , Boks Marco PM , Langeveld Terry , Colas Fabrice , Veldink Jan H , de Kovel Carolien GF , Janson Esther , Strengman Eric , Langfelder Peter , Kahn René S , van den Berg Leonard H , Horvath Steve , Ophoff Roel A
Published: November 2012

Background

The predominant model for regulation of gene expression through DNA methylation is an inverse association in which increased methylation results in decreased gene expression levels. However, recent studies suggest that the relationship between genetic variation, DNA methylation and expression is more complex.

Results

Systems genetic approaches for examining relationships between gene expression and methylation array data were used to find both negative and positive associations between these levels. A weighted correlation network analysis revealed that i) both transcriptome and methylome are organized in modules, ii) co-expression modules are generally not preserved in the methylation data and vice-versa, and iii) highly significant correlations exist between co-expression and co-methylation modules, suggesting the existence of factors that affect expression and methylation of different modules (i.e., trans effects at the level of modules). We observed that methylation probes associated with expression in cis were more likely to be located outside CpG islands, whereas specificity for CpG island shores was present when methylation, associated with expression, was under local genetic control. A structural equation model based analysis found strong support in particular for a traditional causal model in which gene expression is regulated by genetic variation via DNA methylation instead of gene expression affecting DNA methylation levels.

Conclusions

Our results provide new insights into the complex mechanisms between genetic markers, epigenetic mechanisms and gene expression. We find strong support for the classical model of genetic variants regulating methylation, which in turn regulates gene expression. Moreover we show that, although the methylation and expression modules differ, they are highly correlated.
Genomic insights into strategies used by Xanthomonas albilineans with its reduced artillery to spread within sugarcane xylem vessels
Authors: Pieretti Isabelle , Royer Monique , Barbe Valérie , Carrere Sébastien , Koebnik Ralf , Couloux Arnaud , Darrasse Armelle , Gouzy Jérôme , Jacques Marie-Agnès , Lauber Emmanuelle , Manceau Charles , Mangenot Sophie , Poussier Stéphane , Segurens Béatrice , Szurek Boris , Verdier Valérie , Arlat Matthieu , Gabriel Dean W , Rott Philippe , Cociancich Stéphane
Published: November 2012

Background

Xanthomonas albilineanscauses leaf scald, a lethal disease of sugarcane.X. albilineansexhibits distinctive pathogenic mechanisms, ecology and taxonomy compared to other species ofXanthomonas. For example, this species produces a potent DNA gyrase inhibitor called albicidin that is largely responsible for inducing disease symptoms; its habitat is limited to xylem; and the species exhibits large variability. A first manuscript on the complete genome sequence of the highly pathogenicX. albilineansstrain GPE PC73 focused exclusively on distinctive genomic features shared withXylella fastidiosa—another xylem-limitedXanthomonadaceae. The present manuscript on the same genome sequence aims to describe all other pathogenicity-related genomic features ofX. albilineans, and to compare, using suppression subtractive hybridization (SSH), genomic features of two strains differing in pathogenicity.

Results

Comparative genomic analyses showed that most of the known pathogenicity factors from otherXanthomonasspecies are conserved inX. albilineans, with the notable absence of two major determinants of the “artillery” of other plant pathogenic species ofXanthomonas: the xanthan gum biosynthesis gene cluster, and the type III secretion system Hrp (hypersensitive response and pathogenicity). Genomic features specific toX. albilineansthat may contribute to specific adaptation of this pathogen to sugarcane xylem vessels were also revealed. SSH experiments led to the identification of 20 genes common to three highly pathogenic strains but missing in a less pathogenic strain. These 20 genes, which include four ABC transporter genes, a methyl-accepting chemotaxis protein gene and an oxidoreductase gene, could play a key role in pathogenicity. With the exception of hypothetical proteins revealed by our comparative genomic analyses and SSH experiments, no genes potentially involved in any offensive or counter-defensive mechanism specific toX. albilineanswere identified, supposing thatX. albilineanshas a reduced artillery compared to other pathogenicXanthomonasspecies. Particular attention has therefore been given to genomic features specific toX. albilineansmaking it more capable of evading sugarcane surveillance systems or resisting sugarcane defense systems.

Conclusions

This study confirms thatX. albilineansis a highly distinctive species within the genusXanthomonas, and opens new perpectives towards a greater understanding of the pathogenicity of this destructive sugarcane pathogen.
Prospective memory tasks: a more sensitive method for screening cognitive impairment in ALS?
Authors: Ji Ying , Wei Ling , Chui Dehua , Wang Kai , Fan Dongsheng
Published: November 2012

Background

Cognitive change is prevalent in patients with amyotrophic lateral sclerosis (ALS), but still lack a widely accepted and sensitive screening method. In this study, we try to find a sensitive screening battery for detecting subtle cognitive deficits in patients with ALS.

Methods

Eighty consecutive ALS patients and 57 matched normal controls underwent the Mini-Mental Status Examination (MMSE), the verbal fluency test (VFT), the Stroop Color Word Interference Test (CWT), and the prospective memory (PM) tests, including event-based (EBPM) and time-based (TBPM).

Results

The patients did not differ from the controls in the MMSE, the VFT and the CWT. By contrast, statistically significant differences were found in the PM tests (EBPM: P=0.043; TBPM: P<0.001). More interestingly, TBPM was more sensitive than EBPM in the early-phase patients.

Conclusions

Prefrontal lobar dysfunction does exist among ALS patients and may spread from the medial to the lateral region. The PM tests seem more sensitive in ALS patients with frontotemporal dysfunction than are the classical cognitive measures.