bluuebunny/crossref_metadata_2025 huggingface dataset:
Moderators of Negative Peer Influence on Early Adolescent Externalizing Behaviors
Authors: Mrug Sylvie , Windle Michael
Published: November 2008

This study examined the extent to which antisocial behavior, parenting, and school connectedness moderated the association between peer deviancy in preadolescence and externalizing problems in early adolescence. The participants included 500 boys and girls, most of them African Americans. Peer deviancy was measured with teacher reports of aggressive-disruptive behavior for classmates identified by target children as friends. Parents provided information on parenting practices (nurturance and harsh and inconsistent discipline) and children's antisocial behavior. Children reported on their school connectedness and externalizing behaviors (delinquency and substance use) in preadolescence and early adolescence. Externalizing problems in early adolescence were associated with preadolescent externalizing and antisocial behavior and older age. Peer deviancy predicted externalizing problems only when combined with higher levels of antisocial behavior and negative parenting. School connectedness, gender, and ethnicity did not moderate the link between peer deviancy and externalizing problems.
Familism Values as a Protective Factor for Mexican-Origin Adolescents Exposed to Deviant Peers
Authors: Germán Miguelina , Gonzales Nancy A. , Dumka Larry
Published: November 2008

This study examined interactive relations between adolescent, maternal, and paternal familism values and deviant peer affiliations in predicting adolescent externalizing problems within low-income, Mexican-origin families ( N = 598). Adolescent, maternal, and paternal familism values interacted protectively with deviant peer affiliations to predict lower levels of externalizing problems according to two independent teacher reports. These relations were not found with parent reports of adolescent externalizing problems although these models showed a direct, protective effect of maternal familism values. Consistent with the view that traditional cultural values are protective for Latino adolescents, these results suggest that supporting familism values among Mexican-origin groups is a useful avenue for improving adolescent conduct problems, particularly in a school context.
Uncovering the Determinants of Competitive State Government Wages
Authors: Llorens Jared J.
Published: November 2008

Given the importance of competitive public sector wage rates in the recruitment and retention of talented employees, this article seeks to shed light on the determinants of competitive state government wages. Using panel data from the U.S. Bureau of Labor Statistics' Current Population Survey, public—private wage gaps are estimated for all 50 states between 1987 and 2002, and an explanatory analysis of the determinants of state-level public—private wage gaps is performed. Results indicate that, on average, state government employees enjoy a wage premium across the years covered, but when separated by gender, female state employees are found to experience an average wage premium, whereas male state employees are found to experience an average wage penalty. Surprisingly, state fiscal capacity is found not to influence state public—private wage gaps, but in particular cases, state unemployment, citizen liberalism, and unionization are found to be positively.
Idiopathic Intracranial Hypertension in a Pediatric Population: A Retrospective Analysis of the Initial Imaging Evaluation
Authors: Standridge Shannon M. , O'Brien Sarah H.
Published: November 2008

There are few studies in the pediatric population regarding the use of magnetic resonance venography to rule out cerebral venous sinus thrombosis in patients presenting with signs and symptoms of idiopathic intracranial hypertension. The purpose of this study was to compare the clinical characteristics of children with presumed idiopathic intracranial hypertension who did and did not undergo venography during their evaluation at a single children's hospital. The authors found that 45 of 68 (66%) patients underwent magnetic resonance venography. Five of 45 (11%) venography studies revealed a thrombosis. There were no significant clinical differences within patients based on the completion of venography or the presence of thrombosis. Larger studies are needed to identify risk factors for thrombosis in children with presumed idiopathic intracranial hypertension, as well as factors influencing physician decision making in the use of magnetic resonance venography in this evaluation.
Infant Botulism: Two Recent Cases and Literature Review
Authors: Domingo Rose M. , Haller Jerome S. , Gruenthal Michael
Published: November 2008

Infant botulism is a cause for significant pediatric morbidity in the United States, though early recognition and supportive care can greatly improve clinical outcomes. Since the approval of human botulism immune globulin by the United States Food and Drug Administration (FDA) for the treatment of infant botulism in 2003, the importance of prompt initiation of therapy has been emphasized, with clinical suspicion remaining the mainstay of diagnosis. In this report, 2 cases of infant botulism are described. Each presented to the Pediatric Neurology service at our institution in Upstate New York in the spring and summer months of 2007 and were felt to be related to markedly dusty environmental conditions and the probable ingestion of C. botulinum organisms present in soil. Following this, a comprehensive review of the literature regarding infant botulism in the United States is presented, wherein the pathophysiology, clinical features, epidemiology, and treatment are discussed.
Incorporation and Immunogenicity of Cleaned Bovine Bone in a Sheep Model
Authors: Katz Jordan , Mukherjee Nilay , Cobb Ronald R. , Bursac Predrag , York-Ely Amanda
Published: November 2008

This study was conducted to determine if a novel cleaning process could extract antigenic material from bovine bone thereby improving incorporation. Cleaned bovine xenograft, untreated bovine xenograft and sheep allograft were implanted into the tibia of mature sheep for 12 and 24 weeks. Inflammation, bone integration and immunological reactions were evaluated via standardized assays. Cleaned bovine bone dowels induced significantly lower inflammatory responses (p<50.05) when compared to traditionally processed xenograft. Bone integration, measured by in situ biomechanics, was not different between cleaned bovine bone and allograft controls (p = 0.96). A transient antibody response was observed for non-treated xenografts although this response abated by 3 months.
Free Bioverit ® II Implants Coated with a Nanoporous Silica Layer in a Mouse Ear Model — A Histological Study
Authors: Vogt Julia C. , Brandes Gudrun , Ehlert Nina , Behrens Peter , Nolte Ingo , Mueller Peter P. , Lenarz Thomas , Stieve Martin
Published: November 2008

The objective of this study is to evaluate the suitability of a mouse middle ear model for testing ossicular replacement materials. Twenty-four BALB/c mice are implanted with the bioglass-ceramic Bioverit® II which is coated with a silica-nanostructure or with plain Bioverit® II as a control. After 2, 6, and 12 weeks, 4 mice per group are sacrificed and both complete petrous bones are analyzed histologically. All implants revealed in situ an incipient growth of thin connective tissue layers over the surface, followed by a spreading of epithelial cells. The osseogenic response which is increasing with time is more intense in the coated Bioverit ® II specimens. The absence of inflammatory cells suggests an excellent biocompatibility of the silica nano structure. As the results are comparable to a study with the same materials in rabbits, the mouse model described is highly suitable for evaluation of new ossicular replacement materials. Additionally, by gene expression analysis a more detailed insight into cellular interactions of the middle ear is offered.
Surface Characterization and Cytocompatibility of Three Chitosan/Polycation Composite Membranes for Guided Bone Regeneration
Authors: Zheng Zhenhuan , Wei Yujun , Wang Gan , Gong Yandao , Zhang Xiufang
Published: November 2008

Guided bone regeneration is a promising surgical procedure for reconstructing bone defects. In this study, three chitosan/polycation composite membranes for guided bone regeneration are produced by blending chitosan with poly-L-lysine, polyethyleneimine, and poly-L-ornithine. For all composite membranes, the surface characteristics including surface topography, chemistry, and wettability are examined by atomic force microscopy, X-ray photoelectron spectroscopy, and contact angle assay. Their cytocompatibility is also evaluated with MC3T3-E1 osteoblast-like cells at cell, protein, and gene levels through cell biology assays, western blot, and RT-PCR analysis. On chitosan/poly-L-lysine composite membrane, MC3T3-E1 cells present well-developed cytoskeletal organization and significantly higher adhesion, proliferation, and differentiation than those on chitosan and the other two composite membranes. Furthermore, MC3T3-E1 cells on chitosan/poly-L-lysine membrane exhibit increased phosphorylation levels of focal adhesion kinase and extracellular signal-regulated kinase 1/2, and achieve an enhanced mRNA expression of fibronectin, Runx 2, RhoA, integrin α5, and integrin β1. From our results, we conclude that chitosan/ poly-L-lysine composite membrane possesses improved cytocompatibility with osteoblasts when compared to chitosan and holds potential for guided bone regeneration in the near future.
Enhanced Regeneration of Critical Bone Defects Using a Biodegradable Gelatin Sponge and β-Tricalcium Phosphate with Bone Morphogenetic Protein-2
Authors: Matsumoto Goichi , Omi Yasushi , Kubota Eiro , Ozono Satoru , Tsuzuki Hideko , Kinoshita Yukihiko , Yamamoto Masaya , Tabata Yasuhiko
Published: November 2008

We examine the osteogenicity of a sponge biomaterial consisting of a biodegradable mixture of gelatin and β-tricalcium phosphate (βTCP) that bound bone morphogenetic protein 2 (BMP-2) in critical-sized bone defects in rats. Gelatin-βTCP sponges containing either phosphate buffered saline or incorporating BMP-2 are implanted into 5 mm diameter bone defects created in rat mandibles. We assess the defects biweekly for 8 weeks following implantation. There is significantly higher osteoinductive activity and significantly more Gla-osteocalcin content at bone-defect healing sites treated with gelatin-βTCP sponges incorporating BMP-2 than there is in those treated with sponges that did not contain BMP-2. Histologically, new bone that contains bone marrow and that is connected to the original bone almost entirely replaces the regenerated bone. These results show that biodegradable gelatin-βTCP incorporating BMP-2 is osteogenic enough to promote healing in large bone defects.
Correlates of Dating Violence Among Male and Female Heavy-Drinking College Students
Authors: Roudsari Bahman S. , Leahy Matthew M. , Walters Scott T.
Published: November 2008

Objective: To evaluate the correlates for dating violence among heavy-drinking college students. Method: Participants were at least 18 years old and reported at least one heavy-drinking episode in the past 2 weeks. Results: After covariate adjustment, estimated peak blood alcohol concentration during the past month was associated with higher victims’ verbal-emotional abuse score, and perpetrators’ verbal-emotional abuse and threatening abuse scores ( N = 280). In addition, being non-White was significantly associated with higher victims’ threatening abuse, physical abuse, and total abuse scores and perpetrators’ threatening abuse and physical abuse scores. Moreover, male students had significantly lower victims’ threatening abuse and physical abuse scores and perpetrators’ threatening abuse scores compared to female students. Discussion: Preventive programs that target dating violence among heavy-drinking college students should consider alcohol use as an important risk factor for abusive behaviors, both for the victims as well as the perpetrators.
Adding Meaning to Measurement
Authors: Hall Jeremy L.
Published: November 2008

How do states compare to one another, and to themselves, in innovation capacity and past innovation performance? Are there groups of states that are more or less similar in innovation capacity composition? Because different score dimensions vary independently, it is possible for states to be high on some dimensions and low on others. In an effort to give greater meaning to innovation index scores, it is necessary to evaluate the relationships among them. This article subjects Hall's innovation capacity index scores to cluster analysis to reveal clusters of states that are similar in innovation capacity levels across the three dimensions considered. A cluster typology is created, and state changes in typology are observed and compared over the 20-year period of the data set. Patterns observed across states and over time will help policy makers to identify major changes in their typology that may reflect goal progress or regression.
Consumer attitudes and the governance of food safety
Authors: Todt Oliver , Muñoz Emilio , González Marta , Ponce Gloria , Estévez Betty
Published: November 2008

This paper reports the analysis of a recent study of public perception of food safety governance in Spain, using genetically modified (GM) foods as an indicator. The data make clear that Spanish food consumers are aware of their rights and role in the marketplace. They are critical of current regulatory decision making, which they perceive to be unduly influenced by certain social actors, such as industry. In contrast, consumers demand decisions to be based primarily on scientific opinion, as well as consumer preferences. They want authorities to facilitate informed purchasing decisions, and favor labeling of GM foods mostly on the grounds of their right to know. However, consumers' actual level of knowledge with respect to food technology and food safety remains low. There are several ambivalences as to the real impact of these attitudes on actual consumer behavior (specifically when it comes to organizing themselves or searching out background information).
Enhancing Motivation to Complete Math Tasks Using the High-Preference Strategy
Authors: Banda Devender R. , Matuszny Rose Marie , Therrien William J.
Published: November 2008

Designed to enhance the completion of math tasks, high-preference strategy consists of presenting math tasks that students prefer, to enhance their interest in completing difficult math tasks. In this article, a brief review of the literature related to the use of the high-preference strategy is provided along with directions on how to implement the strategy with students with learning and behavior disabilities.
Partial-Year Insurance Coverage and the Health Care Utilization of Children
Authors: Leininger Lindsey Jeanne
Published: November 2008

A large literature examines the effects of health insurance on the health care utilization of children; however, most existing studies conceptualize coverage as a point-in-time measure rather than as a dynamic phenomenon. The major contribution of this article is its provision of estimates on the relationship between the duration of coverage over the course of a calendar year and health care utilization among children. Using child-level fixed-effects regression, we find that an incremental uninsured month is associated with a 0.7 percentage point decline in the probability of receiving a visit over the course of a year and a 3% decrease in the number of visits received. Children with intrayear coverage losses are more likely than those with continuous coverage to lose their usual source of care, which serves as a potential mechanism through which short gaps in coverage may lead to longer-term decrements in utilization.
Family Caregiver Provided Massage for Rural-Dwelling Chronically Ill Persons
Authors: Kempson Diane , Conley Virginia
Published: November 2008

Family caregivers attending to chronically ill family members within the community are vulnerable to psychological and medical health issues. Rural caregivers may be at increased risk because of fewer resources. This pilot study explored whether rural caregivers would learn and provide gentle massage to their chronically ill loved ones, would find study participation burdensome, and would realize benefits from providing the massage. Positive results in each of the three areas suggest that providing caregivers with instruction on gentle massage techniques for their chronically ill loved ones may support and enhance rural caregivers' perceptions of self-efficacy and self-agency and thus possibly decrease caregiver vulnerability. The findings of this study are important in light of increasing numbers of chronically ill persons who rely predominantly on home care by family members within the community.
Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways
Authors: Sepulcre J , Masdeu JC , Goñi J , Arrondo G , Vélez de Mendizábal N , Bejarano B , Villoslada P
Published: November 2008

Background

Fatigue is one of the most frequent and disturbing symptoms in multiple sclerosis (MS), directly affecting the patient’s quality of life. However, many questions remain unclear regarding the anatomic brain correlate of MS-related fatigue.

Objective

To assess the relationship between fatigue and white matter lesion location and gray matter atrophy.

Methods

In this study, 60 patients with MS were evaluated with the Modified Fatigue Impact Scale and magnetic resonance imaging. Location of white matter lesion was analyzed using a voxel-by-voxel lesion probability mapping approach and gray matter atrophy degree and location using an optimized voxel-based morphometry method.

Results

We found a correlation between lesion load and fatigue score (T2 lesion load: r = 0.415, P = 0.001; T1 lesion load r = 0.328, P = 0.011). Moreover, fatigue correlated with lesions in the right parietotemporal (periatrial area, juxtaventricular white matter deep in the parietal lobe and callosal forceps) and left frontal (middle-anterior corpus callosum, anterior cingulum and centrum semiovale of the superior and middle frontal gyri) white matter regions ( P < 0.001 in all cases). Finally, fatigue score significantly correlated with gray matter atrophy in frontal regions, specifically, the left superior frontal gyrus and bilateral middle frontal gyri ( P < 0.001 in all cases).

Conclusion

Our results suggest that the symptom of fatigue is associated with a disruption of brain networks involved in cognitive/attentional processes.
Shifting positions
Authors: Harrison Julia
Published: November 2008

This article discusses the research methodologies used to gain an understanding of what the touristic/cottage experience meant to a group of Canadians who traveled internationally on a regular basis; and a sampling Ontario second home tourists, or cottagers. Spatial, temporal and cultural constraints prevented me from engaging in traditional models of participant observation with them. The article details how I selected my subjects; how I positioned myself in relation to them to find out what I needed to know; and how I gained insight into th affective dimensions of these experiences. I argue here that mobile populations suc as tourists prompt a continual shifting of the ethnographic `I', challenging any taken-for-granted notions of how ethnography is best done. I end with reflections o the tensions between single/multi-sited ethnographic positionings and my research with these two groups of tourists.
Views from here
Authors: Stampe Jennifer
Published: November 2008

In this article, I consider the ethnographic study of tourists and tourism by juxtaposing the perspectives and positions of differently situated members of the tourist-receiving population at Lake Mille Lacs, in the upper midwestern USA. There, I positioned myself as worker at two sites — the Mille Lacs Indian Museum and Trading Post State Historic Site and the Mille Lacs Area Tourism Council's information office. From these two locations, I conducted ethnography by engaging in a range of pursuits including participant-observation, conducting surveys and interviewing both tourists and tourist workers. In discussing this experience, I critique discourses that ascribe `mobility' and `rootedness' in ways that obscure the complex realities of daily life in tourist settings. I argue that these conceptions of the positions available in tourist settings can be usefully unsettled through the practice of ethnography.
Pretibial Injury: Key Factors and Their Use in Developing Laboratory Test Methods
Authors: Laing R.M. , Carr D.J. , Wilson C.A. , Tan S.T. , Niven B.E. , Davis C. , Bialostocki A.
Published: November 2008

Aims were to 1 characterize pretibial injuries and evaluate protection offered by garments/fabrics; and 2 develop a laboratory test to determine the potential protection provided by such fabrics. Most (>85%) of 75 patients treated for pretibial injury at Hutt Hospital, New Zealand sustained injury to one site and required surgery. Injuries were typically grade 3 or 4, 10-250 mm wide 30-350 mm long, and at the mid- to lower third of the tibia. The severity grade was lower when at least one fabric layer covered the site, slightly lower again with more than one layer, and when a knitted fabric/garment was worn, and a trouser type garment. Laboratory test methods and their application reflected these known variables. The force transmitted through multiple fabric layers was less then through one layer: thick pantyhouse and either denim or fabrics used in 'sweat pants' would minimize transmitted force and maximize impulse.
Toward a Critical Historiography of the Episcopal Church
Authors: Harp Gillis
Published: November 2008

Historians of the Episcopal Church of the USA face the challenge of dealing with a tradition of in house ‘self-serving’ biographies and also of a Whiggish meta-narrative which privileged the Anglo Catholic reading of the history of ECUSA. This is similar to the challenge laid out by Diarmaid MacCulloch in relation to the English Reformation. This meta-narrative often read evangelicals out of the story. My book sought in part to correct this approach through a fresh analysis of Phillips Brooks' ministry and teaching. Within a broad tradition such as Anglicanism, argument about the past is part of the contemporary debate about identity in the tradition and of priorities in the present. That is very reasonable and a more candid engagement of the differences would serve everyone better than different perspectives passing each other like ships in the night.
Corporate Governance and Environmental Performance: Industry and Country Effects
Authors: Salo James
Published: November 2008

Portfolio investment managers and institutional investor clients are becoming more sensitive to the investment risks and opportunities that corporate governance and corporate environmental performance pose because of the growth in understanding of their potential financial repercussions. However, while both corporate governance and corporate environmental performance are increasingly examined within the financial marketplace, there is very limited empirical research that examines them together. In this paper, an empirical analysis utilizing proprietary quantitative data from two non-financial rating agencies is conducted in order to develop an understanding of the relationship between these two types of corporate performance, their causes, and their consequences. The findings of this paper do not suggest that there is a direct correlation between corporate governance and environmental performance. However, it is established that each has been improving over time, and that a convergence in standards is occurring between poor and strong performing firms. Perhaps the most salient finding of this research is that both the corporate governance and corporate environmental performance share a common predictor - disclosure. The discovery of a significant relationship between disclosure and performance is very important as it suggests that when a firm discloses non-financial performance information, actors within the firm become increasingly concerned with managing those revealed areas. Therefore, global standards of corporate governance and environmental performance are likely to be improved by of the recent explosion in demand for disclosure by institutional investors in these areas.
Effect of Si target sputtering power on diffusion barrier properties of Ta–Si–N thin films
Authors: Zhou J. C. , Liu Z. , Li Y. Z. , Luo D. T.
Published: November 2008

Ta–Si–N thin films and Cu/Ta–Si–N thin films were deposited on p type Si(111) substrates by magnetron reactive sputtering. Then the films were characterised by four point probe sheet resistance measurement, AFM, SEM and XRD respectively. According to the XRD results, the authors found that the crystallisation of Ta nitrides in Ta–Si–N/Si thin films is suppressed effectively when fabricated by a high Si target sputtering power. As the Si target power varies, the failure temperature of Cu/Ta–Si–N/Si is changed. The sample fabricated by the Si target power of 200 W fails after 800°C rapid thermal annealing and it has the highest failure temperature. The investigation of failure mechanism shows that Cu atoms diffuse through grain boundaries or amorphous structure of the Ta–Si–N barrier, and react with Si to form Cu–Si phase. And it causes the failure of the barrier.
Hemoglobin research and the origins of molecular medicine
Authors: Schechter Alan N.
Published: November 2008

Much of our understanding of human physiology, and of many aspects of pathology, has its antecedents in laboratory and clinical studies of hemoglobin. Over the last century, knowledge of the genetics, functions, and diseases of the hemoglobin proteins has been refined to the molecular level by analyses of their crystallographic structures and by cloning and sequencing of their genes and surrounding DNA. In the last few decades, research has opened up new paradigms for hemoglobin related to processes such as its role in the transport of nitric oxide and the complex developmental control of the α-like and β-like globin gene clusters. It is noteworthy that this recent work has had implications for understanding and treating the prevalent diseases of hemoglobin, especially the use of hydroxyurea to elevate fetal hemoglobin in sickle cell disease. It is likely that current research will also have significant clinical implications, as well as lessons for other aspects of molecular medicine, the origin of which can be largely traced to this research tradition.
Distinctive localization of antigen-presenting cells in human lymph nodes
Authors: Angel Catherine E. , Chen Chun-Jen J. , Horlacher Oliver C. , Winkler Sintia , John Thomas , Browning Judy , MacGregor Duncan , Cebon Jonathan , Dunbar P. Rod
Published: November 2008

Professional antigen-presenting cells (APCs) are sentinel cells of the immune system that present antigen to T lymphocytes and mediate an appropriate immune response. It is therefore surprising that knowledge of the professional APCs in human lymph nodes is limited. Using 3-color immunohistochemistry, we have identified APCs in human lymph nodes, excluding plasmacytoid APCs, that fall into 2 nonoverlapping classes: (1) CD209+ APCs, coexpressing combinations of CD206, CD14, and CD68, that occupied the medullary cords, lined the capsule and trabeculae and were also scattered throughout the diffuse T-lymphocyte areas of the paracortex; and (2) APCs expressing combinations of CD1a, CD207, and CD208, that were always restricted to the paracortex. Surprisingly, this second class of APCs was almost entirely absent from many lymph nodes. Our data suggest that most CD208+ cells, often referred to as “interdigitating cells,” derive from migratory APCs, and that the major APC subset consistently resident in the paracortex of human lymph nodes is the CD209+ subset. All APC subsets were demonstrated to be in close contact with the fibroreticular network. The identification of 2 distinct APC populations in the paracortex of human lymph nodes has important implications for understanding T-lymphocyte responses and optimizing vaccine design.
The transcription factor c-Myc enhances KIR gene transcription through direct binding to an upstream distal promoter element
Authors: Cichocki Frank , Hanson Rebecca J. , Lenvik Todd , Pitt Michelle , McCullar Valarie , Li Hongchuan , Anderson Stephen K. , Miller Jeffrey S.
Published: November 2008

The killer cell immunoglobulin-like receptor (KIR) repertoire of natural killer (NK) cells determines their ability to detect infected or transformed target cells. Although epigenetic mechanisms play a role in KIR gene expression, work in the mouse suggests that other regulatory elements may be involved at specific stages of NK-cell development. Here we report the effects of the transcription factor c-Myc on KIR expression. c-Myc directly binds to, and promotes transcription from, a distal element identified upstream of most KIR genes. Binding of endogenous c-Myc to the distal promoter element is significantly enhanced upon interleukin-15 (IL-15) stimulation in peripheral blood NK cells and correlates with an increase in KIR transcription. In addition, the overexpression of c-Myc during NK-cell development promotes transcription from the distal promoter element and contributes to the overall transcription of multiple KIR genes. Our data demonstrate the significance of the 5′ promoter element upstream of the conventional KIR promoter region and support a model whereby IL-15 stimulates c-Myc binding at the distal KIR promoter during NK-cell development to promote KIR transcription. This finding provides a direct link between NK-cell activation signals and KIR expression required for acquisition of effector function during NK-cell education.
Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia
Authors: Phelps Mitch A. , Lin Thomas S. , Johnson Amy J. , Hurh Eunju , Rozewski Darlene M. , Farley Katherine L. , Wu Di , Blum Kristie A. , Fischer Beth , Mitchell Sarah M. , Moran Mollie E. , Brooker-McEldowney Michelle , Heerema Nyla A. , Jarjoura David , Schaaf Larry J. , Byrd John C. , Grever Michael R. , Dalton James T.
Published: November 2008

We previously reported interim results of a phase 1 trial in patients with chronic lymphocytic leukemia (CLL) whereby flavopiridol was administered intravenously as a 30-minute bolus followed by 4-hour infusion. We now report full pharmacokinetic (PK) data, correlations of PK with clinical outcomes, and final response and progression-free survival (PFS). Twenty-one (40%) of 52 patients with relapsed CLL achieved a partial response (PR) with a median PFS of 12 months. Responders included 17 (40%) of 43 fludarabine refractory patients, 7 (39%) of 18 patients with del(17p13), and 14 (74%) of 19 patients with del(11q22). Six responders received repeat therapy at relapse, and 5 responded again with a second median PFS of 10 months. Noncompartmental analysis and nonlinear mixed effects modeling was used to estimate PK parameters and evaluate covariates. Two-compartment population parameter estimates were 31.4 L/h, 65.8 L, 8.49 L/h, and 157 L for CL, V1, Q, and V2, respectively. Flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome, and glucuronide metabolite AUC correlated with tumor lysis syndrome. These composite results confirm high activity of this pharmacokinetically derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK describes some, but not all, variability in response and toxicity.
Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison
Authors: Cornelissen Jan J. , van der Holt Bronno , Verhoef Gregor E. G. , van 't Veer Mars B. , van Oers Marinus H. J. , Schouten Harry C. , Ossenkoppele Gert , Sonneveld Pieter , Maertens Johan , van Marwijk Kooy Marinus , Schaafsma Martijn R. , Wijermans Pierre W. , Biesma Douwe H. , Wittebol Shulamit , Voogt Paul J. , Baars Joke W. , Zachée Pierre , Verdonck Leo F. , Löwenberg Bob , Dekker Adriaan W.
Published: November 2008

While commonly accepted in poor-risk acute lymphoblastic leukemia (ALL), the role of allogeneic hematopoietic stem cell transplantation (allo-SCT) is still disputed in adult patients with standard-risk ALL. We evaluated outcome of patients with ALL in first complete remission (CR1), according to a sibling donor versus no-donor comparison. Eligible patients (433) were entered in 2 consecutive, prospective studies, of whom 288 (67%) were younger than 55 years, in CR1, and eligible to receive consolidation by either an autologous SCT or an allo-SCT. Allo-SCT was performed in 91 of 96 patients with a compatible sibling donor. Cumulative incidences of relapse at 5 years were, respectively, 24 and 55% for patients with a donor versus those without a donor (hazard ratio [HR], 0.37; 0.23-0.60; P < .001). Nonrelapse mortality estimated 16% (± 4) at 5 years after allo-SCT. As a result, disease-free survival (DFS) at 5 years was significantly better in the donor group: 60 versus 42% in the no-donor group (HR: 0.60; 0.41-0.89; P = .01). After risk-group analysis, improved outcome was more pronounced in standard-risk patients with a donor, who experienced an overall survival of 69% at 5 years (P = .05). In conclusion, standard-risk ALL patients with a sibling donor may show favorable survival following SCT, due to both a strong reduction of relapse and a modest nonrelapse mortality. This trial is registered with http://www.trialregister.nl under trial ID NTR228.
Bone marrow angiogenesis magnetic resonance imaging in patients with acute myeloid leukemia: peak enhancement ratio is an independent predictor for overall survival
Authors: Shih Tiffany Ting-Fang , Hou Hsin-An , Liu Chieh-Yu , Chen Bang-Bin , Tang Jih-Luh , Chen Hsuan-Yu , Wei Shwu-Yuan , Yao Ming , Huang Shang-Yi , Chou Wen-Chien , Hsu Szu-Chun , Tsay Woei , Yu Chih-Wei , Hsu Chao-Yu , Tien Hwei-Fang , Yang Pan-Chyr
Published: November 2008

Emerging evidence suggests that progression of hematologic malignancies is associated with angiogenesis. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide global and functional imaging of tumor angiogenesis. In this study, we performed bone marrow DCE-MRI prospectively at diagnosis and after induction chemotherapy in 78 de novo acute myeloid leukemia (AML) patients and correlated it with treatment outcome. An algorithm to assess bone marrow angiogenesis by measuring the DCE-MRI time-intensity curve pixel by pixel was developed using 3 distinct parameters: peak enhancement ratio (Peak) to indicate tissue blood perfusion; amplitude (Amp) to reflect vascularity; and volume transfer constant (K trans) to indicate vascular permeability. The Peak and Amp decreased significantly at remission status after induction chemotherapy. Patients with higher Peak or Amp at diagnosis had shorter overall survival and disease-free survival than others. Cox multivariate analysis identified higher Peak value (hazard ratio, 9.181; 95% confidence interval, 1.740-48.437; P = .009) as an independent predictor for overall survival in addition to unfavorable karyotype and old age. Our findings provide evidence that increased bone marrow angiogenesis measured by DCE-MRI can predict adverse clinical outcome in AML patients. DCE-MRI may help to select high-risk phenotype AML patients for tailored antiangiogenic therapy and to monitor treatment response.
Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study
Authors: Adès Lionel , Boehrer Simone , Prebet Thomas , Beyne-Rauzy Odile , Legros Laurence , Ravoet Christophe , Dreyfus François , Stamatoullas Aspasia , Pierre Chaury Marie , Delaunay Jacques , Laurent Guy , Vey Norbert , Burcheri Sara , Mbida Rose-Marie , Hoarau Natacha , Gardin Claude , Fenaux Pierre
Published: November 2008

Higher-risk MDS with del5q carry a poor prognosis. In this phase 2 trial, 47 patients with higher-risk MDS received lenalidomide 10 mg/day. International Prognostic Scoring System was high in 60%, intermediate-2 risk in 40%. del 5q was isolated, with one additional and more than one additional abnormality in 19%, 23%, and 58% patients, respectively. Thirteen (27%) patients achieved hematologic response, including 7 hematologic complete remission (CR) (with complete [4] or partial [3] cytogenetic response), 2 marrow CR and 4 hematologic improvement erythroid, and 12 became red blood cell (RBC) transfusion independent, for a median duration of 6.5 months. Median CR duration was 11.5 months. Six of 9 (67%) patients with isolated del 5q achieved CR, versus 1 of 11 and none of 27 patients with one or more than one additional abnormality, respectively (P < .001). Seven of 20 (35%) with initial platelets more than 100 000/mm3 obtained CR, compared with none of the 27 with lower platelet counts less than 100 000/mm3 (P = .001). Our data support a potential role of lenalidomide in higher-risk MDS with isolated del 5q. This trial was registered at www.clinicaltrials.gov as NCT00424229.
Nuclear staining and relative distance for quantifying epidermal differentiation in biomarker expression profiling
Authors: Pommerencke Thora , Steinberg Thorsten , Dickhaus Hartmut , Tomakidi Pascal , Grabe Niels
Published: November 2008

Background

The epidermal physiology results from a complex regulated homeostasis of keratinocyte proliferation, differentiation and death and is tightly regulated by a specific protein expression during cellular maturation. Cellular in silico models are considered a promising and inevitable tool for the understanding of this complex system. Hence, we need to incorporate the information of the differentiation dependent protein expression in cell based systems biological models of tissue homeostasis. Such methods require measuring tissue differentiation quantitatively while correlating it with biomarker expression intensities.

Results

Differentiation of a keratinocyte is characterized by its continuously changing morphology concomitant with its movement from the basal layer to the surface, leading to a decreased average nuclei density throughout the tissue. Based thereon, we designed and evaluated three different mathematical measures (nuclei based, distance based, and joint approach) for quantifying differentiation in epidermal keratinocytes. We integrated them with an immunofluorescent staining and image analysis method for tissue sections, automatically quantifying epidermal differentiation and measuring the corresponding expression of biomarkers. When studying five well-known differentiation related biomarkers in an epidermal neck sample only the resulting biomarker profiles incorporating the relative distance information of cells to the tissue borders (distance based and joint approach) provided a high-resolution view on the whole process of keratinocyte differentiation. By contrast, the inverse nuclei density approach led to an increased resolution at early but heavily decreased resolution at late differentiation. This effect results from the heavy non-linear decay of DAPI intensity per area, probably caused by cytoplasmic growth and chromatin decondensation. In the joint approach this effect could be compensated again by incorporating distance information.

Conclusion

We suppose that key mechanisms regulating tissue homeostasis probably depend more on distance information rather than on nuclei reorganization. Concluding, the distance approach appears well suited for comprehensively observing keratinocyte differentiation.
The prediction of protein-protein interaction networks in rice blast fungus
Authors: He Fei , Zhang Yan , Chen Hao , Zhang Ziding , Peng You-Liang
Published: November 2008

Background

Protein-protein interaction (PPI) maps are useful tools for investigating the cellular functions of genes. Thus far, large-scale PPI mapping projects have not been implemented for the rice blast fungus Magnaporthe grisea, which is responsible for the most severe rice disease. Inspired by recent advances in PPI prediction, we constructed a PPI map of this important fungus.

Results

Using a well-recognized interolog approach, we have predicted 11,674 interactions among 3,017 M. grisea proteins. Although the scale of the constructed map covers approximately only one-fourth of the M. grisea's proteome, it is the first PPI map for this crucial organism and will therefore provide new insights into the functional genomics of the rice blast fungus. Focusing on the network topology of proteins encoded by known pathogenicity genes, we have found that pathogenicity proteins tend to interact with higher numbers of proteins. The pathogenicity proteins and their interacting partners in the entire network were then used to construct a subnet called a pathogenicity network. These data may provide further clues for the study of these pathogenicity proteins. Finally, it has been established that secreted proteins in M. grisea interact with fewer proteins. These secreted proteins and their interacting partners were also compiled into a network of secreted proteins, which may be helpful in constructing an interactome between the rice blast fungus and rice.

Conclusion

We predicted the PPIs of M. grisea and compiled them into a database server called MPID. It is hoped that MPID will provide new hints as to the functional genomics of this fungus. MPID is available at http://bioinformatics.cau.edu.cn/zzd_lab/MPID.html.
Comparative genomics of wild type yeast strains unveils important genome diversity
Authors: Carreto Laura , Eiriz Maria F , Gomes Ana C , Pereira Patrícia M , Schuller Dorit , Santos Manuel AS
Published: November 2008

Background

Genome variability generates phenotypic heterogeneity and is of relevance for adaptation to environmental change, but the extent of such variability in natural populations is still poorly understood. For example, selectedSaccharomyces cerevisiaestrains are variable at the ploidy level, have gene amplifications, changes in chromosome copy number, and gross chromosomal rearrangements. This suggests that genome plasticity provides important genetic diversity upon which natural selection mechanisms can operate.

Results

In this study, we have used wild-typeS. cerevisiae(yeast) strains to investigate genome variation in natural and artificial environments. We have used comparative genome hybridization on array (aCGH) to characterize the genome variability of 16 yeast strains, of laboratory and commercial origin, isolated from vineyards and wine cellars, and from opportunistic human infections. Interestingly, sub-telomeric instability was associated with the clinical phenotype, while Ty element insertion regions determined genomic differences of natural wine fermentation strains. Copy number depletion ofASP3andYRF1genes was found in all wild-type strains. Other gene families involved in transmembrane transport, sugar and alcohol metabolism or drug resistance had copy number changes, which also distinguished wine from clinical isolates.

Conclusion

We have isolated and genotyped more than 1000 yeast strains from natural environments and carried out an aCGH analysis of 16 strains representative of distinct genotype clusters. Important genomic variability was identified between these strains, in particular in sub-telomeric regions and in Ty-element insertion sites, suggesting that this type of genome variability is the main source of genetic diversity in natural populations of yeast. The data highlights the usefulness of yeast as a model system to unravel intraspecific natural genome diversity and to elucidate how natural selection shapes the yeast genome.
Expression of recombinant Clostridium difficile toxin A and B in Bacillus megaterium
Authors: Yang Guilin , Zhou Boping , Wang Jufang , He Xiangyun , Sun Xingmin , Nie Weijia , Tzipori Saul , Feng Hanping
Published: November 2008

Background

MajorClostridium difficilevirulence factors are the exotoxins TcdA and TcdB. Due to the large size and poor stability of the proteins, the active recombinant TcdA and TcdB have been difficult to produce.

Results

The toxin genestcdAandtcdBwere amplified by PCR using chromosomal DNA from a toxigenic strain as a template, and cloned into a shuttle vector pHis1522. The sequences of bothtcdAandtcdBgenes in the vector have been verified by DNA sequencing. The constructs were transformed intoB. megateriumprotoplasts and the protein expression was controlled under a xylose promoter. The recombinant toxins (rTcdA and rTcdB) were purified from bacterial crude extracts. Approximately 5 – 10 mg of highly purified recombinant toxins were obtained from one liter of bacterial culture. The resulting rTcdA and rTcdB had similar molecular masses to the native toxins, and their biological activities were found to be similar to their native counterparts after an extensive examination.

Conclusion

We have generated the full length and active recombinant TcdA and TcdB inBacillus megaterium.
Reduced diversity and increased virulence-gene carriage in intestinal enterobacteria of coeliac children
Authors: Sánchez Ester , Nadal Inmaculada , Donat Ester , Ribes-Koninckx Carmen , Calabuig Miguel , Sanz Yolanda
Published: November 2008

Background

Coeliac disease is an immune-mediated enteropathology triggered by the ingestion of cereal gluten proteins. This disorder is associated with imbalances in the composition of the gut microbiota that could be involved in its pathogenesis. The aim of the present study was to determine whether intestinal Enterobacteriaceae populations of active and non-active coeliac patients and healthy children differ in diversity and virulence-gene carriage, so as to establish a possible link between the pathogenic potential of enterobacteria and the disease.

Methods

Enterobacteriaceae clones were isolated on VRBD agar from faecal samples of 31 subjects (10 active coeliac patients, 10 symptom-free coeliac patients and 11 healthy controls) and identified at species level by the API 20E system. Escherichia coli clones were classified into four phylogenetic groups A, B1, B2 and D and the prevalence of eight virulence-associated genes (type-1 fimbriae [fimA], P fimbriae [papC], S fimbriae [sfaD/E], Dr haemagglutinin [draA], haemolysin [hlyA], capsule K1 [neuB], capsule K5 [KfiC] and aerobactin [iutA]) was determined by multiplex PCR.

Results

A total of 155 Enterobacteriaceae clones were isolated. Non-E. coli clones were more commonly isolated in healthy children than in coeliac patients. The four phylogenetic E. coli groups were equally distributed in healthy children, while in both coeliac patients most commensal isolates belonged to group A. Within the virulent groups, B2 was the most prevalent in active coeliac disease children, while D was the most prevalent in non-active coeliac patients. E coli clones of the virulent phylogenetic groups (B2+D) from active and non-active coeliac patients carried a higher number of virulence genes than those from healthy individuals. Prevalence of P fimbriae (papC), capsule K5 (sfaD/E) and haemolysin (hlyA) genes was higher in E. coli isolated from active and non-active coeliac children than in those from control subjects.

Conclusion

This study has demonstrated that virulence features of the enteric microbiota are linked to coeliac disease.