bluuebunny/crossref_metadata_2025 huggingface dataset:
Fuzzy Rule Based Modeling of Drilling Parameters for Delamination in Drilling GFRP Composites
Authors: Latha B. , Senthilkumar V.S.
Published: May 2008

Fiber reinforced composite materials are used in different industries because of their mechanical and other properties. Drilling is one of the most important operations and is mainly used for joining in the manufacturing sector. Often it is a final operation during assembly. Defects in drilling lead to rejection and impose heavy losses. In drilling of glass fiber reinforced plastic (GFRP) composites, delamination is an important factor and is to be controlled. In this study, drilling tests were carried out on GFRP composite specimens using solid carbide drill bits. A L27 orthogonal array was used for tests. A fuzzy rule based model is developed to predict the delamination in drilling of GFRP composites. Good agreement is observed between the predictive model results and experimental values. The Fuzzy rule based model can be used effectively for predicting the delamination in drilling GFRP composites.
Compression, Impact and Fractographic Studies on Granite Powder-Filled HTPU-Toughened Epoxy Composite
Authors: Shetty Ravindra Rama  , Rai S.K.
Published: May 2008

Hydroxyl-terminated polyurethane (HTPU) in different proportions has been incorporated into DGEBA-based epoxy resin, and cured with triethylene tetramine. Composites are developed using varying weight fractions of silane coupling agent-treated granite powder as reinforcement in pure and toughened epoxy resin. Various mechanical properties, such as compression and impact behavior, have been determined. Also, fractographic studies of the composites have been carried out. Studies revealed that toughened resin composites enhance the properties, compared to neat matrix.
The Influence of Preparing Method on Novel X-Truss/Foam Sandwich Structure
Authors: Hao Jijun  , Zhang Zuoguang  , Li Min  , Sun Zhijie  , Gu Yizuo
Published: May 2008

Novel X-truss/foam sandwich structures were prepared by Z-pin inserted and bias stitching method, respectively, in order to improve the transverse mechanical behavior. With such reinforcements, the collapse resistance capability of the core and the bonding strength between the core and the skins are obviously increased. Thus the principal disadvantages of conventional sandwich structures are solved. The Z-pins and stitches embedding in rigid polyurethane foam configured a truss, which was made of carbon fiber/epoxy resin. The architectures of specimens made from Z-pin inserted and bias stitching methods are very similar but not identical, which make their mechanical performances different from each other. In order to evaluate these two methods, out-of-plane mechanical tests, such as compression, shear, and tension were practiced and failure modes were compared. In some conditions, the specimens made from the Z-pin inserted process have a higher compression modulus, but a lower tension and shear strength compared to that made from the bias stitching process. Moreover, there are big differences in their failure modes.
Histopathologic Progression and a Novel Mutation in a Child With Nemaline Myopathy
Authors: Ladha Shafeeq , Coons Stephen , Johnsen Stanley , Sambuughin Nyamkhishig , Bien-Wilner Ricardo , Sivakumar Kumaraswamy
Published: May 2008

Nemaline myopathy is a clinically heterogeneous congenital myopathy caused by mutations in at least 6 genes related to thin filaments. Histologically, they show a characteristic if not homogeneous picture of nemaline rods, essential for the diagnosis. However, little is known regarding the development and progression of muscle histopathologic changes in nemaline myopathy. Results of muscle biopsies at 7 weeks of age and at 15 months of age from a child with nemaline myopathy due to a novel mutation in the ACTA1 gene are presented. The findings of the biopsies, separated by 13 months, demonstrate progression from vague cytoplasmic bodies in the first biopsy to typical nemaline rods in the second biopsy.
Severe Ataxia as a Complication of Human Parvovirus B19 Acute Encephalitis in a Child
Authors: Greco Filippo , Luisa Barbagallo Maria , Castellano Chiodo Danilo , Guglielmino Rosanna , Sorge Giovanni
Published: May 2008

Human parvovirus B19 generally causes erythema infectiosum in childhood, but it can be associated with unusual findings, particularly in immunocompromised patients. This is a report about an immunocompetent 4-year-old female child affected with acute encephalitis by parvovirus B19, documented by polymerase chain reaction performed on cerebrospinal fluid, who was treated with intravenous immunoglobulins and dexamethasone and who developed a cerebellar syndrome with ataxia, dysmetria, and dysarthria. To the best of the authors' knowledge, this may be the first report of human parvovirus B19 encephalitis complicated by severe ataxia in childhood.
Angelman Syndrome Due to a Novel Splicing Mutation of the UBE3A Gene
Authors: Sartori Stefano , Anesi Laura , Polli Roberta , Toldo Irene , Casarin Alberto , Drigo Paola , Murgia Alessandra
Published: May 2008

Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, absence of speech, seizures, abnormal electroencephalography (EEG), and happy disposition. The syndrome results from lack of function of the maternal copy of the UBE3A gene on the imprinted Prader-Willi/Angelman syndrome critical region; it is caused by large deletions, paternal uniparental disomy, imprinting center defects or UBE3A deletions, and point mutations. We found a novel splice-site mutation of the UBE3A gene in a child with clinical and EEG features of Angelman syndrome. This case further points out the fact that individuals with Angelman syndrome and mutations of the UBE3A gene have a phenotype that tends to be rather mild, however, undistinguishable, both from the clinical and the electrophysiological points of view, from the Angelman syndrome phenotype due to other known molecular mechanisms.
Attitudes Toward Attention-Deficit Hyperactivity Disorder (ADHD) Treatment: Parents' and Children's Perspectives
Authors: Berger Itai , Dor Talia , Nevo Yoram , Goldzweig Gil
Published: May 2008

Attitudes toward pharmacological treatment may be a major factor contributing to adherence to such treatment. In the current study, attitudes toward methylphenidate treatment among 50 children diagnosed with attention-deficit hyperactivity disorder (ADHD) and their parents were assessed. Authors of this study have found that the study population is concerned and suspicious toward methylphenidate treatment. Most participants were exposed to negative information even before treatment initiation, which caused many participants to consult other sources and postpone the treatment initiation. Although experiencing methylphenidate as safe and effective (after 23.5 months of treatment), the leading cause of negative attitudes is the concern regarding long-term effects. The single most effective factor regarding the attitude toward methylphenidate treatment is the neurologist's explanation. It is concluded that the pediatric neurologist has a crucial role in affecting attitudes of children and parents toward methylphenidate treatment.
Adapting the Self-Determined Learning Model for Instruction of College Students With Disabilities
Authors: Finn Donald , Evans Getzel Elizabeth , McManus Shannon
Published: May 2008

As the number of students with disabilities who are entering postsecondary education continues to rise, the need for their adequate preparation to successfully complete programs of study is a critical concern. A common characteristic of students who successfully enter and complete programs of study in postsecondary settings is that of having self-determination skills. This article discusses the results of a pilot study that implemented the self-determined learning model of instruction, modified for use in postsecondary education settings. Evaluation results are discussed with implications for further research.
Substance Use and PTSD Symptoms Impact the Likelihood of Rape and Revictimization in College Women
Authors: Messman-Moore Terri L. , Ward Rose Marie , Brown Amy L.
Published: May 2008

The present study utilized a mixed retrospective and prospective design with an 8-month follow-up period to test a model of revictimization that included multiple childhood (i.e., child sexual, physical, and emotional abuse) and situational variables (i.e., substance use, sexual behavior) for predicting rape among 276 college women. It was of particular interest to determine whether traumatic responses (e.g., posttraumatic symptomatology or risky behavior) increased vulnerability for revictimization. During the 8-month follow-up period, 9% of participants were raped; 88% of assaults involved substance use by the victim. Posttraumatic stress disorder (PTSD) symptomatology predicted rape, substance use, and sexual behavior. Substance use, but not sexual behavior, mediated the relation between PTSD symptomatology and rape during the follow-up period. Sexual behavior indirectly impacted risk for rape via substance use. Results suggest that college women with PTSD symptomatology may be at greater risk for rape if they use substances to reduce distress.
Collective Guilt, Collective Responsibility and the Serbs
Authors: Clark Janine Natalya
Published: May 2008

Can an entire nation be collectively guilty for crimes committed in its name? Focusing on the case of Serbia, this article argues that collective guilt is a morally flawed and untenable concept that should be rejected. It presents various moral and practical objections to both the generic notion of collective guilt and the more specific idea of Serbian collective guilt and contends that the latter is a fundamental impediment to peace-building and reconciliation in the former Yugoslavia. On what basis might it be argued that the Serbs are collectively guilty? To claim that they are collectively guilty for having supported Milošević both exaggerates levels of support for the former Serbian leader and does a major injustice to those individuals who bravely fought against the Milošević regime. Drawing on the work of Hannah Arendt and Karl Jaspers, the article concludes by suggesting that perhaps we can speak of Serbian collective responsibility.
How to Allocate Public Funding to Nongovernmental Development Organizations
Authors: Ruben Ruerd , Schulpen Lau
Published: May 2008

The Dutch co-financing system for nongovernmental development organizations (NGDOs) is unique in Europe. Almost a quarter of public development aid is channeled through a selective group of NGDOs that have to satisfy a broad range of institutional and operational criteria. The procedures for defining the eligibility of these co-financing organizations have recently been streamlined to enhance competition and to guarantee more objective fund allocation. This article provides a critical review of the current system for allocating public funding to private development organizations and discusses the criteria used for comparing institutional performance and assessing the quality of submitted multiyear co-funding requests. Even though important progress has been made in cross-organizational appraisal of development agencies, the operationalization of selected indicators still suffers from ambiguities and arbitrary weighing procedures. Past performance and demand-side criteria are not yet considered, thus reducing the potential relevance of the assessment system for improving the effectiveness of development projects.
Effects of Supervisor Performance Feedback on Increasing Preservice Teachers' Positive Communication Behaviors With Students With Emotional and Behavioral Disorders
Authors: Rathel Jeanna Marie , Drasgow Erik , Christle Christine C.
Published: May 2008

The purposes of this study were to examine the effects of supervisor performance feedback on preservice teachers' rates of positive and negative communication behaviors with students with emotional and behavioral disorders and the effects of the intervention on the preservice teachers' perceptions of classroom management and climate. The authors used a multiple baseline design across preservice teachers with a 1-min interval recording system to measure the frequencies of positive and negative verbal and nonverbal communication behaviors of preservice teachers. They also recorded preservice teachers' statements and gestures to provide specific performance feedback. Preservice teachers' perceptions on the effects of the intervention were monitored using their reflective journal entries. Specific performance feedback increased the ratio of positive-to-negative preservice teacher communication behaviors. In addition, preservice teacher satisfaction was improved. Results suggest that supervisors' use of specific performance feedback may assist preservice teachers to implement a higher ratio of positive-to-negative communications with their students.
Child Care and Employed Parents of Children With Emotional or Behavioral Disorders
Authors: Rosenzweig Julie M. , Brennan Eileen M. , Huffstutter Katherine , Bradley Jennifer R.
Published: May 2008

Lack of appropriate child care is frequently reported by parents of children with disabilities as a major obstacle to finding and maintaining their employment. Care for children with emotional or behavioral disorders is particularly difficult to locate because child care providers often lack adequate training. Findings are presented from interviews with 60 parents employed a minimum of 30 hr per week and caring for at least one school-age child with an emotional or behavioral disorder. Child care arrangements were varied and complex, with parents often making adjustments daily to design suitable care plans for all children in the family. Parental stress levels and work limitations because of child care were associated with levels of work—family fit, flexibility, child care difficulty, and child care satisfaction. We suggest that availability and access to child care options and supports specific to the needs of their children may be essential for employed parents of children with emotional or behavioral disorders to reduce stress and promote work—life integration.
Parental Locus of Control and Externalizing Behavior Problems Among Mexican American Preschoolers
Authors: McCabe Kristen M. , Goehring Kelly , Yeh May , Lau Anna S.
Published: May 2008

Research conducted with non-Hispanic Whites indicates that parents of preschoolers with behavioral problems are more likely to have an external locus of control regarding parenting than parents whose preschoolers are free of such problems. However, it is unclear whether such research can be generalized to Mexican American families, especially given research suggesting that Mexican Americans tend to have a more external locus of control normatively. To address this question, the authors compare parental locus of control (PLOC) among parents of clinic-referred Mexican American preschoolers to parents of nonreferred Mexican American preschoolers. Results demonstrate that referred Mexican American parents exhibited a more external PLOC than nonreferred Mexican American parents across a number of domains. Thus, similar to non-Hispanic Whites, preschoolers' behavioral problems are associated with an external PLOC among Mexican Americans. Implications for the design of culturally sensitive interventions for Mexican American preschoolers with behavior problems are discussed.
Erythropoietin and Erythropoietin Receptor in Colorectal Cancer
Authors: Chabowska Anna M. , Sulkowska Mariola , Chabowski Adrian , Wincewicz Andrzej , Koda Mariusz , Sulkowski Stanislaw
Published: May 2008

Erythropoietin via erythropoietin receptor effectively prevents anemia, giving reasons for a clinical use of erythropoietin in patients with colorectal cancers. However, erythropoietin seems to promote survival of the neoplastic cells in hypoxic environment. The aim of this study was to evaluate immunohistochemically the expression of erythropoietin and erythropoietin receptor in 136 primary colorectal cancers with a correlation to different anatomo-clinical features. Erythropoietin correlated with erythropoietin receptor in colorectal cancers (r = 0.547, P < .00001). Erythropoietin and erythropoietin receptor expressions were statistically higher in adenocarcinomas versus mucinous carcinomas ( P = .05 and P = .03, respectively) and in moderately (G2) versus poorly differentiated (G3) tumors ( P = .001 and P = .02, respectively). This in vivo study is the first study that provides evidences for the presence of erythropoietin and erythropoietin receptor in human colorectal cancer. The expressions of these proteins strictly depended on grading because the better histological differentiation probably comes from trophic influence of erythropoietin and erythropoietin receptor.
Emotional and Personality-Related Aspects of Career-Decision-Making Difficulties
Authors: Saka Noa , Gati Itamar , Kelly Kevin R.
Published: May 2008

This research focuses on developing a theoretical framework for analyzing the emotional and personality-related aspects of career-decision-making difficulties. The proposed model is comprised of three major clusters: pessimistic views, anxiety, and self-concept and identity. In Study 1, the Emotional and Personality Career Difficulties Scale (EPCD) was developed, refined, and used to empirically test the model with an Israeli Internet sample ( N = 728). Study 2 ( N = 276) provided evidence for the cross-cultural validity of the proposed model, using an American college student sample. The relations between the cognitive and emotional components of career-decision-making difficulties are discussed, and theoretical, research, and counseling implications are explored.
Testing for Between-Group Differences in Within-Group Interrater Agreement
Authors: Pasisz Derek J. , Hurtz Gregory M.
Published: May 2008

Users of rwg may find situations where they want to compare the levels of within-group agreement across two or more groups. F tests are presented that compare two values of rwg, rwg(J), or r*wg(J), and recommendations are made for comparing pairwise group values for three or more groups with a control for alpha inflation. More robust and flexible methods based on O'Brien's test are then recommended when sufficient raw data are available. The meaning of findings that agreement statistics are either the same or different across groups is discussed in light of simultaneous comparisons of mean differences. Examples are shown to demonstrate the robust methods using employee responses to questions regarding climate perceptions of organizational support for employee development activities. Other scenarios where the F test may prove useful are discussed, and directions for future research are provided.
The Political Geography of the New Deal Realignment
Authors: Darmofal David
Published: May 2008

Political geography has long played a prominent role in conceptions of political realignments. In this article, I apply a spatial analysis to examine the political geography of voting during one of the principal political realignments in American electoral history, the 1928—1936 Democratic realignment. The spatial analysis challenges some of our common conceptions of this realignment. For example, increased support for the Democrats and Al Smith in 1928 was not limited to urban areas, as Smith enjoyed widespread increases in Democratic support in largely rural Western locations. In the 1932 election, unemployment actually impeded shifts toward Franklin Roosevelt and the Democrats in most locales. Changes in voter support during this period were highly localized and subnational. Geographically Weighted Regressions demonstrate that this localized political geography was shaped by extensive geographic variation in how political and demographic factors influenced voting behavior across the United States.
The Impact of Television Market Size on Voter Turnout in American Elections
Authors: Althaus Scott L. , Trautman Todd C.
Published: May 2008

The turnout literature has identified individual, social, and institutional factors that increase citizen voting. Our article shows that local television market size also affects turnout. Larger television markets tend to give disproportionate attention to higher-level races involving statewide or national offices. Because voters in larger markets should be exposed to less information about the lower-ticket races in which they are eligible to vote, we expect market size to affect levels of turnout. This article tests market size impact using a novel combination of aggregate turnout data for local voting areas, census data giving contextual information about these areas, and data detailing the boundaries of local television media markets. Using the Record of American Democracy data set, our aggregate-level analysis covers four election cycles (1986 to 1990) and nearly every county in the continental United States. Our analysis shows that voter turnout is negatively associated with television market size, a relationship that is stronger in midterm election years.
Spinal Cord Repair: Bridging the Divide
Authors: Verma Poonam , Garcia-Alias Guillermo , Fawcett James W.
Published: May 2008

The normal spinal cord coordinates movement and sensation in the body. It is a complex organ containing nerve cells, supporting cells, and nerve fibers to and from the brain. The spinal cord is arranged in segments, with higher segments controlling movement and sensation in the upper parts of the body and lower segments controlling the lower parts of the body. Recent notable discoveries in the fields of neuroscience and cell biology have ensured that many more people survive injuries to the brain and spinal cord. The consequences of injury reflect this organization. Although these developments have been mirrored by significant strides in our understanding of the evolution and pathology of spinal injuries, complete repair of structure and hence function remain elusive. Most spinal cord injuries still cause lifelong disability, and continued research is critically needed. Here we review the molecular and cellular processes that occur during the evolution of an injury to the central nervous system. Throughout, we highlight several promising therapies aimed to restore the disrupted connections in the brain and spinal cord. These, used in combination with supportive care and rehabilitation strategies, may help patients to achieve significant long-term recovery.
Reversible disruption of BCL6 repression complexes by CD40 signaling in normal and malignant B cells
Authors: Polo Jose M. , Ci Weimin , Licht Jonathan D. , Melnick Ari
Published: May 2008

Germinal center (GC) B cells undergo somatic hypermutation, class switch recombination, and rapid clonal expansion to produce high-affinity antibodies. The BCL6 transcriptional repressor facilitates this phenotype because it can repress DNA damage checkpoint genes. GC B and T cells can make transient direct physical contact; T cells were observed to be associated with dead B-cell fragments. We thus hypothesized that one function of CD40 signaling from T cells within this timeframe could be to modulate BCL6 activity. CD40 signaling rapidly disrupts the ability of BCL6 to recruit the SMRT corepressor complex by excluding it from the nucleus, leading to histone acetylation, RNA polymerase II processivity, and activation of BCL6 target genes, such as CD23b, ATR, and TP53. Washout of CD40 to emulate transient T-cell contact permitted BCL6 target gene mRNA levels to return to their repressed levels, demonstrating that this is a reversible process, which could allow centroblasts that pass quality control to either continue proliferation or undergo terminal differentiation. These data suggest that transient CD40 signaling in the GC might allow T cells to weed out heavily damaged centroblasts while at the same time promoting survival of intact B cells, which could undergo differentiation or additional rounds of proliferation.
Syndromic thrombocytopenia and predisposition to acute myelogenous leukemia caused by constitutional microdeletions on chromosome 21q
Authors: Shinawi Marwan , Erez Ayelet , Shardy Deborah L. , Lee Brendan , Naeem Rizwan , Weissenberger George , Chinault A. Craig , Cheung Sau Wai , Plon Sharon E.
Published: May 2008

Several lines of evidence support the presence of dosage-sensitive genes on chromosome 21 that regulate leukemogenesis and hematopoiesis. We report a detailed clinical and molecular characterization of 3 patients with chronic thrombocytopenia caused by distinct constitutional microdeletions involving chromosomal region 21q22.12. The patients exhibited growth restriction, dysmorphic features, and developmental delays. One patient developed acute myelogenous leukemia (AML) at 6 years of age. All 3 deletions included the RUNX1, CLIC6, DSCR, and KCNE1 genes. Our data provide additional support for the role of RUNX1 haploinsufficiency in megakaryopoiesis and predisposition to AML. The leukemic clone had trisomy 21 resulting from duplication of chromosome 21 containing the RUNX1 deletion. This shows that genes other than RUNX1 must also play a role in AML associated with trisomy 21. We recommend that children with syndromic thrombocytopenia have clinical array-comparative genomic hybridization analysis and appropriate cytogenetic studies to facilitate our ability to provide a definitive diagnosis.
Altered thrombus formation in von Willebrand factor–deficient mice expressing von Willebrand factor variants with defective binding to collagen or GPIIbIIIa
Authors: Marx Isabelle , Christophe Olivier D. , Lenting Peter J. , Rupin Alain , Vallez Marie-Odile , Verbeuren Tony J. , Denis Cécile V.
Published: May 2008

The role of von Willebrand factor (VWF) in thrombosis involves its binding to a number of ligands. To investigate the relative importance of these particular interactions in the thrombosis process, we have introduced mutations into murine VWF (mVWF) cDNA inhibiting VWF binding to glycoprotein (Gp) Ib, GPIIbIIIa, or to fibrillar collagen. These VWF mutants were expressed in VWF-deficient mice (VWF−/−) by using an hydrodynamic injection approach, and the mice were studied in the ferric chloride–induced injury model. Expression of the collagen and the GPIIbIIIa VWF-binding mutants in VWF−/− mice resulted in delayed thrombus growth and significantly increased vessel occlusion times compared with mice expressing wild-type (WT) mVWF (30 ± 3 minutes and 38 ± 4 minutes for the collagen and GPIIbIIIa mutants, respectively, vs 19 ± 3 minutes for WT mVWF). Interestingly, these mutants were able to correct bleeding time as efficiently as WT mVWF. In contrast, VWF−/− mice expressing the GPIb binding mutant failed to restore thrombus formation and were bleeding for as long as they were observed, confirming the critical importance of the VWF-GPIb interaction. Our observations suggest that targeting the VWF-collagen or VWF-GPIIbIIIa interactions could be an interesting alternative for new antithrombotic strategies.
Mutations in EKLF/KLF1 form the molecular basis of the rare blood group In(Lu) phenotype
Authors: Singleton Belinda K. , Burton Nicholas M. , Green Carole , Brady R. Leo , Anstee David J.
Published: May 2008

Comparison of normal erythroblasts and erythroblasts from persons with the rare In(Lu) type of Lu(a-b-) blood group phenotype showed increased transcription levels for 314 genes and reduced levels for 354 genes in In(Lu) cells. Many erythroid-specific genes (including ALAS2, SLC4A1) had reduced transcript levels, suggesting the phenotype resulted from a transcription factor abnormality. A search for mutations in erythroid transcription factors showed mutations in the promoter or coding sequence of EKLF in 21 of 24 persons with the In(Lu) phenotype. In all cases the mutant EKLF allele occurred in the presence of a normal EKLF allele. Nine different loss-of-function mutations were identified. One mutation abolished a GATA1 binding site in the EKLF promoter (−124T>C). Two mutations (Leu127X; Lys292X) resulted in premature termination codons, 2 (Pro190LeufsX47; Arg319GlufsX34) in frameshifts, and 4 in amino acid substitution of conserved residues in zinc finger domain 1 (His299Tyr) or domain 2 (Arg328Leu; Arg328His; Arg331Gly). Persons with the In(Lu) phenotype have no reported pathology, indicating that one functional EKLF allele is sufficient to sustain human erythropoiesis. These data provide the first description of inactivating mutations in human EKLF and the first demonstration of a blood group phenotype resulting from mutations in a transcription factor.
Evolutionary rates and patterns for human transcription factor binding sites derived from repetitive DNA
Authors: Polavarapu Nalini , Mariño-Ramírez Leonardo , Landsman David , McDonald John F , Jordan I King
Published: May 2008

Background

The majority of human non-protein-coding DNA is made up of repetitive sequences, mainly transposable elements (TEs). It is becoming increasingly apparent that many of these repetitive DNA sequence elements encode gene regulatory functions. This fact has important evolutionary implications, since repetitive DNA is the most dynamic part of the genome. We set out to assess the evolutionary rate and pattern of experimentally characterized human transcription factor binding sites (TFBS) that are derived from repetitive versus non-repetitive DNA to test whether repeat-derived TFBS are in fact rapidly evolving. We also evaluated the position-specific patterns of variation among TFBS to look for signs of functional constraint on TFBS derived from repetitive and non-repetitive DNA.

Results

We found numerous experimentally characterized TFBS in the human genome, 7–10% of all mapped sites, which are derived from repetitive DNA sequences including simple sequence repeats (SSRs) and TEs. TE-derived TFBS sequences are far less conserved between species than TFBS derived from SSRs and non-repetitive DNA. Despite their rapid evolution, several lines of evidence indicate that TE-derived TFBS are functionally constrained. First of all, ancient TE families, such as MIR and L2, are enriched for TFBS relative to younger families like Alu and L1. Secondly, functionally important positions in TE-derived TFBS, specifically those residues thought to physically interact with their cognate protein binding factors (TF), are more evolutionarily conserved than adjacent TFBS positions. Finally, TE-derived TFBS show position-specific patterns of sequence variation that are highly distinct from random patterns and similar to the variation seen for non-repeat derived sequences of the same TFBS.

Conclusion

The abundance of experimentally characterized human TFBS that are derived from repetitive DNA speaks to the substantial regulatory effects that this class of sequence has on the human genome. The unique evolutionary properties of repeat-derived TFBS are perhaps even more intriguing. TE-derived TFBS in particular, while clearly functionally constrained, evolve extremely rapidly relative to non-repeat derived sites. Such rapidly evolving TFBS are likely to confer species-specific regulatory phenotypes, i.e. divergent expression patterns, on the human evolutionary lineage. This result has practical implications with respect to the widespread use of evolutionary conservation as a surrogate for functionally relevant non-coding DNA. Most TE-derived TFBS would be missed using the kinds of sequence conservation-based screens, such as phylogenetic footprinting, that are used to help characterize non-coding DNA. Thus, the very TFBS that are most likely to yield human-specific characteristics will be neglected by the comparative genomic techniques that are currently de rigeur for the identification of novel regulatory sites.
Lower energy expenditures in infants from obese biological mothers
Authors: Rising Russell , Lifshitz Fima
Published: May 2008

Background

Previous studies in adults have found that a lower resting metabolic rate is a predictor of future body weight gain.

Methods

To determine if energy expenditures are reduced in infants born to obese mothers, 21 healthy infants (3.9 ± 1.9 months) born to lean (n = 7, BMI < 25 kg/m2), overweight (n = 7, BMI between 25–30) and obese (n = 7, BMI>30) mothers, respectively, participated in this study. Measurements of infant weight, length and skin-fold thicknesses, and mother's weight and height were obtained. Infant energy expenditure was measured for 4-hours using the Enhanced Metabolic Testing Activity Chamber. Metabolic data were extrapolated to 24-hours and adjusted for differences in age and body composition using linear regression analysis (SPSS, version 13) and expressed as kcal/day. Differences between the three groups were determined by one way ANOVA with the Bonferroni Post Hoc test procedure (p < 0.05).

Results

Infants born to obese mothers had a greater BMI (16.7 ± 1.2) than those from both the overweight (15.3 ± 1.4, p < 0.05) and lean groups (15.1 ± 1.3; p < 0.05). The infants of obese mothers had greater body fat (26.8 ± 2.1) than those from the overweight group (22.4 ± 5.0, p < 0.06). Infant BMI correlated (r = 0.53; p < 0.01) with that of their mothers. Extrapolated 24-h EE (kcal/d) correlated with fat-free mass (r = 0.94; p < 0.01). Infants extrapolated 24-h EE from both obese (472.1 ± 30.7 kcal/d; p < 0.05) and overweight groups (471.8 ± 39.5; p < 0.05) were lower than those of the lean group (532.4 ± 30.7).

Conclusion

Lower extrapolated 24-h energy expenditure was present in infants of overweight and obese biological mothers during the first three to six months of life. Furthermore, these infants showed increased BMI and body fat. If these changes are unchecked future childhood obesity may result.
COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro
Authors: Chuang Huan-Ching , Kardosh Adel , Gaffney Kevin J , Petasis Nicos A , Schönthal Axel H
Published: May 2008

Background

An increasing number of reports is challenging the notion that the antitumor potential of the selective COX-2 inhibitor celecoxib (Celebrex®) is mediated primarily via the inhibition of COX-2. We have investigated this issue by applying two different analogs of celecoxib that differentially display COX-2-inhibitory activity: the first analog, called unmethylated celecoxib (UMC), inhibits COX-2 slightly more potently than its parental compound, whereas the second analog, 2,5-dimethyl-celecoxib (DMC), has lost the ability to inhibit COX-2.

Results

With the use of glioblastoma and pancreatic carcinoma cell lines, we comparatively analyzed the effects of celecoxib, UMC, and DMC in various short-term (≤48 hours) cellular and molecular studies, as well as in long-term (≤3 months) focus formation assays. We found that DMC exhibited the most potent antitumor activity; celecoxib was somewhat less effective, and UMC clearly displayed the overall weakest antitumor potential in all aspects. The differential growth-inhibitory and apoptosis-stimulatory potency of these compounds in short-term assays did not at all correlate with their capacity to inhibit COX-2, but was closely aligned with their ability to trigger endoplasmic reticulum stress (ERS), as indicated by the induction of the ERS marker CHOP/GADD153 and activation of the ERS-associated caspase 7. In addition, we found that these compounds were able to restore contact inhibition and block focus formation during long-term, chronic drug exposure of tumor cells, and this was achieved at sub-toxic concentrations in the absence of ERS or inhibition of COX-2.

Conclusion

The antitumor activity of celecoxib in vitro did not involve the inhibition of COX-2. Rather, the drug's ability to trigger ERS, a known effector of cell death, might provide an alternative explanation for its acute cytotoxicity. In addition, the newly discovered ability of this drug to restore contact inhibition and block focus formation during chronic drug exposure, which involved neither ERS nor COX-2, suggests a novel, as yet unrecognized mechanism of celecoxib action.
Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors
Authors: Sunami Eiji , Shinozaki Masaru , Sim Myung-Shin , Nguyen Sandy L , Vu Anh-Thu , Giuliano Armando E , Hoon Dave SB
Published: May 2008

Introduction

Estrogen receptor (ER)-positive breast cancers are considered prognostically more favorable than ER-negative tumors, whereas human epidermal growth factor receptor (HER)2/neu-positive breast cancers are associated with worse prognosis. The objective of the present study was to determine whether ER-positive and ER-negative status relates to epigenetic changes in breast cancer-related genes. To evaluate epigenetic differences in tumor-related genes relating to ER and HER2/neu status of primary tumors, we examined the promoter methylation status of the promoter region CpG islands of eight major breast tumor-related genes (RASSF1A, CCND2, GSPT1, TWIST, APC, NES1, RARβ2, and CDH1).

Methods

Paired ER-positive (n = 65) and ER-negative (n = 65) primary breast tumors (n = 130) matched for prognostic factors were assessed. DNA was extracted from paraffin-embedded tumor tissue after microdissection, and methylation-specific PCR and capillary-array electrophoresis analysis were performed.

Results

In early stages of tumor progression (T1 and N0), RASSF1A and CCND2 were significantly (P < 0.05) more methylated in ER-positive than in ER-negative tumors. GSTP1 hypermethylation was more frequent in the lymph node metastasis positive group than in the negative group. Double negative (ER-negative, HER2/neu-negative) breast cancers had significantly lesser frequencies of RASSF1A, GSTP1, and APC methylation (P < 0.0001, P < 0.0001, and P = 0.0035, respectively). Both ER and HER2/neu status correlated independently with these epigenetic alterations.

Conclusion

We demonstrated significant differences in tumor-related gene methylation patterns relevant to ER and HER2/neu status of breast tumors. This may be of significance in the assessment of targeted therapy resistance related to ER and HER2/neu status in breast cancer patients.
Retinol-Binding Protein 4 and Lipocalin-2 in Childhood and Adolescent Obesity: When Children Are Not Just “Small Adults”
Authors: Kanaka-Gantenbein Christina , Margeli Alexandra , Pervanidou Panagiota , Sakka Sophia , Mastorakos George , Chrousos George P , Papassotiriou Ioannis
Published: May 2008

Background: Although there is much evidence regarding the physiologic and pathogenic roles of the newly described adipokines retinol-binding protein 4 (RBP4) and lipocalin-2 as potential promoters of insulin resistance in obese adults, relatively little information exists regarding their roles in obese children.

Methods: We investigated the circulating concentrations of RBP4 and lipocalin-2 in 80 obese girls (ages 9– 15 years) and their relationships with high-sensitivity C-reactive protein (hs-CRP) and the adipokines leptin and adiponectin. We divided participants by their body mass index standard deviation scores (BMI SDSs) into 4 groups of 20 girls each: overweight [mean BMI SDS (SD), 1.8 (0.4)], obese [2.2 (0.4)], morbidly obese [3.6 (0.4)], and lean controls [−0.11 (0.4)]. We measured plasma-soluble RBP4, the RBP4-binding protein transthyretin, lipocalin-2, hs-CRP, leptin, and adiponectin and calculated the homeostatic assessment model (HOMA) index from fasting glucose and insulin concentrations.

Results: Unexpectedly, plasma RBP4 and lipocalin-2 concentrations were correlated negatively with BMI SDS values (P = 0.005, and P < 0.03, respectively). These results were different from those of adults and were not correlated with the HOMA index. In contrast, hs-CRP and leptin concentrations were positively correlated with BMI SDS values (P < 0.0001, and P < 0.00001, respectively), as expected, whereas the adiponectin concentration was negatively correlated (P = 0.008).

Conclusions: Although the correlations of leptin, adiponectin, and hs-CRP concentrations with BMI in children are similar to those of adults, the correlations of RBP4 and lipocalin-2 with BMI in children are the inverse of those observed in adults. Thus, although systemic inflammation and mild insulin resistance are present in childhood obesity, RBP4 and lipocalin-2 concentrations are not increased in children as they are in obese adults with long-standing severe insulin resistance and type 2 diabetes.
Estimating Glomerular Filtration Rate in Black South Africans by Use of the Modification of Diet in Renal Disease and Cockcroft-Gault Equations
Authors: van Deventer Hendrick E , George Jaya A , Paiker Janice E , Becker Piet J , Katz Ivor J
Published: May 2008

Background: The 4-variable Modification of Diet in Renal Disease (4-v MDRD) and Cockcroft-Gault (CG) equations are commonly used for estimating glomerular filtration rate (GFR); however, neither of these equations has been validated in an indigenous African population. The aim of this study was to evaluate the performance of the 4-v MDRD and CG equations for estimating GFR in black South Africans against measured GFR and to assess the appropriateness for the local population of the ethnicity factor established for African Americans in the 4-v MDRD equation.

Methods: We enrolled 100 patients in the study. The plasma clearance of chromium-51–EDTA (51Cr-EDTA) was used to measure GFR, and serum creatinine was measured using an isotope dilution mass spectrometry (IDMS) traceable assay. We estimated GFR using both the reexpressed 4-v MDRD and CG equations and compared it to measured GFR using 4 modalities: correlation coefficient, weighted Deming regression analysis, percentage bias, and proportion of estimated GFR within 30% of measured GFR (P30).

Results: The Spearman correlation coefficient between measured and estimated GFR for both equations was similar (4-v MDRD R2 = 0.80 and CG R2 = 0.79). Using the 4-v MDRD equation with the ethnicity factor of 1.212 as established for African Americans resulted in a median positive bias of 13.1 (95% CI 5.5 to 18.3) mL/min/1.73 m2. Without the ethnicity factor, median bias was 1.9 (95% CI −0.8 to 4.5) mL/min/1.73 m2.

Conclusions: The 4-v MDRD equation, without the ethnicity factor of 1.212, can be used for estimating GFR in black South Africans.
Sequence-Specific Histone Methylation Is Detectable on Circulating Nucleosomes in Plasma
Authors: Deligezer Ugur , Akisik Ebru E , Erten Nilgün , Dalay Nejat
Published: May 2008

Background: Alterations in DNA methylation and histone modifications have been implicated in carcinogenesis. Although tumor-specific alterations in DNA methylation can be detected in the serum and plasma of cancer patients, no data are available on the presence of histone modifications in circulating blood. We investigated whether histone methylation, as a model of histone modifications, is detectable in plasma. Because methylation at histone 3 lysine 9 (H3K9) has been demonstrated to be enriched at sites of repetitive ALU elements, we addressed the specificity of histone-methylation detection and hypothesized that if monomethylated H3K9 (H3K9me1) is detectable in plasma, the concentrations in mononucleosomes and oligonucleosomes would be different. We also analyzed a single-copy gene, CDKN2A.

Methods: We enrolled 21 multiple myeloma patients in the study. We used ELISA and real-time PCR analysis to evaluate nucleosomes and cell-free DNA, respectively, as evidence of the presence of histones and associated DNA in circulating blood. H3K9me1 was analyzed by chromatin immunoprecipitation.

Results: ELISA and real-time PCR assays indicated the presence of free nucleosomes and DNA in plasma, and the results were quantitatively correlated (P < 0.001). The detection of histone methylation on free nucleosomes was sequence dependent. Fragments representing mono- and oligonucleosomes differed with respect to H3K9me1 concentrations (P = 0.004), in accordance with our hypothesis. In addition, the detection rate and concentrations of H3K9me1 were significantly higher on the fragment covering both mononucleosomes and oligonucleosomes than on the CDKN2A promoter (P < 0.001).

Conclusions: If validated in further studies, our findings may be a basis for investigations of cancer-specific alterations in histone modifications in the circulation.
Celiac Disease and IgA Deficiency: Complications of Serological Testing Approaches Encountered in the Clinic
Authors: McGowan Kelly E , Lyon Martha E , Butzner J Decker
Published: May 2008

Background: IgA deficiency causes false-negative IgA-based celiac serology results in patients with celiac disease. Using a case-finding strategy, we examined the prevalence of IgA deficiency, physician evaluation, and management of IgA deficiency during serological testing for celiac disease.

Methods: We reviewed consecutive IgA-endomysial antibody (EMA) and serum IgA results from the laboratory database over 17 months. We cross-referenced seronegative patients with IgA deficiency (IgA <0.06 g/L) to the pathology database to evaluate intestinal biopsy results. Ordering physicians received a questionnaire regarding the management of seronegative patients with IgA deficiency who had no biopsy record.

Results: Among the 9533 patients tested for IgA-EMA, 4698 (49%) were tested for IgA deficiency. IgA deficiency occurred in 35 of 4698 (0.75%) patients screened for IgA deficiency. Only 19 of 35 (54%) IgA-deficient patients were diagnosed appropriately with either intestinal biopsy (17 patients) or measurement of IgG-tissue transglutaminase (2 patients). Thirteen (76%) of the 17 IgA-deficient patients who underwent upper endoscopy with or without colonoscopy displayed gastrointestinal pathology on biopsies, including 3 (18%) with celiac disease. No further evaluation to exclude celiac disease was performed for the remaining 16 of 35 (46%) IgA-deficient, EMA-negative patients because of inappropriate management (6 patients), administrative error (7 patients), or patient/physician refusal (3 patients).

Conclusions: IgA deficiency occurred in 1:131 patients tested for celiac disease, and celiac disease occurred in 1:6 of those properly evaluated. Inadequate evaluation of IgA deficiency while testing for celiac disease occurred frequently and resulted in the underdiagnosis of both. Changes in testing algorithms and reporting of results were made to improve testing for celiac disease and IgA deficiency.
Anti-proliferative effect of pro-inflammatory cytokines in cultured β cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide -1
Authors: Blandino-Rosano M , Perez-Arana G , Mellado-Gil J M , Segundo C , Aguilar-Diosdado M
Published: May 2008

Pancreatic β-cell homeostasis is a balance between programmed cell death (apoptosis) and regeneration. Although autoimmune diabetes mellitus type 1 (DM1) is the most-studied cause of β-cell mass loss by pro-inflammatory cytokine-induced apoptosis, influences of a pro-inflammatory environment on β-cell regenerative response have been poorly studied. In this study, we assess the anti-proliferative effect of pro-inflammatory cytokines and glucose concentration on rat pancreatic β cells and the potential protective role of glucagon-like peptide (GLP-1). Apoptotic and proliferating islet cells were stained using the DeadEnd Fluorimetric TUNEL System and 5-bromo-2′-deoxyuridine label respectively, in the presence–absence of varying concentrations of glucose, pro-inflammatory cytokines, and GLP-1. The potential signaling pathways involved were evaluated by western blot. Considerable anti-proliferative effects of pro-inflammatory cytokines interleukin (IL)-1β, interferon (IFN)-γ, and tumour necrosis factor-α (TNF-α) were observed. The effects were synergistic and independent of glucose concentration, and appeared to be mediated by the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation, the signaling pathway involved in β-cell replication. GLP-1 completely reversed the cytokine-induced inhibition of ERK phosphorylation and increased β-cell proliferation threefold in cytokine-treated cultures. While pro-inflammatory cytokines reduced islet cell ERK1/2 activation and β-cell proliferation in pancreatic islet culture, GLP-1 was capable of reversing this effect. These data suggest a possible pharmacological application of GLP-1 in the treatment of early stage DM1, to prevent the loss of pancreatic β cells as well as to delay the development of overt diabetes.