bluuebunny/crossref_metadata_2025 huggingface dataset:
The Potential of Exon Skipping for Treatment for Duchenne Muscular Dystrophy
Authors: Partridge Terence
Published: June 2010

Duchenne muscular dystrophy is mainly caused by mutations that disrupt the generation of a translatable mRNA transcript. Most such mutations occur in parts of the gene that are not essential for its function and thus might be eliminated from the transcript to permit translation of a partially functional protein that would convert the disease to a milder clinical form. Two such antisense oligonucleotides of different backbone chemistries have been successful when tested on the mdx mouse, targeting exon 23, containing the nonsense mutation. Subsequently, the morpholino, the more effective of these, has been tested on the dystrophic dog, where it is necessary to skip 2 exons, again with beneficial results. Currently, results of 2 human trials targeting exon 51 have also yielded promising preliminary results.
The Distribution of Federal Economic Development Grant Funds: A Consideration of Need and the Urban/Rural Divide
Authors: Hall Jeremy L.
Published: June 2010

This article seeks to determine the effect of rurality and need on per capita federal grant receipts in local areas over time, controlling for local and regional government capacities. In other words, are rural places treated differently than urban places in federal grant distributions? Kentucky is used as the case state, with 120 county areas considered over an 11-year period from 1993 to 2003. Factor analysis is used to explore the underlying capacity constructs, and a pooled cross-sectional analysis reveals differential effects of grant receipts per person according to a county’s position on the rural—urban continuum (aka Beale code) and need-based indicators. Whereas rurality significantly increases grant funding per capita, need has the opposite effect.
Tri-Value Organization as a Form of Social Enterprise
Authors: Herranz Joaquín , Council Logan R. , McKay Brenna
Published: June 2010

Many depictions of social enterprises underemphasize the role of government in supporting their mission and operation. This article provides a conceptual framework and analysis of government’s financial role in one form of nonprofit social enterprise that we identify as a tri-value social enterprise. The main argument is that some forms of social enterprises are better characterized as tri-value social enterprises because their revenue sources explicitly derive from the nonprofit, for-profit, and public sectors. This analysis extends Moore’s (2000) three-part framework that distinguishes values-based differences in sources of revenue among for-profit, nonprofit, and governmental organizations. The case of the Seattle nonprofit FareStart provides an illustrative example of a tri-value social enterprise because both direct and indirect government-based revenues support FareStart’s operation as a social enterprise. The article discusses the implications for researchers and practitioners of identifying tri-value social enterprises.
Health Against the Odds: Experiences of Employees in Elder Care From a Gender Perspective
Authors: Elwér Sofia , Aléx Lena , Hammarström Anne
Published: June 2010

Women-dominated elder care in Sweden is a low-paid, low-status job with a high prevalence of sick leave. Our aim was to analyze health experiences of employees in elder care from a gender perspective. All caregiving staff at two establishments providing care to the elderly were invited to participate in the study. A moderator led seven focus group discussions. Qualitative content analysis was used to analyze the transcribed focus groups. We identified two central themes in relation to the employees’ health. “Working against the odds” describes gendered workplace stressors of a structural character, to a large extent triggered by societal processes outside the organization. “Making work matter” refers to gendered health resources with a relational character, constructed within the organization. Health-promoting programs directed toward women-dominated workplaces need to include a gender perspective, and focus on creating structural, supportive environments to avoid the negative health effects of the stressors.
Displaced Epithelium After Liposuction for Gynecomastia
Authors: McLaughlin Cristina S. , Petrey Chris , Grant Shawn , Ransdell Jill S. , Reynolds Carol
Published: June 2010

The authors describe the case of a 36-year-old man with gynecomastia who was previously treated with liposuction of the breast for cosmetic purposes. Histologic examination of a subsequent excisional biopsy revealed nests of displaced epithelial cells in adipose tissue. Epithelial cell displacement is a well-known risk of core needle biopsies and fine-needle aspirations of breast lesions. However, to the authors’ knowledge, epithelial displacement in gynecomastia after liposuction, mimicking invasive ductal carcinoma, has not previously been reported.
Examining the Reliability and Validity of Clinician Ratings on the Five-Factor Model Score Sheet
Authors: Few Lauren R. , Miller Joshua D. , Morse Jennifer Q. , Yaggi Kirsten E. , Reynolds Sarah K. , Pilkonis Paul A.
Published: June 2010

Despite substantial research use, measures of the five-factor model (FFM) are infrequently used in clinical settings due, in part, to issues related to administration time and a reluctance to use self-report instruments. The current study examines the reliability and validity of the Five-Factor Model Score Sheet (FFMSS), which is a 30-item clinician rating form designed to assess the five domains and 30 facets of one conceptualization of the FFM. Studied in a sample of 130 outpatients, clinical raters demonstrated reasonably good interrater reliability across personality profiles and the domains manifested good internal consistency with the exception of Neuroticism. The FFMSS ratings also evinced expected relations with self-reported personality traits (e.g., FFMSS Extraversion and Schedule for Nonadaptive and Adaptive Personality Positive Temperament) and consensus-rated personality disorder symptoms (e.g., FFMSS Agreeableness and Narcissistic Personality Disorder). Finally, on average, the FFMSS domains were able to account for approximately 50% of the variance in domains of functioning (e.g., occupational, parental) and were even able to account for variance after controlling for Axis I and Axis II pathology. Given these findings, it is believed that the FFMSS holds promise for clinical use.
Impact of Patient-Centered Medical Home Assignment on Emergency Room Visits Among Uninsured Patients in a County Health System
Authors: Roby Dylan H. , Pourat Nadereh , Pirritano Matthew J. , Vrungos Shelley M. , Dajee Himmet , Castillo Dan , Kominski Gerald F.
Published: June 2010

The Medical Services Initiative program—a safety net—based system of care— in Orange County included assignment of uninsured, low-income residents to a patient-centered medical home. The medical home provided case management, a team-based approach for treating disease, and increased access to primary and specialty care among other elements of a patient-centered medical home. Providers were paid an enhanced fee and pay-for-performance incentives to ensure delivery of comprehensive treatment. Medical Services Initiative enrollees who were assigned to a medical home for longer time periods were less likely to have any emergency room (ER) visits or multiple ER visits. Switching medical homes three or more times was associated with enrollees being more likely to have any ER visits or multiple ER visits. The findings provide evidence that successful implementation of the patient-centered medical home model in a county-based safety net system is possible and can reduce unnecessary ER use.
Medical Utilization Among Wellness Consumers
Authors: Kannan Viji Diane , Gaydos Laura M. , Atherly Adam J. , Druss Benjamin G.
Published: June 2010

This study investigates conventional medicine utilization by wellness-motivated, complementary and alternative medicine (CAM) consumers. While CAM consumers are typically characterized as high health care utilizers, negative correlations have been found between CAM-based wellness programs and the consumption of conventional medical care. We use a nationally representative sample to analyze both illness- and wellness-motivated CAM users, with an interest in whether CAM therapies used for wellness replace conventional medicine, thus potentially offering cost offsets. Results indicate that motivation for CAM use is neither associated with a lower probability nor a lower rate of conventional medicine utilization. Increasingly, individuals, workplaces, and governments incorporate wellness programs involving CAM modalities into health care and policy; as the conventional and unconventional medical spheres begin to integrate and influence one another, understanding our pluralistic medical environment and its consumers will better enable policy makers to balance health and wellness initiatives with economic imperatives.
Topic Areas to Consider When Planning Transition From High School to Postsecondary Education for Students With Autism Spectrum Disorders
Authors: Roberts Kelly D.
Published: June 2010

For many individuals with an autism spectrum disorder (ASD), attending and completing postsecondary education is a viable option. However, success in postsecondary education for these individuals may require more planning and ongoing support than students without an ASD. This article provides educators and transition support personnel with a range of topics to consider when working with students with ASD and their families to develop a comprehensive transition plan. These topic areas include career exploration, academic goal setting and preparation, assessing and knowing learning styles, self-advocacy skills, reasonable accommodations, academic supports, interagency collaboration, technology, and time management skills.
The Effects of Covert Audio Coaching on the Job Performance of Supported Employees
Authors: Bennett Kyle , Brady Michael P. , Scott Jack , Dukes Charles , Frain Michael
Published: June 2010

The importance of employment in society is unmistakable, but for many people sustained employment remains elusive. The unemployment rate for individuals with disabilities is staggering, and the consequences of being unemployed affects those individuals, their families, and society. The effects of performance feedback delivered via covert audio coaching on the job performance of supported employees were examined in this investigation. A multiple baseline design across employees and work tasks was used to evaluate the effects of the intervention on work performance. Supported employees made substantial improvements on their work performance, and the improvements maintained for 4 to 5 weeks following the removal of the intervention. The results have implications for the use of covert audio coaching in employment and other settings.
Conflict and Coordination in the Provision of Public Goods: A Conceptual Analysis of Continuous and Step-Level Games
Authors: Abele Susanne , Stasser Garold , Chartier Christopher
Published: June 2010

Conflicts between individual and collective interests are ubiquitous in social life. Experimental studies have investigated the resolution of such conflicts using public goods games with either continuous or step-level payoff functions. Game theory and social interdependence theory identify consequential differences between these two types of games. Continuous function games are prime examples of social dilemmas because they always contain a conflict between individual and collective interests, whereas step-level games can be construed as social coordination games. Step-level games often provide opportunities for coordinated solutions that benefit both the collective and the individuals. For this and other reasons, the authors conclude that one cannot safely generalize results obtained from step-level to continuous-form games (or vice versa). Finally, the authors identify specific characteristics of the payoff function in public goods games that conceptually mark the transition from a pure dilemma to a coordination problem nested within a dilemma.
Subchronic Toxicity of S-111-S-WB in Sprague Dawley Rats
Authors: Mertens Jozef J. W. M. , Sved Daniel W. , Marit Gary B. , Myers Nichole R. , Stetson Phil L. , Murphy Sandra Reiss , Schmit Bruno , Shinohara Motoki , Farr Craig H.
Published: June 2010

S-111-S-WB, a mixture of perfluoro fatty acid ammonium salts (C6-C13), was administered orally to Crl:CD (SD)IGS-BR rats. Higher hepatic β-oxidation and liver weights with hepatocellular hypertrophy were present at the 0.125 and 0.6 mg/kg/d dosage. The 0.6 mg/kg/d males developed hepatocellular degeneration and necrosis. Lower serum protein and higher bilirubin and BUN were seen in the 0.6 mg/kg/d males and lower globulin and higher alkaline phosphatase in the 0.125 mg/kg/d males and 0.6 mg/kg/d animals. After 2 weeks, serum concentrations of pentadecafluorooctanoic acid (C8), heptadecafluorononanoic acid (C9), perfluoroundecanoic acid (C11), and perfluorotridecanoic acid (C13) were constant for at least 8 hours. After 90 days, only C9 in the 0.025 mg/kg/d females had reached steady state. Serum C8 and C9 concentrations in the males were 10-fold higher than in the females, whereas C11 and C13 were similar for both genders. The main elimination was via the urine for C8 (males) and C9 (females), and via the feces for C11 and C13. The no-observed-effect level (NOEL) was 0.025 mg/kg/d for the males and 0.125 mg/kg/d for the females.
Consumption between Market and Morals: A Socio-cultural Consideration of Moralized Markets
Authors: Stehr Nico , Adolf Marian
Published: June 2010

At a time when the formerly strictly separated roles of citizen and consumer are arguably blurry, and when once powerful social institutions increasingly must yield to new social forces based on heightened knowledgeability and historically unprecedented wealth, it is likely that the economy of modern society is also subject to implicit changes. In this article, we argue that traditional theories of the market are increasingly losing their basis for analysing economic relationships as purely rational acts of exchange and utility maximization. Instead, what can be witnessed is an increase in the influence of values and norms on markets, guiding our attention to how deeply embedded economic action is in modern culture. We put forward the idea of a moralization of markets, which has begun to change our conceptions and theories regarding what is at stake in a modern economy fundamentally. We conclude that in the future, production processes and standards, codes of conduct and consumer reasoning will become all the more important for doing business in Western knowledge societies.
Contemporary Technology Discourse and the Legitimation of Capitalism
Authors: Fisher Eran
Published: June 2010

At the center of contemporary discourse on technology — or the digital discourse — is the assertion that network technology ushers in a new phase of capitalism which is more democratic, participatory, and de-alienating for individuals. Rather than viewing this discourse as a transparent description of the new realities of techno-capitalism and judging its claims as true (as the hegemonic view sees it) or false (a view expressed by few critical voices), this article offers a new framework which sees the digital discourse as signaling a historical shift in the technological legitimation of capitalism, concurrent with the emergence of the post-Fordist phase of capitalism. Technology discourse legitimated the Fordist phase of capitalism by stressing the ability of technology and technique to mitigate exploitation. It hence legitimated the interventionist welfare state, the central planning in businesses and the economy, the hierarchized corporation, and the tenured worker. In contrast, contemporary technology discourse legitimates the post-Fordist phase of capitalism by stressing the ability of technology to mitigate alienation. It hence legitimates the withdrawal of the state from markets, the dehierarchization and decentralization of businesses, and the flexibilization of production and the labor process.
Alternative Media as Critical Media
Authors: Fuchs Christian
Published: June 2010

This article deals with the category of alternative media from a theoretical perspective. It aims to develop a definition and to distinguish different dimensions of alternative media. The article is a contribution to theoretical foundations of alternative media studies. The notion of alternative media as critical media is introduced. Critical media product content shows the suppressed possibilities of existence, antagonisms of reality, and potentials for change. It questions domination, expresses the standpoints of the oppressed and dominated groups and individuals and argues for the advancement of a co-operative society. Critical media product form aims at advancing imagination; it is dialectical because it involves dynamics, non-identity, rupture, and the unexpected. The category of critical media is connected to Negt and Kluge’s notion of the counter-public sphere. Critical media can be seen as the communicative dimension of the counter-public sphere.
Solidarity and Social Cohesion in Late Modernity: A Question of Recognition, Justice and Judgement in Situation
Authors: Juul Søren
Published: June 2010

The aim of this article is to contribute to the formulation of a non-excluding concept of solidarity which is of relevance to contemporary society. The assumption is that in the present individualized and culturally diverse society there is an urgent need for a new form of solidarity to create social cohesion. The central theme is that contemporary solidarity is about recognition and a fair distribution of chances for recognition. This ideal may function as a normative standard for critical research and as a guideline for people in their moral struggles. What ultimately needs to be done is not a purely theoretical question but something which must be settled by a judgement that constitutes a battlefield where conflicting values and perceptions of reality confront each other.
Self and Self—Other Reflexivity: The Apophatic Dimension
Authors: Mouzelis Nicos
Published: June 2010

By referring to mundane practices as well as to more systematic or theoretical discourses (those of Krishnamurti and Buber), this article shows the utility of focusing on the negatory, apophatic aspects of reflexivity, i.e. on attempts at removing obstacles (mainly thinking, decision-making processes) which prevent the spontaneous emergence of open-ended self—self and self—other relationships.
Femoroacetabular Impingement in Athletes, Part 1
Authors: Byrd J. W. Thomas
Published: June 2010

Context:

Femoroacetabular impingement (FAI) is a common cause of intra-articular hip pathology and secondary osteoarthritis. It affects athletes at a young age as they push their bodies beyond the diminished physiologic limits imposed by the altered joint morphology. Understanding the cause of this condition and its assessment in athletes is important.

Evidence Acquisition:

The scientific literature was reviewed to reflect the current understanding of hip joint pathology among athletic individuals. Focus is given to the literature since 2003, when FAI was first reported as a cause of joint damage in the native hip.

Results:

There are 3 types of FAI: pincer, cam, and combined. The pathomechanics and pattern of secondary intra-articular pathology are different among the types. History and examination usually reflect findings of joint damage among athletes, and radiographs can reveal the presence of underlying FAI. Other imaging studies may variably aid in detecting the pathology.

Conclusions:

FAI is a common cause of hip problems in athletes. Early recognition is an important first step in order to avoid the severe secondary damage that can occur.
Effect of primary α content on creep and creep crack growth behaviour of near α-Ti alloy
Authors: Omprakash C M , Satyanarayana D V V , Kumar V
Published: June 2010

The effect of primary α content on creep and creep crack growth behaviour of a near α-Ti alloy has been investigated at 600°C. The alloy was heat treated at different temperatures so as to obtain different volume fractions of equiaxed primary α in the range from 5 to 40%. Constant load creep tests were carried out at 600°C in the stress range 250–400 MPa until rupture of the specimens. Creep crack growth tests were carried out at 600°C and at an initial stress intensity level of 25 MPa m1/2. Creep data reveal that minimum creep rate increases and time to rupture decreases with increase in primary α content indicating that higher primary α leads to creep weakening. On similar lines, maximum creep crack growth resistance is associated with the alloy with lowest primary α content (i.e. 5%). Microstructural and fractographic examination has revealed that creep fracture occurs by nucleation, growth and coalescence of microvoids nucleated at primary α/transformed β (matrix) interfaces. On the other hand, creep crack growth occurs by surface cracks nucleated by fracture of primary α particles as well as by growth and coalescence of microvoids nucleated at primary α/transformed β (matrix) interfaces in the interior of the specimen ahead of the crack tip.
KLF4 is a tumor suppressor in B-cell non-Hodgkin lymphoma and in classic Hodgkin lymphoma
Authors: Guan Hanfeng , Xie Linka , Leithäuser Frank , Flossbach Lucia , Möller Peter , Wirth Thomas , Ushmorov Alexey
Published: June 2010

The transcription factor KLF4 may act both as an oncogene and a tumor suppressor in a tissue-depending manner. In T- and pre-B-cell lymphoma, KLF4 was found to act as tumor suppressor. We found the KLF4 promoter methylated in B-cell lymphoma cell lines and in primary cases of B-cell lymphomas, namely, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, and in classic Hodgkin lymphoma (cHL) cases. Promoter hypermethylation was associated with silencing of KLF4 expression. Conditional overexpression of KLF4 in Burkitt lymphoma cell lines moderately retarded proliferation, via cell-cycle arrest in G0/G1. In the cHL cell lines, KLF4 induced massive cell death that could partially be inhibited with Z-VAD.fmk. A quantitative reverse-transcribed polymerase chain reaction array revealed KLF4 target genes, including the proapoptotic gene BAK1. Using an shRNA-mediated knock-down approach, we found that BAK1 is largely responsible for KLF4-induced apoptosis. In addition, we found that KLF4 negatively regulates CXCL10, CD86, and MSC/ABF-1 genes. These genes are specifically up-regulated in HRS cells of cHL and known to be involved in establishing the cHL phenotype. We conclude that epigenetic silencing of KLF4 in B-cell lymphomas and particularly in cHL may favor lymphoma survival by loosening cell-cycle control and protecting from apoptosis.
Transcriptome analysis of porcine PBMCs after in vitro stimulation by LPS or PMA/ionomycin using an expression array targeting the pig immune response
Authors: Gao Yu , Flori Laurence , Lecardonnel Jérome , Esquerré Diane , Hu Zhi-Liang , Teillaud Angélique , Lemonnier Gaëtan , Lefèvre Francois , Oswald Isabelle P , Rogel-Gaillard Claire
Published: June 2010

Background

Designing sustainable animal production systems that better balance productivity and resistance to disease is a major concern. In order to address questions related to immunity and resistance to disease in pig, it is necessary to increase knowledge on its immune system and to produce efficient tools dedicated to this species.

Results

A long-oligonucleotide-based chip referred to as SLA-RI/NRSP8-13K was produced by combining a generic set with a newly designed SLA-RI set that targets all annotated loci of the pig major histocompatibility complex (MHC) region (SLA complex) in both orientations as well as immunity genes outside the SLA complex.

The chip was used to study the immune response of pigs following stimulation of porcine peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS) or a mixture of phorbol myristate acetate (PMA) and ionomycin for 24 hours. Transcriptome analysis revealed that ten times more genes were differentially expressed after PMA/ionomycin stimulation than after LPS stimulation. LPS stimulation induced a general inflammation response with over-expression of SAA1, pro-inflammatory chemokines IL8, CCL2, CXCL5, CXCL3, CXCL2 and CCL8 as well as genes related to oxidative processes (SOD2) and calcium pathways (S100A9 and S100A12). PMA/ionomycin stimulation induced a stronger up-regulation of T cell activation than of B cell activation with dominance toward a Th1 response, including IL2, CD69 and TNFRSF9 (tumor necrosis factor receptor superfamily, member 9) genes. In addition, a very intense repression of THBS1 (thrombospondin 1) was observed. Repression of MHC class I genes was observed after PMA/ionomycin stimulation despite an up-regulation of the gene cascade involved in peptide processing. Repression of MHC class II genes was observed after both stimulations. Our results provide preliminary data suggesting that antisense transcripts mapping to the SLA complex may have a role during immune response.

Conclusion

The SLA-RI/NRSP8-13K chip was found to accurately decipher two distinct immune response activations of PBMCs indicating that it constitutes a valuable tool to further study immunity and resistance to disease in pig. The transcriptome analysis revealed specific and common features of the immune responses depending on the stimulation agent that increase knowledge on pig immunity.
Omega-3 fatty acids in high-risk cardiovascular patients: a meta-analysis of randomized controlled trials
Authors: Filion Kristian B , El Khoury Fouad , Bielinski Michael , Schiller Ian , Dendukuri Nandini , Brophy James M
Published: June 2010

Background

Multiple randomized controlled trials (RCTs) have examined the cardiovascular effects of omega-3 fatty acids and have provided unexplained conflicting results. A meta-analysis of these RCTs to estimate efficacy and safety and potential sources of heterogeneity may be helpful.

Methods

The Cochrane library, MEDLINE, and EMBASE were systematically searched to identify all interventional trials of omega-3 fatty acids compared to placebo or usual diet in high-risk cardiovascular patients. The primary outcome was all-cause mortality and secondary outcomes were coronary restenosis following percutaneous coronary intervention and safety. Meta-analyses were carried out using Bayesian random-effects models, and heterogeneity was examined using meta-regression.

Results

A total of 29 RCTs (n = 35,144) met our inclusion criteria, with 25 reporting mortality and 14 reporting restenosis. Omega-3 fatty acids were not associated with a statistically significant decreased mortality (relative risk [RR] = 0.88, 95% Credible Interval [CrI] = 0.64, 1.03) or with restenosis prevention (RR = 0.89, 95% CrI = 0.72, 1.06), though the probability of some benefit remains high (0.93 and 0.90, respectively). However in meta-regressions, there was a >90% probability that larger studies and those with longer follow-up were associated with smaller benefits. No serious safety issues were identified.

Conclusions

Although not reaching conventional statistical significance, the evidence to date suggests that omega-3 fatty acids may result in a modest reduction in mortality and restenosis. However, caution must be exercised in interpreting these benefits as results were attenuated in higher quality studies, suggesting that bias may be at least partially responsible. Additional high quality studies are required to clarify the role of omega-3 fatty acid supplementation for the secondary prevention of cardiovascular disease.
Validation of the GenoType®MTBDRplus assay for diagnosis of multidrug resistant tuberculosis in South Vietnam
Authors: Huyen Mai NT , Tiemersma Edine W , Lan Nguyen TN , Cobelens Frank GJ , Dung Nguyen H , Sy Dinh N , Buu Tran N , Kremer Kristin , Hang Pham T , Caws Maxine , O'Brien Richard , van Soolingen Dick
Published: June 2010

Background

To control multidrug resistant tuberculosis (MDR-TB), the drug susceptibility profile is needed to guide therapy. Classical drug susceptibility testing (DST) may take up to 2 to 4 months. The GenoType® MTBDRplus test is a commercially available line-probe assay that rapidly detects Mycobacterium tuberculosis (MTB) complex, as well as the most common mutations associated with rifampin and isoniazid resistance.

We assessed sensitivity and specificity of the assay by using a geographically representative set of MTB isolates from the South of Vietnam.

Methods

We re-cultured 111 MTB isolates that were MDR, rifampin-resistant or pan-susceptible according to conventional DST and tested these with the GenoType® MTBDRplus test.

Results

By conventional DST, 55 strains were classified as MDR-TB, four strains were rifampicin mono-resistant and 52 strains were susceptible to all first-line drugs. The sensitivity of the GenoType® MTBDRplus was 93.1% for rifampicin, 92.6% for isoniazid and 88.9% for the combination of both; its specificity was 100%. The positive predictive value of the GenoType® MTBDRplus test for MDR-TB was 100% and the negative predictive value 90.3%.

Conclusions

We found a high specificity and positive predictive value of the GenoType® MTBDRplus test for MDR-TB which merits its use in the MDR-TB treatment program in Vietnam.
Evaluation of 6 candidate genes on chromosome 11q23 for coeliac disease susceptibility: a case control study
Authors: Brophy Karen , Ryan Anthony W , Turner Graham , Trimble Valerie , Patel Kunal D , O'Morain Colm , Kennedy Nicholas P , Egan Brian , Close Eimear , Lawlor Garrett , MacMathuna Padraic , Stevens Fiona M , Abuzakouk Mohamed , Feighery Conleth , Kelleher Dermot , McManus Ross
Published: June 2010

Background

Recent whole genome analysis and follow-up studies have identified many new risk variants for coeliac disease (CD, gluten intolerance). The majority of newly associated regions encode candidate genes with a clear functional role in T-cell regulation. Furthermore, the newly discovered risk loci, together with the well established HLA locus, account for less than 50% of the heritability of CD, suggesting that numerous additional loci remain undiscovered. Linkage studies have identified some well-replicated risk regions, most notably chromosome 5q31 and 11q23.

Methods

We have evaluated six candidate genes in one of these regions (11q23), namely CD3E, CD3D, CD3G, IL10RA, THY1 and IL18, as risk factors for CD using a 2-phase candidate gene approach directed at chromosome 11q. 377 CD cases and 349 ethnically matched controls were used in the initial screening, followed by an extended sample of 171 additional coeliac cases and 536 additional controls.

Results

Promotor SNPs (-607, -137) in the IL18 gene, which has shown association with several autoimmune diseases, initially suggested association with CD (P < 0.05). Follow-up analyses of an extended sample supported the same, moderate effect (P < 0.05) for one of these. Haplotype analysis of IL18-137/-607 also supported this effect, primarily due to one relatively rare haplotype IL18-607C/-137C (P < 0.0001), which was independently associated in two case-control comparisons. This same haplotype has been noted in rheumatoid arthritis.

Conclusion

Haplotypes of the IL18 promotor region may contribute to CD risk, consistent with this cytokine's role in maintaining inflammation in active CD.
Low level exposure to cadmium increases the risk of chronic kidney disease: analysis of the NHANES 1999-2006
Authors: Ferraro Pietro Manuel , Costanzi Stefano , Naticchia Alessandro , Sturniolo Antonio , Gambaro Giovanni
Published: June 2010

Background

Environmental factors have been associated with the outbreak of chronic kidney disease (CKD). We evaluated the association of Cadmium (Cd) exposure with the risk of CKD in U.S. adults who participated in the 1999-2006 National Health and Nutrition Examination Surveys (NHANES).

Methods

5426 subjects ≥ 20 years were stratified for values of urinary and blood Cd and a multivariate logistic regression was performed to test the association between blood and urinary Cd, CKD and albuminuria (ALB) after adjustment for age, gender, race/ethnicity, body mass index and smoking habits.

Results

Subjects with urinary Cd > 1 mcg/g and subjects with blood Cd > 1 mcg/L showed a higher association with ALB (OR 1.63, 95% CI 1.23, 2.16; P = 0.001). Subjects with blood Cd > 1 mcg/L showed a higher association with both CKD (OR 1.48, 95% CI 1.01, 2.17; P = 0.046) and ALB (OR 1.41, 95% CI 1.10, 1.82; P = 0.007). An interaction effect on ALB was found for high levels of urinary and blood Cd (P = 0.014).

Conclusions

Moderately high levels of urinary and blood Cd are associated with a higher proportion of CKD and ALB in the United States population.
Stable expression and phenotypic impact of attacin Etransgene in orchard grown apple trees over a 12 year period
Authors: Borejsza-Wysocka Ewa , Norelli John L , Aldwinckle Herb S , Malnoy Mickael
Published: June 2010

Background

Transgenic trees currently are being produced by Agrobacterium-mediated transformation and biolistics. The future use of transformed trees on a commercial basis depends upon thorough evaluation of the potential environmental and public health risk of the modified plants, transgene stability over a prolonged period of time and the effect of the gene on tree and fruit characteristics. We studied the stability of expression and the effect on resistance to the fire blight disease of the lytic protein gene, attacin E, in the apple cultivar 'Galaxy' grown in the field for 12 years.

Results

Using Southern and western blot analysis, we compared transgene copy number and observed stability of expression of this gene in the leaves and fruit in several transformed lines during a 12 year period. No silenced transgenic plant was detected. Also the expression of this gene resulted in an increase in resistance to fire blight throughout 12 years of orchard trial and did not affect fruit shape, size, acidity, firmness, weight or sugar level, tree morphology, leaf shape or flower morphology or color compared to the control.

Conclusion

Overall, these results suggest that transgene expression in perennial species, such as fruit trees, remains stable in time and space, over extended periods and in different organs. This report shows that it is possible to improve a desirable trait in apple, such as the resistance to a pathogen, through genetic engineering, without adverse alteration of fruit characteristics and tree shape.
An experimental and numerical study of the flow and mass transfer in a model of the wearable artificial kidney dialyzer
Authors: Rambod Edmond , Beizai Masoud , Rosenfeld Moshe
Published: June 2010

Background

Published studies of the past decades have established that mass transfer across the dialyzer membrane is governed by diffusion, convection and osmosis. While the former is independent of the pressure in the liquids, the latter two are pressure dependent and are enhanced when the pressure difference across the membrane is increased. The goal of the present study is to examine the impact of pulsatile flow on the transport phenomena across the membrane of a high-flux dialyzer in a wearable artificial kidney (WAK) with a novel single small battery-operated pulsatile pump that drives both the blood and dialysate in a counter-phased manner, maximizing the trans-membrane pressure.

Methods

Both in-vitro experimental and numerical tools are employed to compare the performance of the pulsatile WAK dialyzer with a traditional design of a single-channel roller blood pump together with a centrifugal pump that drives the dialysate flow. The numerical methods utilize the axisymmetric Navier-Stokes and mass transfer equations to model the flow in the fibers of the dialyzer.

Results

While diffusion is still the dominating transport regime, the WAK pump enhances substantially the trans-membrane pressure and thus increases mass convection that might be as high as 30% of the overall transfer. This increase is obtained due to the design of the pulsatile WAK pump that increases ultrafiltration by increasing the trans-membrane pressure.

Conclusions

The experimental and numerical results revealed that when pumping at similar flow rates, a small battery-operated pulsatile pump provides clearances of urea and creatinine similar as or better than a large heavy AC-powered roller pump.
A generalized physiologically-based toxicokinetic modeling system for chemical mixtures containing metals
Authors: Sasso Alan F , Isukapalli Sastry S , Georgopoulos Panos G
Published: June 2010

Background

Humans are routinely and concurrently exposed to multiple toxic chemicals, including various metals and organics, often at levels that can cause adverse and potentially synergistic effects. However, toxicokinetic modeling studies of exposures to these chemicals are typically performed on a single chemical basis. Furthermore, the attributes of available models for individual chemicals are commonly estimated specifically for the compound studied. As a result, the available models usually have parameters and even structures that are not consistent or compatible across the range of chemicals of concern. This fact precludes the systematic consideration of synergistic effects, and may also lead to inconsistencies in calculations of co-occurring exposures and corresponding risks. There is a need, therefore, for a consistent modeling framework that would allow the systematic study of cumulative risks from complex mixtures of contaminants.

Methods

A Generalized Toxicokinetic Modeling system for Mixtures (GTMM) was developed and evaluated with case studies. The GTMM is physiologically-based and uses a consistent, chemical-independent physiological description for integrating widely varying toxicokinetic models. It is modular and can be directly "mapped" to individual toxicokinetic models, while maintaining physiological consistency across different chemicals. Interaction effects of complex mixtures can be directly incorporated into the GTMM.

Conclusions

The application of GTMM to different individual metals and metal compounds showed that it explains available observational data as well as replicates the results from models that have been optimized for individual chemicals. The GTMM also made it feasible to model toxicokinetics of complex, interacting mixtures of multiple metals and nonmetals in humans, based on available literature information. The GTMM provides a central component in the development of a "source-to-dose-to-effect" framework for modeling population health risks from environmental contaminants. As new data become available on interactions of multiple chemicals, the GTMM can be iteratively parameterized to improve mechanistic understanding of human health risks from exposures to complex mixtures of chemicals.
Use of monoclonal antibodies against Hendra and Nipah viruses in an antigen capture ELISA
Authors: Chiang Cheng-Feng , Lo Michael K , Rota Paul A , Spiropoulou Christina F , Rollin Pierre E
Published: June 2010

Background

Outbreaks of Hendra (HeV) and Nipah (NiV) viruses have been reported starting in 1994 and 1998, respectively. Both viruses are capable of causing fatal disease in humans and effecting great economical loss in the livestock industry.

Results

Through screening of hybridomas derived from mice immunized with γ-irradiated Nipah virus, we identified two secreted antibodies; one reactive with the nucleocapsid (N) protein and the other, the phosphoprotein (P) of henipaviruses. Epitope mapping and protein sequence alignments between NiV and HeV suggest the last 14 amino acids of the carboxyl terminus of the N protein is the target of the anti-N antibody. The anti-P antibody recognizes an epitope in the amino-terminal half of P protein. These monoclonal antibodies were used to develop two antigen capture ELISAs, one for virus detection and the other for differentiation between NiV and HeV. The lower limit of detection of the capture assay with both monoclonal antibodies was 400 pfu. The anti-N antibody was used to successfully detect NiV in a lung tissue suspension from an infected pig.

Conclusion

The antigen capture ELISA developed is potentially affordable tool to provide rapid detection and differentiation between the henipaviruses.
A Novel Alternatively Spliced Isoform of the Mu-Opioid Receptor: Functional Antagonism
Authors: Gris Pavel , Gauthier Josee , Cheng Philip , Gibson Dustin G , Gris Denis , Laur Oskar , Pierson John , Wentworth Sean , Nackley Andrea G , Maixner William , Diatchenko Luda
Published: June 2010

Background:

Opioids are the most widely used analgesics for the treatment of clinical pain. They produce their therapeutic effects by binding to μ-opioid receptors (MORs), which are 7 transmembrane domain (7TM) G-protein-coupled receptors (GPCRs), and inhibiting cellular activity. However, the analgesic efficacy of opioids is compromised by side-effects such as analgesic tolerance, dependence and opioid-induced hyperalgesia (OIH). In contrast to opioid analgesia these side effects are associated with cellular excitation. Several hypotheses have been advanced to explain these phenomena, yet the molecular mechanisms underlying tolerance and OIH remain poorly understood.

Results:

We recently discovered a new human alternatively spliced isoform of MOR (MOR1K) that is missing the N-terminal extracellular and first transmembrane domains, resulting in a 6TM GPCR variant. To characterize the pattern of cellular transduction pathways activated by this human MOR1K isoform, we conducted a series of pharmacological and molecular experiments. Results show that stimulation of MOR1K with morphine leads to excitatory cellular effects. In contrast to stimulation of MOR1, stimulation of MOR1K leads to increased Ca2+levels as well as increased nitric oxide (NO) release. Immunoprecipitation experiments further reveal that unlike MOR1, which couples to the inhibitory Gαi/ocomplex, MOR1 K couples to the stimulatory Gαscomplex.

Conclusion:

The major MOR1 and the alternative MOR1K isoforms mediate opposite cellular effects in response to morphine, with MOR1K driving excitatory processes. These findings warrant further investigations that examine animal and human MORK1 expression and function following chronic exposure to opioids, which may identify MOR1K as a novel target for the development of new clinically effective classes of opioids that have high analgesic efficacy with diminished ability to produce tolerance, OIH, and other unwanted side-effects.
In search of traditional bio-ecological knowledge useful for fisheries co-management: the case of jaraquis Semaprochilodus spp. (Characiformes, Prochilodontidae) in Central Amazon, Brazil
Authors: Batista Vandick S , Lima Liane G
Published: June 2010

The jaraquis (Semaprochilodus spp.) are the most abundant group in the fishing landing in Manaus. However, just command and control management strategies have been used by the fishery governmental agency in the region without the power to enforce centralized decisions. The fishermen and their culture represent a source of information on dynamics of the resources and aquatic environments, fundamental in making possible the co-management of the fishing resources. The present study aims to contribute to management through identification of common information available in scientific and traditional knowledge about the jaraquis' bio-ecology. There were 57 semi-structured interviews recorded with fishermen of Manaus and rural areas of Manacapuru in 2002 concerning biological and ecological aspects. Similarity was observed between scientific and traditional knowledge in the following items: size of first sexual maturation, spawning type, parental care, trophic relationships and migratory behavior, as well as in some aspects of the mortality and growth of the species. However, there was less ethnoicthyological information on fecundity and the determination of the age and growth of adult fish. Common information would be used preferably by agencies to start an effective and technical dialogue with commercial and riverine fishermen to design management plans in a decentralized strategy.
Ordered structure of the transcription network inherited from the yeast whole-genome duplication
Authors: Fusco Diana , Grassi Luigi , Bassetti Bruno , Caselle Michele , Cosentino Lagomarsino Marco
Published: June 2010

Background

Gene duplication, a major evolutionary path to genomic innovation, can occur at the scale of an entire genome. One such "whole-genome duplication" (WGD) event among the Ascomycota fungi gave rise to genes with distinct biological properties compared to small-scale duplications.

Results

We studied the evolution of transcriptional interactions of whole-genome duplicates, to understand how they are wired into the yeast regulatory system. Our work combines network analysis and modeling of the large-scale structure of the interactions stemming from the WGD.

Conclusions

The results uncover the WGD as a major source for the evolution of a complex interconnected block of transcriptional pathways. The inheritance of interactions among WGD duplicates follows elementary "duplication subgraphs", relating ancestral interactions with newly formed ones. Duplication subgraphs are correlated with their neighbours and give rise to higher order circuits with two elementary properties: newly formed transcriptional pathways remain connected (paths are not broken), and are preferentially cross-connected with ancestral ones. The result is a coherent and connected "WGD-network", where duplication subgraphs are arranged in an astonishingly ordered configuration.
Decreased frequency and activated phenotype of blood CD27 IgD IgM B lymphocytes is a permanent abnormality in systemic lupus erythematosus patients
Authors: Rodríguez-Bayona Beatriz , Ramos-Amaya Ana , Pérez-Venegas José J , Rodríguez Carmen , Brieva José A
Published: June 2010

Introduction

Systemic lupus erythematosus (SLE) is characterized by B cell hyper-activation and auto-reactivity resulting in pathogenic auto-antibody generation. The phenotypic analysis of blood B cell subsets can be used to understand these alterations.

Methods

The combined detection of CD19, CD27 and IgD (or IgM) by flow cytometry (FC) analysis delineates five well-defined blood B cell-subsets: naive, switched (S) memory, double negative (DN) memory and CD27 IgD IgM (non-switched memory) B lymphocytes, and plasma cells (PCs). This phenotypic study was performed in 69 consecutive SLE patients and 31 healthy controls.

Results

SLE patients exhibited several abnormalities in the distribution of these B cell subsets, including elevated levels of DN memory B cells and PCs, and decreased CD27 IgD IgM B cells. Active SLE patients also showed decreased presence of S memory B cells and increased proportions of naive B lymphocytes. Nevertheless, when the patients in remission who did not require treatment were studied separately, the only remaining abnormality was a reduction of the CD27 IgD IgM B cell-subset detectable in most of these patients. The level of reduction of CD27 IgD IgM B cells was associated with elevated values of serum SLE auto-antibodies. Further analysis of this latter B cell-subset specifically showed increased expression of CD80, CD86, CD95, 9G4 idiotype and functional CXCR3 and CXCR4.

Conclusions

The presence of a reduced blood CD27 IgD IgM B cell-subset, exhibiting an activated state and enriched for auto-reactivity, is a consistent B cell abnormality in SLE. These findings suggest that CD27 IgD IgM B lymphocytes play a role in the pathogenesis of this disease.