bluuebunny/crossref_metadata_2025 huggingface dataset:
Upregulation of Glutathione Peroxidase Offsets Stretch-Induced Proatherogenic Gene Expression in Human Endothelial Cells
Authors: Wagner Andreas H. , Kautz Ocko , Fricke Kathrin , Zerr-Fouineau Murielle , Demicheva Elena , Güldenzoph Björn , Bermejo Justo Lorenzo , Korff Thomas , Hecker Markus
Published: September 2009

Objective—

Localization of atherosclerotic plaques typically correlates with areas of biomechanical strain where shear stress is decreased while stretch, thought to promote atherogenesis through enhanced oxidative stress, is increased.

Methods and Results—

In human cultured endothelial cells, nitric oxide synthase expression was exclusively shear stress–dependent whereas expression of glutathione peroxidase-1 (GPx-1), but not that of Cu
2+
/Zn
2+
-superoxide dismutase or Mn
2+
-superoxide dismutase, was upregulated solely in response to cyclic stretch. GPx-1 expression was also enhanced in isolated mouse arteries perfused at high pressure. Combined pharmacological and decoy oligodeoxynucleotide blockade revealed that activation of p38 MAP kinase followed by nuclear translocation of CCAAT/enhancer binding protein plays a pivotal role in stretch-induced GPx-1 expression in human endothelial cells. Antisense oligodeoxynucleotide knockdown of GPx-1 reinforced both their capacity to generate hydrogen peroxide and the transient stretch-induced expression of CD40, monocyte chemoatractant protein-1, and vascular cell adhesion molecule-1. Consequently, THP-1 monocyte adhesion to the GPx-1–depleted cells was augmented.

Conclusions—

Stretch-induced proatherosclerotic gene expression in human endothelial cells seems to be hydrogen peroxide-mediated. The concomitant rise in GPx-1 expression, but not that of other antioxidant enzymes, may comprise an adaptive mechanism through which the cells maintain their antiatherosclerotic properties in spite of a decreased bioavailability of nitric oxide.
p300 Plays a Critical Role in Maintaining Cardiac Mitochondrial Function and Cell Survival in Postnatal Hearts
Authors: Nakagawa Yasuaki , Kuwahara Koichiro , Takemura Genzo , Akao Masaharu , Kato Masashi , Arai Yuji , Takano Makoto , Harada Masaki , Murakami Masao , Nakanishi Michio , Usami Satoru , Yasuno Shinji , Kinoshita Hideyuki , Fujiwara Masataka , Ueshima Kenji , Nakao Kazuwa
Published: September 2009

Rationale
:

It is known that the transcriptional coactivator p300 is crucially involved in the differentiation and growth of cardiac myocytes during development. However, the physiological function of p300 in the postnatal hearts remains to be characterized.

Objective
:

We have now investigated the physiological function of p300 in adult hearts.

Methods and Results
:

We analyzed transgenic mice exhibiting cardiac-specific overexpression of a dominant-negative p300 mutant lacking the C/H3 domain (p300ΔC/H3 transgenic [TG] mice). p300ΔC/H3 significantly inhibited p300-induced activation of GATA- and myocyte enhancer factor 2-dependent promoters in cultured ventricular myocytes, and p300ΔC/H3-TG mice showed cardiac dysfunction that was lethal by 20 weeks of age. The numbers of mitochondria in p300ΔC/H3-TG myocytes were markedly increased, but the mitochondria were diminished in size. Moreover, cardiac mitochondrial gene expression, mitochondrial membrane potential and ATP contents were all significantly disrupted in p300ΔC/H3-TG hearts, suggesting that mitochondrial dysfunction contributes to the progression of the observed cardiomyopathy. Transcription of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α, a master regulator of mitochondrial gene expression, and its target genes was significantly downregulated in p300ΔC/H3-TG mice, and p300ΔC/H3 directly repressed myocyte enhancer factor 2C-dependent PGC-1α promoter activity and disrupted the transcriptional activity of PGC-1α in cultured ventricular myocytes. In addition, myocytes showing features of autophagy were observed in p300ΔC/H3-TG hearts.

Conclusions
:

Collectively, our findings suggest that p300 is essential for the maintenance of mitochondrial integrity and for myocyte survival in the postnatal left ventricular myocardium.
Noninvasive Assessment of Subclinical Atherosclerosis in Children and Adolescents
Authors: Urbina Elaine M. , Williams Richard V. , Alpert Bruce S. , Collins Ronnie T. , Daniels Stephen R. , Hayman Laura , Jacobson Marc , Mahoney Larry , Mietus-Snyder Michele , Rocchini Albert , Steinberger Julia , McCrindle Brian
Published: September 2009

Deterioration in endothelial function and arterial stiffness are early events in the development of cardiovascular diseases. In adults, noninvasive measures of atherosclerosis have become established as valid and reliable tools for refining cardiovascular risk to target individuals who need early intervention. With limited pediatric data, the use of these techniques in children and adolescents largely has been reserved for research purposes. Therefore, this scientific statement was written to (1) review the current literature on the noninvasive assessment of atherosclerosis in children and adolescents, (2) make recommendations for the standardization of these tools for research, and (3) stimulate further research with a goal of developing valid and reliable techniques with normative data for noninvasive clinical evaluation of atherosclerosis in pediatric patients. Precise and reliable noninvasive tests for atherosclerosis in youth will improve our ability to estimate future risk for heart attack and stroke. Currently, large longitudinal studies of cardiovascular risk factors in youth, such as the Bogalusa and Muscatine studies, lack sufficient adult subjects experiencing hard outcomes, such as heart attack and stroke, to produce meaningful risk scores like those developed from Framingham data.
The Impact of Valvular Oxidative Stress on the Development of Venous Stasis Ulcer Valvular Oxidative Stress and Venous Ulcers
Authors: Karatepe Oguzhan , Unal Orcun , Ugurlucan Murat , Kemik Ahu , Karahan Servet , Aksoy Murat , Kurtoglu Mehmet
Published: September 2009

Background: It is widely believed that venous ulcers result from venous insufficiency related to venous valve damages. To further investigate the pathogenesis of venous ulcers, we compared the influence of oxidative stress in venous valvular tissue on stasis ulcer formation in patients with venous ulcers secondary to superficial venous reflux disease. Methods: Thirty-nine consecutive patients with superficial venous reflux who underwent saphenectomy were included in the study. Patients were divided into 2 groups: with healed venous ulcers (group 1, n = 15) and without ulcers (group 2, n = 24). All patients were preoperatively evaluated with duplex ultrasound scanning and their blood samples were obtained to examine leukocyte count, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) levels. All patients underwent standard above-knee saphenectomy. Extracted saphenous vein segments were from the saphenofemoral junction, the first valve along. The biochemical analysis of the valve tissues included matrix metalloproteinase (MMP)-9, MMP-2, IL-6, TNF-α, superoxide dismutase (SOD), malondialdehyde (MDA), and nitric oxide (NO) studies. Results: There was no significant difference between patients in terms of age, gender, hospital stay, and preoperative blood levels of leukocyte, IL-6, TNF-α, and CRP (P > .05). Biochemical examination of valve tissue showed that the levels of MMP-9, MMP-2, IL-6, TNF-α, SOD, MDA, and NO in patients with healing venous ulcer were higher than those of the second group. Conclusion: A higher oxidative stress in the valvular tissue may contribute to venous stasis ulcer formation.
The Impact of Outliers on Cronbach’s Coefficient Alpha Estimate of Reliability: Ordinal/Rating Scale Item Responses
Authors: Liu Yan , Wu Amery D. , Zumbo Bruno D.
Published: September 2009

In a recent Monte Carlo simulation study, Liu and Zumbo showed that outliers can severely inflate the estimates of Cronbach’s coefficient alpha for continuous item response data—visual analogue response format. Little, however, is known about the effect of outliers for ordinal item response data—also commonly referred to as Likert, Likert-type, ordered categorical, or ordinal/rating scale item responses. Building on the work of Liu and Zumbo, the authors investigated the effects of outlier contamination for binary and ordinal response scales. Their results showed that coefficient alpha estimates were severely inflated with the presence of outliers, and like the earlier findings, the effects of outliers were reduced with increasing theoretical reliability. The efficiency of coefficient alpha estimates (i.e., sample-to-sample variation) was inflated as well and affected by the number of scale points. It is worth noting that when there were no outliers, the alpha estimates were downward biased because of the ordinal scaling. However, the alpha estimates were, in general, inflated in the presence of outliers leading to positive bias.
A Tale of Two Scales: Evaluating the Relationship Among Life Satisfaction, Social Capital, Income, and the Natural Environment at Individual and Neighborhood Levels in Metropolitan Baltimore
Authors: Vemuri Amanda W. , Morgan Grove J. , Wilson Matthew A. , Burch William R.
Published: September 2009

With the rapid growth of cities worldwide, there is a need to better understand factors contributing to life satisfaction in urban environments. Using data from a long-term study of the Baltimore metropolitan region, we build on existing social scientific literature to examine a suite of theoretical factors that have been proposed to explain higher life satisfaction. We find support for many previous theoretical arguments in the literature. Importantly, however, our findings reveal that these results are strikingly scale dependent. For individuals, higher incomes contribute to higher levels of satisfaction, yet social capital does not. For neighborhoods, more social capital strongly increases satisfaction, but higher incomes do not; and access to a clean natural environment always contributes to higher satisfaction, regardless of the scale of analysis. Given these findings, we conclude with the observation that future research must carefully match the “scale” of life satisfaction measurements with the explanatory variables used.
Investigating Mechanical Behaviors of Silica Nanoparticle Reinforced Composites
Authors: Tsai Jia-Lin , Hsiao Hung , Cheng Yi-Lieh
Published: September 2009

The research is aimed to investigate the mechanical behaviors of epoxy-based nanocomposites reinforced with spherical nanoparticles. Five different contents of silica nanoparticles — 5, 10, 15, 20, and 40 wt% — were introduced in the samples. Through a sol—gel technique, the silica particles with a diameter of 25 nm were exfoliated uniformly in the epoxy matrix. Experimental results obtained from tensile tests indicate that the modulus of nanocomposites increases with the increment of particulate inclusions, and the enhancing behavior is coincided with the model predictions obtained from the Mori—Tanaka micromechanical model. In addition, the fracture tests conducted on single-edge-notch bending specimens reveal that the inclusion of nanoparticles can effectively increase the fracture toughness of the nanocomposites. Furthermore, the extent of the enhancement is more appreciable in the brittle matrix system rather than in the ductile matrix system. Subsequently, by inserting the silica epoxy mixture into the unidirectional glass fiber through a vacuum hand lay-up process, the glass fiber/silica/epoxy composite samples were fabricated. Results depicted that the in-plane shear strength increases until the increment of particle loadings are up to 10 wt%. In addition, results obtained from the compression tests revealed that the glass/epoxy specimens with 20 wt% silica loading exhibit superior compressive strengths than those that do not contain any silica particles.
Neutrophil Response to Dental Plaque by Gender and Race
Authors: Wahaidi V.Y. , Dowsett S.A. , Eckert G.J. , Kowolik M.J.
Published: September 2009

The inflammatory response, which has both genetic and environmental components, is a central mechanism linking oral and systemic diseases. We hypothesized that dental plaque accumulation over 21 days in the experimental gingivitis model would elicit systemic inflammatory responses [change in white blood cell (WBC) count and neutrophil activity], and that these responses would differ by gender/race. We recruited 156 healthy young adults, including black and white males and females. Plaque Index (PI), Gingival Index (GI), systemic WBC counts, and peripheral neutrophil oxidative activity were recorded. Overall, 128 participants completed the study. During the experimental phase, the correlation between PI and GI was 0.79. Total WBC and neutrophil counts did not change. Neutrophil activity increased in blacks but not whites, suggesting that there may be racial differences in the inflammatory response to dental plaque accumulation.
Variable Cell Responses to P. gingivalis Lipopolysaccharide
Authors: Kocgozlu L. , Elkaim R. , Tenenbaum H. , Werner S.
Published: September 2009

Porphyromonas gingivalis is a major etiological agent of chronic periodontal diseases, the virulence of which has been attributed to different factors, including lipopolysaccharide (LPS). We investigated the differential responses induced by P. gingivalis LPS stimulation of human umbilical vein endothelial cells and human oral epithelial cells. RT-PCR analysis showed that P. gingivalis LPS used Toll-like receptor 2 (TLR2) to activate epithelial cells and Toll-like receptor 4 (TLR4) to activate endothelial cells. Both cell types were stimulated by P. gingivalis LPS to produce pro-inflammatory cytokines. Cytokine Array assay showed that although patterns of cytokine expression were similar in both cell types, some cytokines were specifically secreted by the endothelial cells, and others were specific to epithelial cells. These results support the idea that the same LPS preparation can act as a TLR2 or TLR4 agonist, depending on TLR expression of the host cell, inducing cytokine profiles that differ according to the cell type.
Biomimetic Remineralization of Resin-bonded Acid-etched dentin
Authors: Tay F.R. , Pashley D.H.
Published: September 2009

Degradation of denuded collagen within adhesive resin-infiltrated dentin is a pertinent problem in dentin bonding. A biomimetic remineralization scheme that incorporates non-classic crystallization pathways of fluidic amorphous nanoprecursors and mesoscopic transformation has been successful in remineralizing resin-free, acid-etched dentin, with evidence of intrafibrillar and interfibrillar remineralization. This study tested the hypothesis that biomimetic remineralization provides a means for remineralizing incompletely infiltrated resin-dentin interfaces created by etch-and-rinse adhesives. The remineralization medium consists of a Portland cement/simulated body fluid that includes polyacrylic acid and polyvinylphosphonic acid biomimetic analogs for amorphous calcium phosphate dimension regulation and collagen targeting. Both interfibrillar and intrafibrillar apatites became readily discernible within the hybrid layers after 2–4 months. In addition, intra-resin apatite clusters were deposited within the porosities of the adhesive resin matrices. The biomimetic remineralization scheme provides a proof-of-concept for the adoption of nanotechnology as an alternative strategy to extend the longevity of resin-dentin bonds.
Stress, support and well-being as perceived by probation trainees
Authors: Collins Stewart , Coffey Margaret , Cowe Francis
Published: September 2009

A study on stress, support and well-being was carried out with probation trainees ( n = 110). The study indicated that working as a probation trainee entailed high demands. Greater levels of demands were experienced by trainees with children and those undertaking part-time work. A large majority of trainees reported a high sense of personal accomplishment, had good self esteem, held positive attitudes towards themselves and enjoyed their work with offenders. Female trainees had significantly less positive attitudes towards themselves than males. Small, but significant numbers of trainees experienced problems with stress, well-being, low self-esteem, tiredness and emotional exhaustion. They might benefit from receiving more individual support, mutual group support and stress management courses. ‘Professional’ support opportunities from fellow students and practice development assessors were perceived as more important than from family or friends. There were some significant differences between trainees in their perceptions of support offered by Consortia and their tutors. Overall, there were no significant differences in relation to age or ethnicity.
Tracing Sexual Identities in “Old Age”: Gender and Seniority in Advice Literature of the Early-modern and Modern Periods
Authors: van Tilburg Marja
Published: September 2009

Thus far, historians have interpreted representations of elderly women with reference to women’s roles or to women’s positions in society.This article proposes a different approach toward gender: to relate representations of the aged to the sexual identities of both men and women. This article analyzes representations of old age in conduct books of the early-modern period and the nineteenth century. By drawing a comparison, the eighteenth-century change of “identity regime” in European culture is brought to the fore.The article points to the influence of sexual identities on the representations of senior persons in advice literature both in Dutch and translated into Dutch.
The Anatomy of the Medial Patellofemoral Ligament
Authors: Baldwin James L.
Published: September 2009

Background

Fibrous connections and fibrofatty tissue between the layers of the medial retinaculum have prevented accurate definition of the true anatomy of the medial patellofemoral ligament. This has led to confusion about the origin, form, course, and insertion of this structure.

Hypothesis

The medial patellofemoral ligament is a discrete structure that can be approached, isolated, and definitively described.

Study Design

Descriptive laboratory study.

Methods

Fifty fresh or fresh-frozen human knee specimens were carefully dissected to determine the precise anatomy of the medial patellofemoral ligament.

Results

Present in all specimens, the medial patellofemoral ligament was found to have 2 origins: (1) a transverse 10.6-mm origin from the bony groove between the medial epicondyle and the adductor tubercle, and (2) an oblique decussation originating from the proximal 30 mm of the leading edge of the superficial medial collateral ligament. The 2 origins combined and inseparably joined the vastus medialis obliquus tendon and inserted securely into the ventral edge of the bony patella over a span of 28.2 ± 5.6 mm adjacent to the articular surface of the patella. The length from the femoral origin to the patella was 59.8 ± 4.8 mm. The key to the dissection was finding the fine capsular vessels from the descending genicular artery that is between layers I and II of the medial retinacular structures.

Conclusion

The medial patellofemoral ligament is a constant structure in la‡yer II, with a complex anatomy that can be defined by careful dissection using the capsular branches of the descending genicular artery as a guide.

Clinical Relevance

This study provides essential new information that could help surgeons safely locate the medial patellofemoral ligament and repair or reconstruct it anatomically.
The Value of Using Radiographic Criteria for the Treatment of Persistent Symptomatic Olecranon Physis in Adolescent Throwing Athletes
Authors: Matsuura Tetsuya , Kashiwaguchi Shinji , Iwase Takenobu , Enishi Tetsuya , Yasui Natsuo
Published: September 2009

Background

Previously published reports present a variety of nonoperative and operative treatments for a persistent olecranon physis. However, the radiographic indication for the operative treatment is not clear.

Hypothesis

Our radiographic classification of persistent olecranon physis is helpful in formulating treatment decisions. Study Design: Cohort study; Level of evidence, 3.

Methods

Sixteen male baseball players with persistent olecranon physis were retrospectively evaluated. The mean age at first presentation was 14.7 years (range, 12-17 years). The lesion was classified into 2 stages based on radiographic appearance. Stage I demonstrated widening of the olecranon epiphyseal plate when compared with the contralateral elbow on the lateral view. Sclerotic change indicated stage II. All patients underwent nonoperative treatment for at least 3 months. Follow-up radiographs were taken at 1-month intervals. Operative treatment was provided to the patients whose condition had failed to improve after nonoperative treatment.

Results

Of the 16 patients, 12 had stage I lesions and 4 had stage II lesions. Nonoperative management produced healing in 91.7% of patients with stage I lesions and none of the patients with stage II lesions.

Conclusion

Our radiographic classification of persistent olecranon physis is useful for treatment decision making. In addition, our results demonstrated that sclerotic change is a high predictive indicator of the need for operative treatment.
Spirituality and Well-Being: The Relationship Between Religious Coping and Recovery From Sexual Assault
Authors: Ahrens Courtney E. , Abeling Samantha , Ahmad Sarah , Hinman Jessica
Published: September 2009

Despite a growing body of literature documenting beneficial outcomes of religious coping, there are virtually no studies examining sexual assault survivors’ use of religious coping. To fill this gap in the literature, the current study examines predictors and outcomes of positive and negative religious coping among 100 sexual assault survivors who believed in God. Results suggested that African American survivors were more likely to use both forms of religious coping than survivors from other ethnicities. Yet, results also suggest that positive religious coping is related to higher levels of psychological well-being and lower levels of depression, whereas negative religious coping is related to higher levels of depression, regardless of ethnicity. The only outcome where ethnicity makes a difference is posttraumatic growth with a stronger relationship between positive religious coping and posttraumatic growth among Caucasian survivors space. The implications of these findings for research and practice are discussed.
Comparison of genotoxic effect between smokeless tobacco (Maras powder) users and cigarette smokers by the alkaline comet assay
Authors: Sardas S , Cimen B , Karsli S , Yurdun T , Donbak L
Published: September 2009

Maras powder (MP) is a kind of smokeless tobacco used in the south-eastern region of Turkey and in several other countries of Middle and Far East. The present study was performed to assess the impacts of MP and cigarette smoking on the possible DNA damaging effect. Alkaline comet assay, which is a reliable and an important tool in human biomonitoring studies in the area of genetic toxicology, was used in peripheral lymphocytes of MP users, cigarette smokers, and non-smokers while their frequencies of total comet scores (TCS) were evaluated. The mean TCS (±SD) frequency in the peripheral lymphocytes was 14.4 (±10.04) for MP users and 8.26 (±5.38), 5.94 (±3.87) for cigarette smokers ( P < 0.05) and non-smoking control subjects, respectively ( P < 0.001). There was no significant effect of daily consumption of MP and the duration of MP usage on comet frequencies. In reply to a wrong belief among MP users (“the use of smokeless tobacco product is substantially less hazardous than cigarettes”), the present study shows that the oral use of smokeless tobacco represents a genotoxic hazard which is even higher than the DNA damage observed in cigarette smokers. Therefore, habitual use of MP should be taken into account and could be considered unsafe, equally harmful, and it should not be viewed as a safe alternative to cigarettes.
Protective effect of N-acetylcysteine on experimental chronic cadmium nephrotoxicity in immature female rats
Authors: Wang L , Chen D , Cao J , Liu Z
Published: September 2009

In the present study, female Sprague-Dawley rats received CdCl2 (50 mg/L through drinking water) and/or N-acetylcysteine (NAC, 120 mg/kg/day, orally) to investigate the protective effect of NAC on Cd-induced renal damage. Renal toxicity was evaluated by measuring the contents of total protein, β2-microglobulin, and α1-microglobulin in the urine and urinary enzyme markers of tubular necrosis, as well as levels of serum urea nitrogen and serum creatinine. Activities of antioxidant enzymes and contents of glutathione, malondialdehyde, and trace elements in the kidney were also measured. Animals that received both Cd and NAC showed a better renal function than those receiving Cd alone. In addition, NAC significantly reduced the levels of lipid peroxidation (LPO) in the kidney of cadmium-treated rats. The enzymic and nonenzymatic antioxidants levels are not restored, but their further decrease is prevented by NAC. Also NAC administration does not modify the urinary excretion of cadmium or contents of cadmium in the serum and kidney. In conclusion, NAC exerts its protective effect by decreased LPO and improving antioxidants status to prevent renal tubular damage induced by chronic Cd administration, most probably through its antioxidant properties.
The Gaming of Policy and the Politics of Gaming: A Review
Authors: Mayer Igor S.
Published: September 2009

This article examines the foundations of gaming and related concepts, such as policy exercises and serious gaming, in a public policy making context. Examining the relevant publications in Simulation & Gaming since 1969, the author looks back at the development of gaming simulation for purposes such as public policy analysis and planning, and reviews the underlying theories and empirical evidence. The author highlights the recognition that the success of gaming for policy making derives largely from the unique power of that gaming to capture and integrate both the technical-physical and the social-political complexities of policy problems.
Prevalence of Child Maltreatment in the Netherlands
Authors: Euser Eveline M. , van IJzendoorn Marinus H. , Prinzie Peter , Bakermans-Kranenburg Marian J.
Published: September 2009

The first nationwide prevalence study of child maltreatment in the Netherlands (NPM-2005) was designed as a replication of the National Incidence Studies (NISs) conducted in the United States. Child maltreatment cases were reported by 1,121 professionals from various occupational branches, trained in a detailed registration system of six types of abuse and neglect. In addition, cases registered by the Dutch Child Protection Services (CPS) were analyzed. For 2005, the overall prevalence rate was estimated to be 107,200 (95% CI 102,054-112,882) maltreated children aged 0-18 years, or 30 cases per 1,000 children. Neglect was the most prevalent type (56% of all cases) and sexual abuse had the lowest rate (4%). Of the maltreated children, 47% experienced more than one type of maltreatment. Major risk factors were very low parental education and unemployment. It is worrisome that CPS agencies only see the tip of the iceberg as only 12.6% of all maltreatment cases were reported to the CPS. Training of professionals in observing and reporting child maltreatment is badly needed. The absence of a legal obligation to report in the Netherlands needs reconsideration.
Opening and closing communicative space with teachers investigating race and racism in their own practice
Authors: Hyland Nora E.
Published: September 2009

This article explores the very practical challenges that the author experienced as she and a racially mixed elementary school teaching staff negotiated communicative space within a critical inquiry group exploring race and racism in their teaching context. Specifically, the author explores her role of critical friend as crucial to forming communicative space; the ways that communicative space was contested and challenged within the critical inquiry group; and the new communicative spaces that arose from the original group. This article offers implications for action researchers attempting to create communicative spaces around difficult issues such as race and racism.
Local communities empowered to plan?
Authors: Bodorkós Barbara , Pataki György
Published: September 2009

This article presents the second cycle of an ongoing participatory action research (PAR) project that aimed at facilitating bottom-up, sustainability planning and development in one of the most socio-economically disadvantageous micro-regions of Hungary. The process at the very beginning started as conventional qualitative research, and gradually emerged to a PAR process as deeper relationships with local people were developed and previous research practices and research focus were questioned. Current institutional changes, such as the availability of European Union funding for rural development and the micro-regional re-districting driven both by top-down and bottom-up processes, were structural factors that created a more promising context for participatory planning. Although a PAR project generally targets silenced groups, for this to happen it is arguably necessary to legitimize such development work in the eyes of local decision-makers and funding organizations, in order to establish more inclusive communicative spaces around future rural development. However, this also creates a controversial situation: breaking away from prevailing structural inequalities and hierarchies remains difficult through a process which is designed around consensus-building.
Cost analysis of an integrated care model in the management of acute exacerbations of chronic obstructive pulmonary disease
Authors: Bakerly N. Diar , Davies C. , Dyer M. , Dhillon P.
Published: September 2009

Home treatment models for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) proved to be a safe alternative to hospitalization. These models have the potential to free up resources; however, in the United Kingdom, it remains unclear to whether they provide cost savings compared with hospital treatment. Over a 12-month period from August 2003, 130 patients were selected for the integrated care group (total admissions with AECOPD = 546). These patients were compared with 95 retrospective controls in the hospital treatment group. Controls were selected from admissions during the previous 12 months (total of 662 admissions) to match the integrated care group in age, sex, and postal code. Resource use data were collected for both groups and compared using National Health Service (NHS) perspective for cost minimization analysis. In the integrated care group (130 patients), 107 (82%) patients received home support with average length of stay 3.3 (SD 3.9) days compared with 10.4 (SD 7.7) in the hospital group (95 patients). Average number of visits per patients in the integrated care group was 3.08 (SD = 0.95; 95% CI = 2.9—3.2). Cost per patient in the integrated care group was £1653 (95% CI, £1521—1802) compared with £2256 (95% CI, £2126— 2407) in the hospital group. The integrated care group resulted in cost saving of approximately £600 (P < 0.001) per patient. This integrated care model for the management of patients with AECOPD offered cost savings of £600 per patient over the conventional hospital treatment model using the new NHS tariff from an acute trust provider perspective.
Combined Botulinum Toxin Type A With Modified Constraint-Induced Movement Therapy for Chronic Stroke Patients With Upper Extremity Spasticity: A Randomized Controlled Study
Authors: Sun Shu-Fen , Hsu Chien-Wei , Sun Hsien-Pin , Hwang Chiao-Wen , Yang Chia-Lin , Wang Jue-Long
Published: September 2009

Background and objective . Botulinum toxin type A (BtxA) injection and modified constraint-induced movement therapy (mCIMT) are both promising approaches to enhance recovery after stroke. The combined application of these 2 promising modalities has rarely been studied. The aim was to investigate whether combined BtxA and mCIMT would improve spasticity and upper extremity motor function more than BtxA plus conventional rehabilitation in chronic stroke patients with upper extremity spasticity. Methods. In a prospective, randomized controlled, observer-blinded trial with 6-month follow-up, 32 patients (≥1 year after stroke) with ability to actively extend >10° at metacarpophalangeal and interphalangeal joints and 20° at wrist of the affected upper limb were randomized to receive BtxA + mCIMT (combination group) or BtxA + conventional rehabilitation (control group) for 2 hours/day, 3 days/week for 3 months.The primary outcome assessed spasticity on the Modified Ashworth Scale. Secondary outcomes assessed real-world arm function (Motor Activity Log), laboratory motor activity (Action Research Arm Test), and patients’ global satisfaction. Results. A total of 32 stroke patients were recruited, and 29 completed the study. Spasticity significantly improved in all subjects at 4 weeks and 3 months postinjection without between-group differences.The combination group showed significantly greater improvements in elbow, wrist, and finger spasticity ( P = .019, P = .019, and P < .001, respectively), affected upper extremity real-world arm function ( P < .001) and laboratory motor activity ( P < .001) than the control group at 6-month postinjection. Patients reported considerable satisfaction and no serious adverse events occurred. Conclusions. Combining BtxA and mCIMT is an effective and safe intervention for improving spasticity and motor function in chronic stroke patients. The results are promising enough to justify further studies. We recommend future research to address the likely need for including rehabilitation with BtxA to improve function in patients with poststroke spasticity.
The role and regulation of friend of GATA-1 (FOG-1) during blood development in the zebrafish
Authors: Amigo Julio D. , Ackermann Gabriele E. , Cope John J. , Yu Ming , Cooney Jeffrey D. , Ma Dongdong , Langer Nathaniel B. , Shafizadeh Ebrahim , Shaw George C. , Horsely Wyatt , Trede Nikolaus S. , Davidson Alan J. , Barut Bruce A. , Zhou Yi , Wojiski Sarah A. , Traver David , Moran Tyler B. , Kourkoulis George , Hsu Karl , Kanki John P. , Shah Dhvanit I. , Lin Hui Feng , Handin Robert I. , Cantor Alan B. , Paw Barry H.
Published: September 2009

The nuclear protein FOG-1 binds transcription factor GATA-1 to facilitate erythroid and megakaryocytic maturation. However, little is known about the function of FOG-1 during myeloid and lymphoid development or how FOG-1 expression is regulated in any tissue. We used in situ hybridization, gain- and loss-of-function studies in zebrafish to address these problems. Zebrafish FOG-1 is expressed in early hematopoietic cells, as well as heart, viscera, and paraspinal neurons, suggesting that it has multifaceted functions in organogenesis. We found that FOG-1 is dispensable for endoderm specification but is required for endoderm patterning affecting the expression of late-stage T-cell markers, independent of GATA-1. The suppression of FOG-1, in the presence of normal GATA-1 levels, induces severe anemia and thrombocytopenia and expands myeloid-progenitor cells, indicating that FOG-1 is required during erythroid/myeloid commitment. To functionally interrogate whether GATA-1 regulates FOG-1 in vivo, we used bioinformatics combined with transgenic assays. Thus, we identified 2 cis-regulatory elements that control the tissue-specific gene expression of FOG-1. One of these enhancers contains functional GATA-binding sites, indicating the potential for a regulatory loop in which GATA factors control the expression of their partner protein FOG-1.
E3 ligase–defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease
Authors: Bandi Srinivasa Rao , Brandts Christian , Rensinghoff Marion , Grundler Rebekka , Tickenbrock Lara , Köhler Gabriele , Duyster Justus , Berdel Wolfgang E. , Müller-Tidow Carsten , Serve Hubert ,   on behalf of the Study Alliance Leukemias, Sargin Bülent
Published: September 2009

Somatic mutations of Kit have been found in leukemias and gastrointestinal stromal tumors. The proto-oncogene c-Cbl negatively regulates Kit and Flt3 by its E3 ligase activity and acts as a scaffold. We recently identified the first c-Cbl mutation in human disease in an acute myeloid leukemia patient, called Cbl-R420Q. Here we analyzed the role of Cbl mutants on Kit-mediated transformation. Coexpression of Cbl-R420Q or Cbl-70Z with Kit induced cytokine-independent proliferation, survival, and clonogenic growth. Primary murine bone marrow retrovirally transduced with c-Cbl mutants and transplanted into mice led to a generalized mastocytosis, a myeloproliferative disease, and myeloid leukemia. Overexpression of these Cbl mutants inhibited stem cell factor (SCF)–induced ubiquitination and internalization of Kit. Both Cbl mutants enhanced the basal activation of Akt and prolonged the ligand-dependent activation. Importantly, transformation was observed also with kinase-dead forms of Kit and Flt3 in the presence of Cbl-70Z, but not in the absence of Kit or Flt3, suggesting a mechanism dependent on receptor tyrosine kinases, but independent of their kinase activity. Instead, transformation depends on the Src family kinase Fyn, as c-Cbl coimmunoprecipitated with Fyn and inhibition abolished transformation. These findings may explain primary resistance to tyrosine kinase inhibitors targeted at receptor tyrosine kinases.
Acute ablation of PERK results in ER dysfunctions followed by reduced insulin secretion and cell proliferation
Authors: Feng Daorong , Wei Jianwen , Gupta Sounak , McGrath Barbara C , Cavener Douglas R
Published: September 2009

Background

A deficiency in Perk (EIF2AK3) causes multiple neonatal defects in humans known as the Wolcott Rallison syndrome. Perk KO mice exhibit the same array of defects including permanent neonatal diabetes (PND). PND in mice was previously shown by us to be due to a decrease in beta cell proliferation and insulin secretion. The aim of this study was to determine if acute ablation of PERK in the 832/13 beta cells recapitulates these defects and to identify the primary molecular basis for beta cell dysfunction.

Results

The INS1 832/13 transformed rat beta cell line was transduced with a dominant-negative Perk transgene via an adenoviral vector. AdDNPerk-832/13 beta cells exhibited reduced expression of insulin and MafA mRNAs, reduced insulin secretion, and reduced cell proliferation. Although proinsulin content was reduced in AdDNPerk-832/13 beta cells, proinsulin was abnormally retained in the endoplasmic reticulum. A temporal study of the acute ablation of Perk revealed that the earliest defect seen was induced expression of two ER chaperone proteins, GRP78/BiP and ERp72. The oxidized states of ERp72 and ERp57 were also increased suggesting an imbalance in the redox state of the ER.

Conclusion

Acute ablation of Perk in INS 832/13 beta cells exhibited all of the major defects seen in Perk KO mice and revealed abnormal expression and redox state of key ER chaperone proteins. Dysregulation of ER chaperone/folding enzymes ERp72 and GRP78/BiP occurred early after ablation of PERK function suggesting that changes in ER secretory functions may give rise to the other defects including reduced insulin gene expression, secretion, and cell proliferation.
Rapid high-throughput analysis of DNaseI hypersensitive sites using a modified Multiplex Ligation-dependent Probe Amplification approach
Authors: Ohnesorg Thomas , Eggers Stefanie , Leonhard Wouter N , Sinclair Andrew H , White Stefan J
Published: September 2009

Background

Mapping DNaseI hypersensitive sites is commonly used to identify regulatory regions in the genome. However, currently available methods are either time consuming and laborious, expensive or require large numbers of cells. We aimed to develop a quick and straightforward method for the analysis of DNaseI hypersensitive sites that overcomes these problems.

Results

We have developed a modified Multiplex Ligation-dependent Probe Amplification (MLPA) approach for the identification and analysis of genomic regulatory regions. The utility of this approach was demonstrated by simultaneously analysing 20 loci from the ENCODE project for DNaseI hypersensitivity in a range of different cell lines. We were able to obtain reproducible results with as little as 5 × 104 cells per DNaseI treatment. Our results broadly matched those previously reported by the ENCODE project, and both technical and biological replicates showed high correlations, indicating the sensitivity and reproducibility of this method.

Conclusion

This new method will considerably facilitate the identification and analysis of DNaseI hypersensitive sites. Due to the multiplexing potential of MLPA (up to 50 loci can be examined) it is possible to analyse dozens of DNaseI hypersensitive sites in a single reaction. Furthermore, the high sensitivity of MLPA means that fewer than 105 cells per DNaseI treatment can be used, allowing the discovery and analysis of tissue specific regulatory regions without the need for pooling. This method is quick and easy and results can be obtained within 48 hours after harvesting of cells or tissues. As no special equipment is required, this method can be applied by any laboratory interested in the analysis of DNaseI hypersensitive regions.
Salivary cotinine concentrations in daily smokers in Barcelona, Spain: a cross-sectional study
Authors: Fu Marcela , Fernandez Esteve , Martínez-Sánchez Jose M , Pascual José A , Schiaffino Anna , Agudo Antoni , Ariza Carles , Borràs Josep M , Samet Jonathan M ,   the DCOT Study investigators
Published: September 2009

Background

Characterizing and comparing the determinant of cotinine concentrations in different populations should facilitate a better understanding of smoking patterns and addiction. This study describes and characterizes determinants of salivary cotinine concentration in a sample of Spanish adult daily smoker men and women.

Methods

A cross-sectional study was carried out between March 2004 and December 2005 in a representative sample of 1245 people from the general population of Barcelona, Spain. A standard questionnaire was used to gather information on active tobacco smoking and passive exposure, and a saliva specimen was obtained to determine salivary cotinine concentration. Two hundred and eleven adult smokers (>16 years old) with complete data were included in the analysis. Determinants of cotinine concentrations were assessed using linear regression models.

Results

Salivary cotinine concentration was associated with the reported number of cigarettes smoked in the previous 24 hours (R2= 0.339; p < 0.05). The inclusion of a quadratic component for number of cigarettes smoked in the regression analyses resulted in an improvement of the fit (R2= 0.386; p < 0.05). Cotinine concentration differed significantly by sex, with men having higher levels.

Conclusion

This study shows that salivary cotinine concentration is significantly associated with the number of cigarettes smoked and sex, but not with other smoking-related variables.
Prediction of outcome of non-small cell lung cancer patients treated with chemotherapy and bortezomib by time-course MALDI-TOF-MS serum peptide profiling
Authors: Voortman Johannes , Pham Thang V , Knol Jaco C , Giaccone Giuseppe , Jimenez Connie R
Published: September 2009

Background

Only a minority of patients with advanced non-small cell lung cancer (NSCLC) benefit from chemotherapy. Serum peptide profiling of NSCLC patients was performed to investigate patterns associated with treatment outcome.

Using magnetic bead-assisted serum peptide capture coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), serum peptide mass profiles of 27 NSCLC patients treated with cisplatin-gemcitabine chemotherapy and bortezomib were obtained. Support vector machine-based algorithms to predict clinical outcome were established based on differential pre-treatment peptide profiles and dynamic changes in peptide abundance during treatment.

Results

A 6-peptide ion signature distinguished with 82% accuracy, sensitivity and specificity patients with a relatively short vs. long progression-free survival (PFS) upon treatment. Prediction of long PFS was associated with longer overall survival. Inclusion of 7 peptide ions showing differential changes in abundance during treatment led to a 13-peptide ion signature with 86% accuracy at 100% sensitivity and 73% specificity. A 5-peptide ion signature could separate patients with a partial response vs. non-responders with 89% accuracy at 100% sensitivity and 83% specificity. Differential peptide profiles were also found when comparing the NSCLC serum profiles to those from cancer-free control subjects.

Conclusion

This study shows that serum peptidome profiling using MALDI-TOF-MS coupled to pattern diagnostics may aid in prediction of treatment outcome of advanced NSCLC patients treated with chemotherapy.
Glypican-1 controls brain size through regulation of fibroblast growth factor signaling in early neurogenesis
Authors: Jen Yi-Huei Linda , Musacchio Michele , Lander Arthur D
Published: September 2009

Background

Cell surface heparan sulfate proteoglycans (HSPGs) act as co-receptors for multiple families of growth factors that regulate animal cell proliferation, differentiation and patterning. Elimination of heparan sulfate during brain development is known to produce severe structural abnormalities. Here we investigate the developmental role played by one particular HSPG, glypican-1 (Gpc1), which is especially abundant on neuronal cell membranes, and is the major HSPG of the adult rodent brain.

Results

Mice with a null mutation in Gpc1 were generated and found to be viable and fertile. The major phenotype associated with Gpc1 loss is a highly significant reduction in brain size, with only subtle effects on brain patterning (confined to the anterior cerebellum). The brain size difference emerges very early during neurogenesis (between embryonic days 8.5 and 9.5), and remains roughly constant throughout development and adulthood. By examining markers of different signaling pathways, and the differentiation behaviors of cells in the early embryonic brain, we infer that Gpc1-/- phenotypes most likely result from a transient reduction in fibroblast growth factor (FGF) signaling. Through the analysis of compound mutants, we provide strong evidence that Fgf17 is the FGF family member through which Gpc1 controls brain size.

Conclusion

These data add to a growing literature that implicates the glypican family of HSPGs in organ size control. They also argue that, among heparan sulfate-dependent signaling molecules, FGFs are disproportionately sensitive to loss of HSPGs. Finally, because heterozygous Gpc1 mutant mice were found to have brain sizes half-way between homozygous and wild type, the data imply that endogenous HSPG levels quantitatively control growth factor signaling, a finding that is both novel and relevant to the general question of how the activities of co-receptors are exploited during development.