bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological distress measured by the GHQ-12 and mortality: A prospective population-based study
Authors: Puustinen Pekka Johannes , Koponen Hannu , Kautiainen Hannu , Mäntyselkä Pekka , Vanhala Mauno
Published: July 2011

Aims: To examine whether persons with psychological distress have a greater risk of all-cause mortality in the Scandinavian population; whether this association is gender-specific; and what is the influence of socioeconomic status, body mass index (BMI) and health behaviour in this association. Methods: A total of 923 (414 male and 509 female) people, aged 36 to 56 years, participated in a population-based study from 1997—98 in Pieksämäki, Finland. Psychological distress was measured using the 12-item General Health Questionnaire (GHQ-12). The GHQ-12 points were summed to a global score ranging from 0—12. Mortality data until 31 December 2009 were drawn from the national mortality register. Results: There were 44 death events (27 men, 17 women) during the mean observation time of 11 years. The hazard ratio (HR) increased by 16% for every GHQ-12 point (gender and age adjusted HR 1.16, 95% confidence interval (95% CI): 1.07—1.25, p < 0.001). In the fully adjusted model with gender, age, socioeconomic status, BMI, smoking and physical activity, HR was 1.13 (95% CI: 1.04—1.22, p = 0.003). In men, the 10-year survival for distressed (GHQ-12 score ≥4) participants was 84% (95% CI: 73— 91) and for non-distressed (GHQ-12 score 0—3) participants it was 96% (95% CI: 93—97), HR = 3.38 (95% CI: 1.55—7.39, p = 0.002). Among women, no significant association was found. Conclusions: Psychological distress measured by the GHQ-12 is associated with all-cause mortality risk during an 11-year observation time. This is mainly due to excess mortality among distressed men.
Do informal caregivers in mental illness feel more burdened? A comparative study of mental versus somatic illnesses
Authors: Hastrup Lene H. , Van Den Berg Bernard , Gyrd-Hansen Dorte
Published: July 2011

Aims: This study investigates a possible added subjective burden among informal caregivers to care recipients with a mental illness or a combination of mental and somatic illnesses compared with caregivers to care recipients with a somatic illness. The study also investigates the subjective caregiver burden by caregivers’ characteristics and objective burden. Methods: The association between subjective caregiver burden and socio-demographic factors, objective burden, and health-related quality of life was analyzed in a population of 865 Dutch informal caregivers, using multiple linear regression analysis. Results: Controlling for other factors in the analysis, we found that caring for a recipient with mental illness or a combination of mental and somatic illness was associated with an extra subjective caregiver burden (measured by Caregiver Strain Index). Objective burden, in terms of more than 50 hours of care provision per week, less than three years of caregiving, or living together with the care recipients was associated with higher subjective caregiver burden. Other factors associated with higher subjective caregiver burden were being partners or a child of care recipient, having a paid job, a low health-related quality of life (EQ-5D), or having an illness. Conclusions: This study suggests that caregivers to care recipients with a mental and especially a combination of mental and somatic illnesses have a higher subjective caregiver burden compared with caregivers to care recipients with a somatic illness. Because the study is not representative of all caregivers, more research focusing on identifying and contacting informal caregivers is needed to confirm the result.
The development of an empirical model for regional public health reporting. A descriptive study in two Dutch pilot regions
Authors: Van Bon-Martens M.J.H. , Van De Goor L.A.M. , Achterberg P.W. , Van Oers J.A.M.
Published: July 2011

Aim: To develop and describe an empirical model for regional public health reporting, based on the model and experience of the Dutch national Public Health Status and Forecasts (PHSF) as well as on relevant theories and literature. Methods: Three basic requirements were chosen in a preparatory feasibility study: the products to be developed, the project organization of the pilot study, and a regional elaboration of the conceptual model of the national PHSF. Subsequently, from November 2005 to June 2007, a regional PHSF was developed in two Dutch pilot regions, to serve as a base for the empirical model for regional public health reporting. Results: The developed empirical regional PHSF model consists of different products for different purposes and target groups. Regional and Municipal Reports aim to underpin strategic regional and local public health policy. Websites contain up-to-date information, aiming to underpin tactical regional and local public health policy by providing building blocks for translating strategic policy priorities into concrete plans of action. Numerous stakeholders are involved in the development of a regional PHSF. The developed empirical process model for a regional PHSF connects to the theoretical framework in which interaction between researchers and policymakers is an important condition for the use of research data in public health policy. Conclusions: The empirical model for a regional PHSF can be characterized by its 1) products, 2) content and design, and 3) underlying process and organization. This empirical model can be seen as a first step in the direction of a generic model for regional public health reporting.
Role perceptions of senior politicians’ wives in Israel
Authors: Simon Sara , Zach Sima , Oglesby Carole , Bar-Eli Michael
Published: July 2011

This investigation examined how wives of senior politicians perceived their role as the spouse of a politician, and how this perception affected their lives. Ten wives of Israeli senior politicians participated in the study. Semi-structured, in-depth interviews were conducted individually, with topics and issues specified in advance. Results demonstrated an inherent structural conflict between the personal and the public aspects of the role of ‘politician’s wife’. The lifestyle of the participants influenced their perception of their roles and they reported a selection by preference of the roles that best fit their existing lifestyle. Four different attitudes relating to the women’s roles and lifestyles emerged from their personal stories. Findings were interpreted in terms of the preference approach.
A metapsychological exploration of the role of popular media in engineering public belief on planning issues
Authors: Gunder Michael
Published: July 2011

The article considers how planning, in its various dimensions of engagement with popular communication media, plays an important role in helping to ideologically constitute a polity’s desired spatial reality. In doing so it will consider the historical deployment in public relations of psychoanalytical theory to facilitate the construction of public issues and beliefs, as well as to engineer consent for planning and related policy. The article will consider the role of contemporary media in shaping public aspirations as to what is desired for the future of our cities and settlements. The article will conclude that psychoanalytical insight gives us one effective handle from which to begin to understand planning’s ideologically shaping role in the formulation of our desires for our future communities.
Psychometric Analysis of the Diagnostic Evaluation of Language Variation Assessment
Authors: Petscher Yaacov , Connor Carol McDonald , Al Otaiba Stephanie
Published: July 2011

This study investigated the psychometrics of the Diagnostic Evaluation of Language Variation–Screening Test (DELV-S) test using confirmatory factor analysis, item response theory, and differential item functioning (DIF). Responses from 1,764 students in kindergarten through second grade were used in the study, with results indicating that the DELV-S is multidimensional and measures syntactic skills and nonword repetition ability. Item response theory suggested that most items were easy and that the measured skills were most reliable for students who had low language abilities. Standardized effect sizes for DIF suggested small differences existed on syntactic skills between white and minority students. Scores were vertically scaled to produce reference tables to assess performance at specific points in time, as well as growth over time.
Psychometric Properties of Maze Tasks in Middle School Students
Authors: Tolar Tammy D. , Barth Amy E. , Francis David J. , Fletcher Jack M. , Stuebing Karla K. , Vaughn Sharon
Published: July 2011

Maze tasks have appealing properties as progress-monitoring tools, but there is a need for a thorough examination of the psychometric properties of Maze tasks among middle school students. We evaluated form effects, reliability, validity, and practice effects of Maze among students in Grades 6 through 8. We administered the same (familiar) and novel Maze passages for progress monitoring of a reading intervention among typical readers ( n = 588), struggling readers receiving researcher-provided intervention ( n = 471), and struggling readers not receiving intervention ( n = 284). Form effects accounted for significant variance in Maze performance. Familiar passages had greater test–retest reliability than novel passages. Both administrative conditions had similar, moderate correlations (validity coefficients) with other measures of reading fluency and comprehension. There were also significant practice effects. Students who read the same passage showed steeper slopes in Maze performance than students who read different passages over time. Practice effects were influenced by beginning levels of reading comprehension and by intervention status.
Development of Conceptually Focused Early Numeracy Skill Indicators
Authors: Methe Scott A. , Begeny John C. , Leary Lemontrel L.
Published: July 2011

This research was conducted to evaluate the technical properties of a set of early numeracy CBM tests that were designed to operationalize early numeric concepts. Data were collected over the course of a school year from 113 kindergarten and first-grade children using nine separate tests with three alternative forms. In addition, test–retest reliability was examined. Correlational design methods were used to examine the consistency of the tests as well as their relation to criterion measures. Receiver operating characteristic (ROC) curves were also generated and inspected to examine diagnostic accuracy. Results indicated that two tests demonstrated strong technical properties across all three analyses, and an additional two demonstrated promise. Methodological improvements to test procedures should be addressed in future research, and linking assessment to intervention can be facilitated using tests developed in the current study.
A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q
Authors: Fenaux Pierre , Giagounidis Aristoteles , Selleslag Dominik , Beyne-Rauzy Odile , Mufti Ghulam , Mittelman Moshe , Muus Petra , te Boekhorst Peter , Sanz Guillermo , del Cañizo Consuelo , Guerci-Bresler Agnes , Nilsson Lars , Platzbecker Uwe , Lübbert Michael , Quesnel Bruno , Cazzola Mario , Ganser Arnold , Bowen David , Schlegelberger Brigitte , Aul Carlo , Knight Robert , Francis John , Fu Tommy , Hellström-Lindberg Eva ,   for the MDS-004 Lenalidomide del5q Study Group
Published: July 2011

This phase 3, randomized, double-blind study assessed the efficacy and safety of lenalidomide in 205 red blood cell (RBC) transfusion-dependent patients with International Prognostic Scoring System Low-/Intermediate-1-risk del5q31 myelodysplastic syndromes. Patients received lenalidomide 10 mg/day on days 1-21 (n = 69) or 5 mg/day on days 1-28 (n = 69) of 28-day cycles; or placebo (n = 67). Crossover to lenalidomide or higher dose was allowed after 16 weeks. More patients in the lenalidomide 10- and 5-mg groups achieved RBC-transfusion independence (TI) for ≥ 26 weeks (primary endpoint) versus placebo (56.1% and 42.6% vs 5.9%; both P < .001). Median duration of RBC-TI was not reached (median follow-up, 1.55 years), with 60% to 67% of responses ongoing in patients without progression to acute myeloid leukemia (AML). Cytogenetic response rates were 50.0% (10 mg) versus 25.0% (5 mg; P = .066). For the lenalidomide groups combined, 3-year overall survival and AML risk were 56.5% and 25.1%, respectively. RBC-TI for ≥ 8 weeks was associated with 47% and 42% reductions in the relative risks of death and AML progression or death, respectively (P = .021 and .048). The safety profile was consistent with previous reports. Lenalidomide is beneficial and has an acceptable safety profile in transfusion-dependent patients with Low-/Intermediate-1-risk del5q myelodysplastic syndrome. This trial was registered at www.clinicaltrials.gov as #NCT00179621.
The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3K14 and required for fetal liver erythropoiesis
Authors: Mishima Yuta , Miyagi Satoru , Saraya Atsunori , Negishi Masamitsu , Endoh Mitsuhiro , Endo Takaho A. , Toyoda Tetsuro , Shinga Jun , Katsumoto Takuo , Chiba Tetsuhiro , Yamaguchi Naoto , Kitabayashi Issay , Koseki Haruhiko , Iwama Atsushi
Published: July 2011

The histone acetyltransferases (HATs) of the MYST family include TIP60, HBO1, MOZ/MORF, and MOF and function in multisubunit protein complexes. Bromodomain-containing protein 1 (BRD1), also known as BRPF2, has been considered a subunit of the MOZ/MORF H3 HAT complex based on analogy with BRPF1 and BRPF3. However, its physiologic function remains obscure. Here we show that BRD1 forms a novel HAT complex with HBO1 and regulates erythropoiesis. Brd1-deficient embryos showed severe anemia because of impaired fetal liver erythropoiesis. Biochemical analyses revealed that BRD1 bridges HBO1 and its activator protein, ING4. Genome-wide mapping in erythroblasts demonstrated that BRD1 and HBO1 largely colocalize in the genome and target key developmental regulator genes. Of note, levels of global acetylation of histone H3 at lysine 14 (H3K14) were profoundly decreased in Brd1-deficient erythroblasts and depletion of Hbo1 similarly affected H3K14 acetylation. Impaired erythropoiesis in the absence of Brd1 accompanied reduced expression of key erythroid regulator genes, including Gata1, and was partially restored by forced expression of Gata1. Our findings suggest that the Hbo1-Brd1 complex is the major H3K14 HAT required for transcriptional activation of erythroid developmental regulator genes.
Diagnostic approach to pulmonary embolism and lessons from a busy acute assessment unit in the UK
Authors: Hamad M.M.A. , Bhatia P. , Ellidir E. , Abdelaziz M.M. , Connolly V.
Published: July 2011

The diagnosis of pulmonary embolism (PE) can be very elusive and, if missed, may have fatal consequences. Conversely, PE can be over-diagnosed, with the concomitant risks associated with unnecessary anticoagulation. Although there are many tests that used in the diagnosis of PE, no test can exclude this condition with 100% certainty, and PE has been reported even after a negative pulmonary angiography. The diagnosis of PE depends on the interpretation of the available tests in the context of pre-test clinical probabilities. Ventilation/perfusion (V′/Q′) scan and computerised tomographic pulmonary angiography (CTPA) are the main screening tests used for patients with suspected PE. However, bothV′/Q′ scan and CTPA have to be supplemented by other diagnostic modalities because of their diagnostic limitations. This article reviews the literature concerning the diagnosis of PE, with particular reference to the approach in our acute assessment unit. We conclude by describing two learning points from real cases presenting with suspected PE, in order to highlight how the diagnosis can be missed or made inaccurately.
Bronchoscopic techniques in diagnosis and staging of lung cancer
Authors: Herth F.J.F.
Published: July 2011

Technologic advances in bronchoscopy continue to improve our ability to perform minimally invasive, accurate evaluations of the tracheobronchial tree and to perform an ever-increasing array of diagnostic, therapeutic, and palliative interventions. The role of both “old” and “new” diagnostic bronchoscopy will continue to evolve as further improvements are made in bronchoscopes, accessory equipment, and imaging technologies. The major challenge in the adoption of the many new bronchoscopic techniques into routine clinical practice is the need for well-designed studies to delineate the appropriate use of these interventions and to better define their limitations.
Antioxidant components of naturally-occurring oils exhibit marked anti-inflammatory activity in epithelial cells of the human upper respiratory system
Authors: Gao Meixia , Singh Anju , Macri Kristin , Reynolds Curt , Singhal Vandana , Biswal Shyam , Spannhake Ernst W
Published: July 2011

Background

The upper respiratory tract functions to protect lower respiratory structures from chemical and biological agents in inspired air. Cellular oxidative stress leading to acute and chronic inflammation contributes to the resultant pathology in many of these exposures and is typical of allergic disease, chronic sinusitis, pollutant exposure, and bacterial and viral infections. Little is known about the effective means by which topical treatment of the nose can strengthen its antioxidant and anti-inflammatory defenses. The present study was undertaken to determine if naturally-occurring plant oils with reported antioxidant activity can provide mechanisms through which upper respiratory protection might occur.

Methods

Controlled exposure of the upper respiratory system to ozone and nasal biopsy were carried out in healthy human subjects to assess mitigation of the ozone-induced inflammatory response and to assess gene expression in the nasal mucosa induced by a mixture of five naturally-occurring antioxidant oils - aloe, coconut, orange, peppermint and vitamin E. Cells of the BEAS-2B and NCI-H23 epithelial cell lines were used to investigate the source and potential intracellular mechanisms of action responsible for oil-induced anti-inflammatory activity.

Results

Aerosolized pretreatment with the mixed oil preparation significantly attenuated ozone-induced nasal inflammation. Although most oil components may reduce oxidant stress by undergoing reduction, orange oil was demonstrated to have the ability to induce long-lasting gene expression of several antioxidant enzymes linked to Nrf2, including HO-1, NQO1, GCLm and GCLc, and to mitigate the pro-inflammatory signaling of endotoxin in cell culture systems. Nrf2 activation was demonstrated. Treatment with the aerosolized oil preparation increased baseline levels of nasal mucosal HO-1 expression in 9 of 12 subjects.

Conclusions

These data indicate that selected oil-based antioxidant preparations can effectively reduce inflammation associated with oxidant stress-related challenge to the nasal mucosa. The potential for some oils to activate intracellular antioxidant pathways may provide a powerful mechanism through which effective and persistent cytoprotection against airborne environmental exposures can be provided in the upper respiratory mucosa.
Modeling measurement error in tumor characterization studies
Authors: Rakovski Cyril , Weisenberger Daniel J , Marjoram Paul , Laird Peter W , Siegmund Kimberly D
Published: July 2011

Background

Etiologic studies of cancer increasingly use molecular features such as gene expression, DNA methylation and sequence mutation to subclassify the cancer type. In large population-based studies, the tumor tissues available for study are archival specimens that provide variable amounts of amplifiable DNA for molecular analysis. As molecular features measured from small amounts of tumor DNA are inherently noisy, we propose a novel approach to improve statistical efficiency when comparing groups of samples. We illustrate the phenomenon using the MethyLight technology, applying our proposed analysis to compare MLH1 DNA methylation levels in males and females studied in the Colon Cancer Family Registry.

Results

We introduce two methods for computing empirical weights to model heteroscedasticity that is caused by sampling variable quantities of DNA for molecular analysis. In a simulation study, we show that using these weights in a linear regression model is more powerful for identifying differentially methylated loci than standard regression analysis. The increase in power depends on the underlying relationship between variation in outcome measure and input DNA quantity in the study samples.

Conclusions

Tumor characteristics measured from small amounts of tumor DNA are inherently noisy. We propose a statistical analysis that accounts for the measurement error due to sampling variation of the molecular feature and show how it can improve the power to detect differential characteristics between patient groups.
Statistical Mutation Calling from Sequenced Overlapping DNA Pools in TILLING Experiments
Authors: Missirian Victor , Comai Luca , Filkov Vladimir
Published: July 2011

Background

TILLING (Targeting induced local lesions IN genomes) is an efficient reverse genetics approach for detecting induced mutations in pools of individuals. Combined with the high-throughput of next-generation sequencing technologies, and the resolving power of overlapping pool design, TILLING provides an efficient and economical platform for functional genomics across thousands of organisms.

Results

We propose a probabilistic method for calling TILLING-induced mutations, and their carriers, from high throughput sequencing data of overlapping population pools, where each individual occurs in two pools. We assign a probability score to each sequence position by applying Bayes' Theorem to a simplified binomial model of sequencing error and expected mutations, taking into account the coverage level. We test the performance of our method on variable quality, high-throughput sequences from wheat and rice mutagenized populations.

Conclusions

We show that our method effectively discovers mutations in large populations with sensitivity of 92.5% and specificity of 99.8%. It also outperforms existing SNP detection methods in detecting real mutations, especially at higher levels of coverage variability across sequenced pools, and in lower quality short reads sequence data. The implementation of our method is available from: http://www.cs.ucdavis.edu/~filkov/CAMBa/.
Cellular Expression of Smarca4 (Brg1)-regulated Genes in Zebrafish Retinas
Authors: Hensley Monica R , Emran Farida , Bonilla Sylvia , Zhang Liyun , Zhong Wenxuan , Grosu Paul , Dowling John E , Leung Yuk Fai
Published: July 2011

Background

In a recent genomic study, Leung et al. used a factorial microarray analysis to identify Smarca4 (Brg1)-regulated genes in micro-dissected zebrafish retinas. Two hundred and fifty nine genes were grouped in three-way ANOVA models which carried the most specific retinal change. To validate the microarray results and to elucidate cellular expression patterns of the significant genes for further characterization, 32 known genes were randomly selected from this group.In situhybridization of these genes was performed on the same types of samples (wild-type (WT) andsmarca4a50/a50(yng) mutant) at the same stages (36 and 52 hours post-fertilization (hpf)) as in the microarray study.

Results

Thirty out of 32 riboprobes showed a positivein situstaining signal. Twenty seven out of these 30 genes were originally further classified as Smarca4-regulated retinal genes, while the remaining three as retinal-specific expression independent of Smarca4 regulation. It was found that 90.32% of the significant microarray comparisons that were used to identify Smarca4-regulated retinal genes had a corresponding qualitative expression change in thein situhybridization comparisons. This is highly concordant with the theoretical true discovery rate of 95%. Hierarchical clustering was used to investigate the similarity of the cellular expression patterns of 25 out of the 27 Smarca4-regulated retinal genes that had a sufficiently high expression signal for an unambiguous identification of retinal expression domains. Three broad groups of expression pattern were identified; including 1) photoreceptor layer/outer nuclear layer specific expression at 52 hpf, 2) ganglion cell layer (GCL) and/or inner nuclear layer (INL) specific expression at both 36 & 52 hpf, and 3) GCL and/or INL specific expression at 52 hpf only. Some of these genes have recently been demonstrated to play key roles in retinal cell-type specification, differentiation and lamination. For the remaining three retinal-specific genes that are independent of Smarca4 regulation, they all had a subtle expression difference between WT andsmarca4a50/a50retinas as detected byin situhybridization. This subtle expression difference was also detected by the original microarray analysis. However, the difference was lower than the fold change cut-off used in that study and hence these genes were not inferred as Smarca4-regulated retinal genes.

Conclusions

This study has successfully investigated the expression pattern of 32 genes identified from the original factorial microarray analysis. The results have demonstrated that the true discovery rate for identifying Smarca4-regulated retinal genes is 90.3%. Hence, the significant genes from the microarray study are good candidates for cell-type specific markers and will aid further investigation of retinal differentiation.
Somatic sex-specific transcriptome differences in Drosophila revealed by whole transcriptome sequencing
Authors: Chang Peter L , Dunham Joseph P , Nuzhdin Sergey V , Arbeitman Michelle N
Published: July 2011

Background

Understanding animal development and physiology at a molecular-biological level has been advanced by the ability to determine at high resolution the repertoire of mRNA molecules by whole transcriptome resequencing. This includes the ability to detect and quantify rare abundance transcripts and isoform-specific mRNA variants produced from a gene.

The sex hierarchy consists of a pre-mRNA splicing cascade that directs the production of sex-specific transcription factors that specify nearly all sexual dimorphism. We have used deep RNA sequencing to gain insight into how the Drosophila sex hierarchy generates somatic sex differences, by examining gene and transcript isoform expression differences between the sexes in adult head tissues.

Results

Here we find 1,381 genes that differ in overall expression levels and 1,370 isoform-specific transcripts that differ between males and females. Additionally, we find 512 genes not regulated downstream of transformer that are significantly more highly expressed in males than females. These 512 genes are enriched on the × chromosome and reside adjacent to dosage compensation complex entry sites, which taken together suggests that their residence on the × chromosome might be sufficient to confer male-biased expression. There are no transcription unit structural features, from a set of features, that are robustly significantly different in the genes with significant sex differences in the ratio of isoform-specific transcripts, as compared to random isoform-specific transcripts, suggesting that there is no single molecular mechanism that generates isoform-specific transcript differences between the sexes, even though the sex hierarchy is known to include three pre-mRNA splicing factors.

Conclusions

We identify thousands of genes that show sex-specific differences in overall gene expression levels, and identify hundreds of additional genes that have differences in the abundance of isoform-specific transcripts. No transcription unit structural feature was robustly enriched in the sex-differentially expressed transcript isoforms. Additionally, we found that many genes with male-biased expression were enriched on the × chromosome and reside adjacent to dosage compensation entry sites, suggesting that differences in sex chromosome composition contributes to dimorphism in gene expression. Taken together, this study provides new insight into the molecular underpinnings of sexual differentiation.
Cocaine- and amphetamine-regulated transcript promotes the differentiation of mouse bone marrow-derived mesenchymal stem cells into neural cells
Authors: Liu Zhuo , Huang Danqing , Zhang Meijuan , Chen Zhibin , Jin Jiali , Huang Siyuan , Zhang Zhuo , Wang Zhongyuan , Chen Lei , Chen Ling , Xu Yun
Published: July 2011

Background

Neural tissue has limited potential to self-renew after neurological damage. Cell therapy using BM-MSCs (bone marrow mesenchymal stromal cells) seems like a promising approach for the treatment of neurological diseases. However, the neural differentiation of stem cells influenced by massive factors and interactions is not well studied at present.

Results

In this work, we isolated and identified MSCs from mouse bone marrow. Co-cultured with CART (0.4 nM) for six days, BM-MSCs were differentiated into neuron-like cells by the observation of optical microscopy. Immunofluorescence demonstrated that the differentiated BM-MSCs expressed neural specific markers including MAP-2, Nestin, NeuN and GFAP. In addition, NeuN positive cells could co-localize with TH or ChAT by double-labled immunofluorescence and Nissl bodies were found in several differentiated cells by Nissl stain. Furthermore, BDNF and NGF were increased by CART using RT-PCR.

Conclusion

This study demonstrated that CART could promote the differentiation of BM-MSCs into neural cells through increasing neurofactors, including BNDF and NGF. Combined application of CART and BM-MSCs may be a promising cell-based therapy for neurological diseases.
Primary care providers' perspective on prescribing opioids to older adults with chronic non-cancer pain: A qualitative study
Authors: Spitz Aerin , Moore Alison A , Papaleontiou Maria , Granieri Evelyn , Turner Barbara J , Reid M Carrington
Published: July 2011

Background

The use of opioid medications as treatment for chronic non-cancer pain remains controversial. Little information is currently available regarding healthcare providers' attitudes and beliefs about this practice among older adults. This study aimed to describe primary care providers' experiences and attitudes towards, as well as perceived barriers and facilitators to prescribing opioids as a treatment for chronic pain among older adults.

Methods

Six focus groups were conducted with a total of 23 physicians and three nurse practitioners from two academically affiliated primary care practices and three community health centers located in New York City. Focus groups were audiotape recorded and transcribed. The data were analyzed using directed content analysis; NVivo software was used to assist in the quantification of identified themes.

Results

Most participants (96%) employed opioids as therapy for some of their older patients with chronic pain, although not as first-line therapy. Providers cited multiple barriers, including fear of causing harm, the subjectivity of pain, lack of education, problems converting between opioids, and stigma. New barriers included patient/family member reluctance to try an opioid and concerns about opioid abuse by family members/caregivers. Studies confirming treatment benefit, validated tools for assessing risk and/or dosing for comorbidities, improved conversion methods, patient education, and peer support could facilitate opioid prescribing. Participants voiced greater comfort using opioids in the setting of delivering palliative or hospice care versus care of patients with chronic pain, and expressed substantial frustration managing chronic pain.

Conclusions

Providers perceive multiple barriers to prescribing opioids to older adults with chronic pain, and use these medications cautiously. Establishing the long-term safety and efficacy of these medications, generating improved prescribing methods, and implementing provider and patient educational interventions could help to improve the management of chronic pain in later life.
Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma
Authors: Busch Jonas , Seidel Christoph , Weikert Steffen , Wolff Ingmar , Kempkensteffen Carsten , Weinkauf Lisa , Hinz Stefan , Magheli Ahmed , Miller Kurt , Grünwald Viktor
Published: July 2011

Background

Data on sequential therapy in patients with metastatic renal cell carcinoma (mRCC) and intrinsic resistance to receptor tyrosine kinase inhibitor (rTKI) treatment remains vague.

Methods

We retrospectively studied treatment characteristics and outcome of mRCC patients refractory to first rTKI therapy.

Results

Thirty-five mRCC patients (male, 18; female, 11) with primary resistance to first rTKI therapy (sunitinib, n = 28; sorafenib, n = 7) and a median treatment interval of 2.4 months (1 - 4.6) were identified. In 22 patients, progressive disease (PD) was determined by a new metastatic lesion. Of these, 16 patients received subsequent therapy with 12 patients remaining refractory and 4 patients achieving disease stabilization. In 13 patients continuous growth of existing metastatic lesions determined PD. Of these, 9 received sequential therapy with 6 achieving disease stabilization. Altogether, 25 patients were treated sequentially (rTKI: n = 15; mTOR-inhibitor: n = 10) and achieved a median PFS of 3.2 months (range, 1-16.6). Fifteen patients failed to respond to either line of therapy. Disease control was not associated with type of subsequent therapy. Median OS was 14.9 months (CI: 5.5-24.4).

Conclusion

Intrinsic resistance to rTKI is associated with a low chance of response to sequential therapy and a poor prognosis in mRCC patients.
A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells
Authors: Serrano Fabiana A , Matsuo Alisson L , Monteforte Priscila T , Bechara Alexandre , Smaili Soraya S , Santana Débora P , Rodrigues Tiago , Pereira Felipe V , Silva Luis S , Machado Joel , Santos Edson L , Pesquero João B , Martins Rafael M , Travassos Luiz R , Caires Antonio CF , Rodrigues Elaine G
Published: July 2011

Background

Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd2[S(-)C2, N-dmpa]2(μ-dppe)Cl2} named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies.

Methods

B16F10-Nex2 cells were treatedin vitrowith C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treatedin vitrowith C7a.

Results

Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineagesin vitro, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells.

Conclusions

The cyclopalladated C7a complex is an effective chemotherapeutic anticancer compound against primary and metastatic murine and human tumors, including cisplatin-resistant cells, inducing apoptotic cell death via the intrinsic pathway.
Peptide binding prediction for the human class II MHC allele HLA-DP2: a molecular docking approach
Authors: Patronov Atanas , Dimitrov Ivan , Flower Darren R , Doytchinova Irini
Published: July 2011

Background

MHC class II proteins bind oligopeptide fragments derived from proteolysis of pathogen antigens, presenting them at the cell surface for recognition by CD4+ T cells. Human MHC class II alleles are grouped into three loci: HLA-DP, HLA-DQ and HLA-DR. In contrast to HLA-DR and HLA-DQ, HLA-DP proteins have not been studied extensively, as they have been viewed as less important in immune responses than DRs and DQs. However, it is now known that HLA-DP alleles are associated with many autoimmune diseases. Quite recently, the X-ray structure of the HLA-DP2 molecule (DPA*0103, DPB1*0201) in complex with a self-peptide derived from the HLA-DR α-chain has been determined. In the present study, we applied a validated molecular docking protocol to a library of 247 modelled peptide-DP2 complexes, seeking to assess the contribution made by each of the 20 naturally occurred amino acids at each of the nine binding core peptide positions and the four flanking residues (two on both sides).

Results

The free binding energies (FBEs) derived from the docking experiments were normalized on a position-dependent (npp) and on an overall basis (nap), and two docking score-based quantitative matrices (DS-QMs) were derived: QMnpp and QMnap. They reveal the amino acid preferences at each of the 13 positions considered in the study. Apart from the leading role of anchor positions p1 and p6, the binding to HLA-DP2 depends on the preferences at p2. No effect of the flanking residues was found on the peptide binding predictions to DP2, although all four of them show strong preferences for particular amino acids. The predictive ability of the DS-QMs was tested using a set of 457 known binders to HLA-DP2, originating from 24 proteins. The sensitivities of the predictions at five different thresholds (5%, 10%, 15%, 20% and 25%) were calculated and compared to the predictions made by the NetMHCII and IEDB servers. Analysis of the DS-QMs indicated an improvement in performance. Additionally, DS-QMs identified the binding cores of several known DP2 binders.

Conclusions

The molecular docking protocol, as applied to a combinatorial library of peptides, models the peptide-HLA-DP2 protein interaction effectively, generating reliable predictions in a quantitative assessment. The method is structure-based and does not require extensive experimental sequence-based data. Thus, it is universal and can be applied to model any peptide - protein interaction.
Effect of silibinin on endothelial dysfunction and ADMA levels in obese diabetic mice
Authors: Li Volti Giovanni , Salomone Salvatore , Sorrenti Valeria , Mangiameli Andrea , Urso Vincenzo , Siarkos Ilias , Galvano Fabio , Salamone Federico
Published: July 2011

Background

Cardiovascular diseases (CVD) in diabetic patients have endothelial dysfunction as a key pathogenetic event. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), plays a pivotal role in endothelial dysfunction. Different natural polyphenols have been shown to preserve endothelial function and prevent CVD. In this study, we assessed the effect of silibinin, a widely used flavonolignan from milk thistle, on ADMA levels and endothelial dysfunction in db/db mice.

Methods

Eight-week-old db/db mice were administrated a 20 mg/Kg i.p. daily dose of silibinin (n = 6) or vehicle (n = 6) for four weeks. Heterozygous lean db/m mice served as control. Plasma, aorta and liver ADMA levels were determined by ELISA. Vascular reactivity to phenilephrine (PE), acetylcholine (ACh), sodium nitroprusside (SNP) and ADMA was assessed in isolated aortic segments, in wire myograph.

Results

Plasma and aorta ADMA levels were higher in db/db than in control lean mice. Silibinin administration markedly decreased plasma ADMA; consistently, aorta ADMA was reduced in silibinin-treated animals. Plasma and aorta ADMA levels exhibited a positive correlation, whereas liver ADMA was inversely correlated with both plasma and aorta ADMA concentrations. Endothelium-(NO)-dependent vasodilatation to ACh was impaired in db/db mice and was restored in the silibinin group, in accordance with the observed reduction of plasma and vascular levels of ADMA. Endothelium-independent vasodilatation to SNP was not modified by silibinin administration; contractile tone induced in isolated aorta from db/db mice by challenging with exogenous ADMA was not affected by the treatment.

Conclusions

Silibinin markedly improves endothelial dysfunction in db/db mice by reducing circulating and vascular ADMA levels. Clinical studies are warranted to assess the efficacy of silibinin for cardiovascular protection.
Climate forcing and desert malaria: the effect of irrigation
Authors: Baeza Andres , Bouma Menno J , Dobson Andy P , Dhiman Ramesh , Srivastava Harish C , Pascual Mercedes
Published: July 2011

Background

Rainfall variability and associated remote sensing indices for vegetation are central to the development of early warning systems for epidemic malaria in arid regions. The considerable change in land-use practices resulting from increasing irrigation in recent decades raises important questions on concomitant change in malaria dynamics and its coupling to climate forcing. Here, the consequences of irrigation level for malaria epidemics are addressed with extensive time series data for confirmed Plasmodium falciparum monthly cases, spanning over two decades for five districts in north-west India. The work specifically focuses on the response of malaria epidemics to rainfall forcing and how this response is affected by increasing irrigation.

Methods and Findings

Remote sensing data for the Normalized Difference Vegetation Index (NDVI) are used as an integrated measure of rainfall to examine correlation maps within the districts and at regional scales. The analyses specifically address whether irrigation has decreased the coupling between malaria incidence and climate variability, and whether this reflects (1) a breakdown of NDVI as a useful indicator of risk, (2) a weakening of rainfall forcing and a concomitant decrease in epidemic risk, or (3) an increase in the control of malaria transmission. The predictive power of NDVI is compared against that of rainfall, using simple linear models and wavelet analysis to study the association of NDVI and malaria variability in the time and in the frequency domain respectively.

Conclusions

The results show that irrigation dampens the influence of climate forcing on the magnitude and frequency of malaria epidemics and, therefore, reduces their predictability. At low irrigation levels, this decoupling reflects a breakdown of local but not regional NDVI as an indicator of rainfall forcing. At higher levels of irrigation, the weakened role of climate variability may be compounded by increased levels of control; nevertheless this leads to no significant decrease in the actual risk of disease. This implies that irrigation can lead to more endemic conditions for malaria, creating the potential for unexpectedly large epidemics in response to excess rainfall if these climatic events coincide with a relaxation of control over time. The implications of our findings for control policies of epidemic malaria in arid regions are discussed.
Plasmodium falciparum glutamate dehydrogenase a is dispensable and not a drug target during erythrocytic development
Authors: Storm Janet , Perner Jan , Aparicio Isabela , Patzewitz Eva-Maria , Olszewski Kellen , Llinas Manuel , Engel Paul C , Müller Sylke
Published: July 2011

Background

Plasmodium falciparum contains three genes encoding potential glutamate dehydrogenases. The protein encoded by gdha has previously been biochemically and structurally characterized. It was suggested that it is important for the supply of reducing equivalents during intra-erythrocytic development of Plasmodium and, therefore, a suitable drug target.

Methods

The gene encoding the NADP(H)-dependent GDHa has been disrupted by reverse genetics in P. falciparum and the effect on the antioxidant and metabolic capacities of the resulting mutant parasites was investigated.

Results

No growth defect under low and elevated oxygen tension, no up- or down-regulation of a number of antioxidant and NADP(H)-generating proteins or mRNAs and no increased levels of GSH were detected in the D10Δgdha
parasite lines. Further, the fate of the carbon skeleton of [13C] labelled glutamine was assessed by metabolomic studies, revealing no differences in the labelling of α-ketoglutarate and other TCA pathway intermediates between wild type and mutant parasites.

Conclusions

First, the data support the conclusion that D10Δgdha
parasites are not experiencing enhanced oxidative stress and that GDHa function may not be the provision of NADP(H) for reductive reactions. Second, the results imply that the cytosolic, NADP(H)-dependent GDHa protein is not involved in the oxidative deamination of glutamate but that the protein may play a role in ammonia assimilation as has been described for other NADP(H)-dependent GDH from plants and fungi. The lack of an obvious phenotype in the absence of GDHa may point to a regulatory role of the protein providing glutamate (as nitrogen storage molecule) in situations where the parasites experience a limiting supply of carbon sources and, therefore, under in vitro conditions the enzyme is unlikely to be of significant importance. The data imply that the protein is not a suitable target for future drug development against intra-erythrocytic parasite development.
Vaginal treatment of endometrial cancer: role in the elderly
Authors: Moscarini Massimo , Ricciardi Enzo , Quarto Alessandro , Maniglio Paolo , Caserta Donatella
Published: July 2011

Background

To compare abdominal hysterectomy, the most currently used for treating cancer of the endometrium, to the vaginal hysterectomy in term of survival, morbidity and failure rates.

Methods

We retrospectively analyzed 68 cases divided into two sub-groups. A study group of 31 cases received vaginal surgery; a control group of 37 cases was treated with a laparotomy. Mean operative time, median hospital stay, intra- and post-operative complications, DFS and OS time as well as occurrence of local or distant recurrences have been evaluated and reported. Cases included patients with a higher rate of medical morbidities (p = 0.01) than controls.

Results

Mean age was 76.2 and 70.4 years in the vaginal (V) group and abdominal (A) group respectively. Mean operative time was longer for the group A. Group V patients had a lower mean post-operative hospital stay (p < 0.05). Differences in the two groups regarding intra- and post-operative complications, occurrence of local or distant recurrences and DFS time were not statistically significant. Disease specific survival time at 5 years scored 97% for group V, and 97% for group A.

Conclusions

Results show how vaginal approach had a similar outcome in selected patients. Vaginal surgery could therefore be the proper choice in patients with early stages and lower surgical risk, in addition to elderly patients exposed to a higher surgical risk.