bluuebunny/crossref_metadata_2025 huggingface dataset:
A Mixed Methods Approach to Measuring Depth of Group Information Processing in the Context of Deliberative Public Involvement
Authors: Seekamp Erin , Harris Charles C. , Hall Troy E. , Craig Traci Y.
Published: June 2010

This article presents a mixed methods procedure for evaluating information processing and the role of social influences in deliberative public involvement groups. Specifically, it describes an interpretive, qualitative coding scheme for analyzing group discussions to quantitatively assess how group differences in information processing and social influences affect decision judgments. To substantiate the need for this new approach, the contributions of social psychology for better understanding persuasive influences in groups and individual information processing are described in relation to participatory public involvement contexts. The approach is then described using examples from a deliberative public involvement process. The article concludes with a discussion of the challenges associated with the proposed technique and suggestions for research to advance the technique and assess its contribution to mixed methods research.
Measuring cough severity: development and pilot testing of a new seven-item cough severity patient-reported outcome measure
Authors: Vernon Margaret , Kline Leidy Nancy , Nacson Alise , Nelsen Linda
Published: June 2010

Objective: Although chronic and subacute cough are clinically problematic and a target of therapeutic interventions, there are no validated cough severity patient-reported outcome (PRO) instruments for comprehensively evaluating cough severity in clinical trials. The Cough Severity Diary (CSD) is a simple, seven-item daily diary developed to meet this need. The objective of this study was to assess preliminary measurement characteristics in a small sample of patients with chronic or subacute cough.

Methods: Thirty-nine patients (24 chronic; 15 subacute) participated in a two-week prospective pilot study. Patients completed the CSD each evening and validation instruments (cough severity visual analog scale [VAS], Leicester Cough Questionnaire [LCQ], Medical Outcomes Study 36-Item Short Form [SF-36], Work Productivity Index [WPAI], MOS Sleep Scale [MOS-SS]) at baseline, days 8 and 15, and a global rating of change at days 8 and 15.

Results: Confirmatory factor analyses supported three severity subscales: frequency (three items), intensity (two items), and disruption (two items) (χ2 = 10.57 (11)). For the CSD total score, internal consistency (α) on day 1 was 0.89, and on day 8 was 0.96; reproducibility (intraclass correlation coefficients [ICC]) was 0.68 on day 1 to day 8 and 0.94 on day 8 to day 15. CSD total scores correlated with the VAS (r = 0.84, p < 0.0001), LCQ total (r =-0.62, p < 0.0001) and subscale scores (r =-0.43, p < 0.01 to -0.60, p < 0.0001), and WPAI subscale scores (r = 0.27 (ns) to 0.51, p < 0.01). No significant relationships with SF-36 or MOS-SS were found. Subacute patients showed significant improvement over time (F = 3.20, p < 0.05).

Conclusions: Results suggest that the CSD is ready for further testing in larger naturalistic studies or as an exploratory endpoint in clinical trials of patients with subacute or chronic cough.
Efficacy of amlodipine and olmesartan medoxomil in patients with hypertension: the AZOR Trial Evaluating Blood Pressure Reductions and Control (AZTEC) study
Authors: Punzi Henry , Neutel Joel M. , Kereiakes Dean J. , Shojaee Ali , Waverczak William F. , Dubiel Robert , Maa Jen-Fue
Published: June 2010

The aim of the present study was to use ambulatory blood pressure (BP) monitoring (ABPM) to determine the efficacy of a fixed-dose combination of amlodipine (AML) and olmesartan medoxomil (OM) over the 24-hour dosing interval. This 12-week, titrate-to-goal study was conducted in 185 patients with hypertension. Patients were initially treated with AML 5 mg/ day and uptitrated to AML/OM 5/20, 5/40, and 10/40 mg/day every 3 weeks if mean seated BP (SeBP) was ≥120/80 mmHg. The primary efficacy endpoint was the change from baseline in mean 24-hour systolic BP at week 12 as assessed by ABPM. At baseline, the mean 24-hour ambulatory BP (±standard deviation [SD]) was 144.8±11.1/85.7±7.9 mmHg. At week 12, the change from baseline in mean 24-hour ambulatory BP (±standard error of the mean [SEM]) was -21.4±0.8/-12.7±0.5 mmHg (p < 0.0001 versus baseline). At baseline, the mean SeBP (±SD) was 158.2±12.6/92.8±8.6 mmHg and at week 12, the mean SeBP change (±SEM) from baseline (last observation carried forward) was -24.1±1.1/-12.1±0.7 mmHg (p < 0.0001 versus baseline). Proportions of patients achieving mean 24-hour ambulatory BP prespecified study targets were 70.9% (<130/80 mmHg), 48.3% (<125/75 mmHg), and 40.7% (<120/80 mmHg). Cumulatively, 76.8% of patients uptitrated to AML/OM 10/40 mg/day attained an SeBP goal of <140/90 mmHg. The study drug was well tolerated with few adverse events (peripheral edema, 2.2%; dizziness, 1.1%). An AML/OM-based titration regimen effectively reduces BP in patients with hypertension.
Review: Novel insights on diagnosis, cause and treatment of diabetic neuropathy: focus on painful diabetic neuropathy
Authors: Tavakoli Mitra , Asghar Omar , Alam Uazman , Petropoulos Ioannis N. , Fadavi Hassan , Malik Rayaz A.
Published: June 2010

Diabetic neuropathy is common, under or misdiagnosed, and causes substantial morbidity with increased mortality. Defining and developing sensitive diagnostic tests for diabetic neuropathy is not only key to implementing earlier interventions but also to ensure that the most appropriate endpoints are employed in clinical intervention trials. This is critical as many potentially effective therapies may never progress to the clinic, not due to a lack of therapeutic effect, but because the endpoints were not sufficiently sensitive or robust to identify benefit. Apart from improving glycaemic control, there is no licensed treatment for diabetic neuropathy, however, a number of pathogenetic pathways remain under active study. Painful diabetic neuropathy is a cause of considerable morbidity and whilst many pharmacological and nonpharmacological interventions are currently used, only two are approved by the US Food and Drug Administration. We address the important issue of the ‘placebo effect’ and also consider potential new pharmacological therapies as well as nonpharmacological interventions in the treatment of painful diabetic neuropathy.
BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib
Authors: Sherbenou Daniel W. , Hantschel Oliver , Kaupe Ines , Willis Stephanie , Bumm Thomas , Turaga Lalita P. , Lange Thoralf , Dao Kim-Hien , Press Richard D. , Druker Brian J. , Superti-Furga Giulio , Deininger Michael W.
Published: June 2010

Point mutations in the kinase domain of BCR-ABL are the most common mechanism of drug resistance in chronic myeloid leukemia (CML) patients treated with ABL kinase inhibitors, including imatinib. It has also been shown in vitro that mutations outside the kinase domain in the neighboring linker, SH2, SH3, and Cap domains can confer imatinib resistance. In the context of ABL, these domains have an autoinhibitory effect on kinase activity, and mutations in this region can activate the enzyme. To determine the frequency and relevance to resistance of regulatory domain mutations in CML patients on imatinib, we screened for such mutations in a cohort of consecutive CML patients with various levels of response. Regulatory domain mutations were detected in 7 of 98 patients, whereas kinase domain mutations were detected in 29. One mutation (T212R) conferred in vitro tyrosine kinase inhibitor resistance and was associated with relapse, whereas most other mutations did not affect drug sensitivity. Mechanistic studies showed that T212R increased the activity of ABL and BCR-ABL and that T212R-induced resistance may be partially the result of stabilization of an active kinase conformation. Regulatory domain mutations are uncommon but may explain resistance in some patients without mutations in the kinase domain.
microRNA-dependent modulation of histone acetylation in Waldenström macroglobulinemia
Authors: Roccaro Aldo M. , Sacco Antonio , Jia Xiaoying , Azab Abdel Kareem , Maiso Patricia , Ngo Hai T. , Azab Feda , Runnels Judith , Quang Phong , Ghobrial Irene M.
Published: June 2010

Waldenström macroglobulinemia (WM) cells present with increased expression of microRNA-206 (miRNA-206) and reduced expression of miRNA-9*. Predicted miRNA-206– and -9*–targeted genes include histone deacetylases (HDACs) and histone acetyl transferases (HATs), indicating that these miRNAs may play a role in regulating histone acetylation. We were able to demonstrate that primary WM cells are characterized by unbalanced expression of HDACs and HATs, responsible for decreased acetylated histone-H3 and -H4, and increased HDAC activity. We next examined whether miRNA-206 and -9* modulate the aberrant expression of HDAC and HATs in WM cells leading to increased transcriptional activity. We found that restoring miRNA-9* levels induced toxicity in WM cells, supported by down-modulation of HDAC4 and HDAC5 and up-regulation of acetyl-histone-H3 and -H4. These, together with inhibited HDAC activity, led to induction of apoptosis and autophagy in WM cells. To further confirm that miRNA-9*–dependent modulation of histone acetylation is responsible for induction of WM cytotoxicity, a novel class of HDAC inhibitor (LBH589) was used; we confirmed that inhibition of HDAC activity leads to toxicity in this disease. These findings confirm that histone-modifying genes and HDAC activity are deregulated in WM cells, partially driven by the aberrant expression of miRNA-206 and -9* in the tumor clone.
Saliva Ontology: An ontology-based framework for a Salivaomics Knowledge Base
Authors: Ai Jiye , Smith Barry , Wong David T
Published: June 2010

Background

The Salivaomics Knowledge Base (SKB) is designed to serve as a computational infrastructure that can permit global exploration and utilization of data and information relevant to salivaomics. SKB is created by aligning (1) the saliva biomarker discovery and validation resources at UCLA with (2) the ontology resources developed by the OBO (Open Biomedical Ontologies) Foundry, including a new Saliva Ontology (SALO).

Results

We define the Saliva Ontology (SALO; http://www.skb.ucla.edu/SALO/) as a consensus-based controlled vocabulary of terms and relations dedicated to the salivaomics domain and to saliva-related diagnostics following the principles of the OBO (Open Biomedical Ontologies) Foundry.

Conclusions

The Saliva Ontology is an ongoing exploratory initiative. The ontology will be used to facilitate salivaomics data retrieval and integration across multiple fields of research together with data analysis and data mining. The ontology will be tested through its ability to serve the annotation ('tagging') of a representative corpus of salivaomics research literature that is to be incorporated into the SKB.
Detecting internally symmetric protein structures
Authors: Kim Changhoon , Basner Jodi , Lee Byungkook
Published: June 2010

Background

Many functional proteins have a symmetric structure. Most of these are multimeric complexes, which are made of non-symmetric monomers arranged in a symmetric manner. However, there are also a large number of proteins that have a symmetric structure in the monomeric state. These internally symmetric proteins are interesting objects from the point of view of their folding, function, and evolution. Most algorithms that detect the internally symmetric proteins depend on finding repeating units of similar structure and do not use the symmetry information.

Results

We describe a new method, called SymD, for detecting symmetric protein structures. The SymD procedure works by comparing the structure to its own copy after the copy is circularly permuted by all possible number of residues. The procedure is relatively insensitive to symmetry-breaking insertions and deletions and amplifies positive signals from symmetry. It finds 70% to 80% of the TIM barrel fold domains in the ASTRAL 40 domain database and 100% of the beta-propellers as symmetric. More globally, 10% to 15% of the proteins in the ASTRAL 40 domain database may be considered symmetric according to this procedure depending on the precise cutoff value used to measure the degree of perfection of the symmetry. Symmetrical proteins occur in all structural classes and can have a closed, circular structure, a cylindrical barrel-like structure, or an open, helical structure.

Conclusions

SymD is a sensitive procedure for detecting internally symmetric protein structures. Using this procedure, we estimate that 10% to 15% of the known protein domains may be considered symmetric. We also report an initial, overall view of the types of symmetries and symmetric folds that occur in the protein domain structure universe.
Characterisation of the dynamic behaviour of lipid droplets in the early mouse embryo using adaptive harmonic generation microscopy
Authors: Watanabe Tomoko , Thayil Anisha , Jesacher Alexander , Grieve Kate , Debarre Delphine , Wilson Tony , Booth Martin , Srinivas Shankar
Published: June 2010

Background

Lipid droplets (LD) are organelles with an important role in normal metabolism and disease. The lipid content of embryos has a major impact on viability and development. LD in Drosophila embryos and cultured cell lines have been shown to move and fuse in a microtubule dependent manner. Due to limitations in current imaging technology, little is known about the behaviour of LD in the mammalian embryo. Harmonic generation microscopy (HGM) allows one to image LD without the use of exogenous labels. Adaptive optics can be used to correct aberrations that would otherwise degrade the quality and information content of images.

Results

We have built a harmonic generation microscope with adaptive optics to characterise early mouse embryogenesis. At fertilization, LD are small and uniformly distributed, but in the implanting blastocyst, LD are larger and enriched in the invading giant cells of the trophectoderm. Time-lapse studies reveal that LD move continuously and collide but do not fuse, instead forming aggregates that subsequently behave as single units. Using specific inhibitors, we show that the velocity and dynamic behaviour of LD is dependent not only on microtubules as in other systems, but also on microfilaments. We explore the limits within which HGM can be used to study living embryos without compromising viability and make the counterintuitive finding that 16 J of energy delivered continuously over a period of minutes can be less deleterious than an order of magnitude lower energy delivered dis-continuously over a period of hours.

Conclusions

LD in pre-implantation mouse embryos show a previously unappreciated complexity of behaviour that is dependent not only on microtubules, but also microfilaments. Unlike LD in other systems, LD in the mouse embryo do not fuse but form aggregates. This study establishes HGM with adaptive optics as a powerful tool for the study of LD biology and provides insights into the photo-toxic effects of imaging embryos.
Culture of human pluripotent stem cells using completely defined conditions on a recombinant E-cadherin substratum
Authors: Nagaoka Masato , Si-Tayeb Karim , Akaike Toshihiro , Duncan Stephen A
Published: June 2010

Background

To maintain pluripotency of human embryonic stem (huES) cells in feeder-free culture it has been necessary to provide a Matrigel substratum, which is a complex of poorly defined extracellular matrices and growth factors derived from mouse Engelbreth-Holm-Swarm sarcoma cells. Culture of stem cells under ill-defined conditions can inhibit the effectiveness of maintaining cells in a pluripotent state and reduce reproducibility of differentiation protocols. Moreover recent batches of Matrigel have been found to be contaminated with the single stranded RNA virus, Lactate Dehydrogenase Elevating Virus (LDEV), raising concerns regarding the safety of using stem cells that have been cultured on Matrigel in a therapeutic setting. To circumvent such concerns, we attempted to identify a recombinant matrix that could be used as an alternative to Matrigel for the culture of human pluripotent stem cells. huES and human induced pluripotent stem (hiPS) cells were grown on plates coated with a fusion protein consisting of E-cadherin and the IgG Fc domain using mTeSR1 medium.

Results

Cells grown under these conditions maintained similar morphology and growth rate to those grown on Matrigel and retained all pluripotent stem cell features, including an ability to differentiate into multiple cell lineages in teratoma assays. We, therefore, present a culture system that maintains the pluripotency of huES and hiPS cells under completely defined conditions.

Conclusions

We propose that this system should facilitate growth of stem cells using good manufacturing practices (GMP), which will be necessary for the clinical use of pluripotent stem cells and their derivatives.
Exploring the HME and HAE1 efflux systems in the genus Burkholderia
Authors: Perrin Elena , Fondi Marco , Papaleo Maria Cristiana , Maida Isabel , Buroni Silvia , Pasca Maria Rosalia , Riccardi Giovanna , Fani Renato
Published: June 2010

Background

The genus Burkholderia includes a variety of species with opportunistic human pathogenic strains, whose increasing global resistance to antibiotics has become a public health problem. In this context a major role could be played by multidrug efflux pumps belonging to Resistance Nodulation Cell-Division (RND) family, which allow bacterial cells to extrude a wide range of different substrates, including antibiotics. This study aims to i) identify rnd genes in the 21 available completely sequenced Burkholderia genomes, ii) analyze their phylogenetic distribution, iii) define the putative function(s) that RND proteins perform within the Burkholderia genus and iv) try tracing the evolutionary history of some of these genes in Burkholderia.

Results

BLAST analysis of the 21 Burkholderia sequenced genomes, using experimentally characterized ceoB sequence (one of the RND family counterpart in the genus Burkholderia) as probe, allowed the assembly of a dataset comprising 254 putative RND proteins. An extensive phylogenetic analysis revealed the occurrence of several independent events of gene loss and duplication across the different lineages of the genus Burkholderia, leading to notable differences in the number of paralogs between different genomes. A putative substrate [antibiotics (HAE1 proteins)/heavy-metal (HME proteins)] was also assigned to the majority of these proteins. No correlation was found between the ecological niche and the lifestyle of Burkholderia strains and the number/type of efflux pumps they possessed, while a relation can be found with genome size and taxonomy. Remarkably, we observed that only HAE1 proteins are mainly responsible for the different number of proteins observed in strains of the same species. Data concerning both the distribution and the phylogenetic analysis of the HAE1 and HME in the Burkholderia genus allowed depicting a likely evolutionary model accounting for the evolution and spreading of HME and HAE1 systems in the Burkholderia genus.

Conclusion

A complete knowledge of the presence and distribution of RND proteins in Burkholderia species was obtained and an evolutionary model was depicted. Data presented in this work may serve as a basis for future experimental tests, focused especially on HAE1 proteins, aimed at the identification of novel targets in antimicrobial therapy against Burkholderia species.
Identification of novel non-coding small RNAs from Streptococcus pneumoniae TIGR4 using high-resolution genome tiling arrays
Authors: Kumar Ranjit , Shah Pratik , Swiatlo Edwin , Burgess Shane C , Lawrence Mark L , Nanduri Bindu
Published: June 2010

Background

The identification of non-coding transcripts in human, mouse, and Escherichia coli has revealed their widespread occurrence and functional importance in both eukaryotic and prokaryotic life. In prokaryotes, studies have shown that non-coding transcripts participate in a broad range of cellular functions like gene regulation, stress and virulence. However, very little is known about non-coding transcripts in Streptococcus pneumoniae (pneumococcus), an obligate human respiratory pathogen responsible for significant worldwide morbidity and mortality. Tiling microarrays enable genome wide mRNA profiling as well as identification of novel transcripts at a high-resolution.

Results

Here, we describe a high-resolution transcription map of the S. pneumoniae clinical isolate TIGR4 using genomic tiling arrays. Our results indicate that approximately 66% of the genome is expressed under our experimental conditions. We identified a total of 50 non-coding small RNAs (sRNAs) from the intergenic regions, of which 36 had no predicted function. Half of the identified sRNA sequences were found to be unique to S.
pneumoniae genome. We identified eight overrepresented sequence motifs among sRNA sequences that correspond to sRNAs in different functional categories. Tiling arrays also identified approximately 202 operon structures in the genome.

Conclusions

In summary, the pneumococcal operon structures and novel sRNAs identified in this study enhance our understanding of the complexity and extent of the pneumococcal 'expressed' genome. Furthermore, the results of this study open up new avenues of research for understanding the complex RNA regulatory network governing S. pneumoniae physiology and virulence.
Blockade of stress-induced increase of glutamate release in the rat prefrontal/frontal cortex by agomelatine involves synergy between melatonergic and 5-HT2C receptor-dependent pathways
Authors: Tardito Daniela , Milanese Marco , Bonifacino Tiziana , Musazzi Laura , Grilli Massimo , Mallei Alessandra , Mocaer Elisabeth , Gabriel-Gracia Cecilia , Racagni Giorgio , Popoli Maurizio , Bonanno Giambattista
Published: June 2010

Background

Agomelatine is a melatonergic receptor agonist and a 5HT2C receptor antagonist that has shown antidepressant efficacy. In order to analyze separately the effect of the two receptorial components, rats were chronically treated with agomelatine, melatonin (endogenous melatonergic agonist), or S32006 (5-HT2C antagonist), and then subjected to acute footshock-stress.

Results

Only chronic agomelatine, but not melatonin or S32006, completely prevented the stress-induced increase of glutamate release in the rat prefrontal/frontal cortex.

Conclusions

These results suggest a potential synergy between melatonergic and serotonergic pathways in the action of agomelatine.
Prognostic relevance of ALT-associated markers in liposarcoma: a comparative analysis
Authors: Venturini Lorenza , Motta Rosita , Gronchi Alessandro , Daidone MariaGrazia , Zaffaroni Nadia
Published: June 2010

Background

Most cancers maintain telomeres by activating telomerase but a significant minority, mainly of mesenchymal origin, utilize an alternative lengthening of telomeres (ALT) mechanism.

Methods

In this study we comparatively analyzed the prognostic relevance of ALT in a monoinstitutional series of 85 liposarcoma patients as a function of the marker (ALT-associated promyelocytic leukemia bodies (APB) versus heterogeneous telomeres) used to classify the tumor.

Results

Independently of the detection approach, ALT proved to be a prognostic discriminant of increased mortality, although the prognostic relevance of the two markers appeared at different follow-up intervals (at 10 years for APB and 15 years for telomeres).

Conclusions

Overall, we confirmed ALT as an indicator of poor clinical outcome in this disease and provide the first evidence that the sensitivity of the ALT predictive power depends, at least in part, on the method used.
The standard error of measurement is a more appropriate measure of quality for postgraduate medical assessments than is reliability: an analysis of MRCP(UK) examinations
Authors: Tighe Jane , McManus IC , Dewhurst Neil G , Chis Liliana , Mucklow John
Published: June 2010

Background

Cronbach's alpha is widely used as the preferred index of reliability for medical postgraduate examinations. A value of 0.8-0.9 is seen by providers and regulators alike as an adequate demonstration of acceptable reliability for any assessment. Of the other statistical parameters, Standard Error of Measurement (SEM) is mainly seen as useful only in determining the accuracy of a pass mark. However the alpha coefficient depends both on SEM and on the ability range (standard deviation, SD) of candidates taking an exam. This study investigated the extent to which the necessarily narrower ability range in candidates taking the second of the three part MRCP(UK) diploma examinations, biases assessment of reliability and SEM.

Methods

a) The interrelationships of standard deviation (SD), SEM and reliability were investigated in a Monte Carlo simulation of 10,000 candidates taking a postgraduate examination. b) Reliability and SEM were studied in the MRCP(UK) Part 1 and Part 2 Written Examinations from 2002 to 2008. c) Reliability and SEM were studied in eight Specialty Certificate Examinations introduced in 2008-9.

Results

The Monte Carlo simulation showed, as expected, that restricting the range of an assessment only to those who had already passed it, dramatically reduced the reliability but did not affect the SEM of a simulated assessment. The analysis of the MRCP(UK) Part 1 and Part 2 written examinations showed that the MRCP(UK) Part 2 written examination had a lower reliability than the Part 1 examination, but, despite that lower reliability, the Part 2 examination also had a smaller SEM (indicating a more accurate assessment). The Specialty Certificate Examinations had small Ns, and as a result, wide variability in their reliabilities, but SEMs were comparable with MRCP(UK) Part 2.

Conclusions

An emphasis upon assessing the quality of assessments primarily in terms of reliability alone can produce a paradoxical and distorted picture, particularly in the situation where a narrower range of candidate ability is an inevitable consequence of being able to take a second part examination only after passing the first part examination. Reliability also shows problems when numbers of candidates in examinations are low and sampling error affects the range of candidate ability. SEM is not subject to such problems; it is therefore a better measure of the quality of an assessment and is recommended for routine use.
Enhanced anti-tumor activity of a new curcumin-related compound against melanoma and neuroblastoma cells
Authors: Pisano Marina , Pagnan Gabriella , Dettori Maria Antonietta , Cossu Sara , Caffa Irene , Sassu Ilaria , Emionite Laura , Fabbri Davide , Cilli Michele , Pastorino Fabio , Palmieri Giuseppe , Delogu Giovanna , Ponzoni Mirco , Rozzo Carla
Published: June 2010

Background

Sharing the common neuroectodermal origin, melanoma and neuroblastoma are tumors widely diffused among adult and children, respectively. Clinical prognosis of aggressive neuroectodermal cancers remains dismal, therefore the search for novel therapies against such tumors is warranted. Curcumin is a phytochemical compound widely studied for its antioxidant, anti-inflammatory and anti-cancer properties. Recently, we have synthesized and tested in vitro various curcumin-related compounds in order to select new anti-tumor agents displaying stronger and selective growth inhibition activity on neuroectodermal tumors.

Results

In this work, we have demonstrated that the new α,β-unsaturated ketone D6 was more effective in inhibiting tumor cells growth when compared to curcumin. Normal fibroblasts proliferation was not affected by this treatment. Clonogenic assay showed a significant dose-dependent reduction in both melanoma and neuroblastoma colony formation only after D6 treatment. TUNEL assay, Annexin-V staining, caspases activation and PARP cleavage unveiled the ability of D6 to cause tumor cell death by triggering apoptosis, similarly to curcumin, but with a stronger and quicker extent. These apoptotic features appear to be associated with loss of mitochondrial membrane potential and cytochrome c release. In vivo anti-tumor activity of curcumin and D6 was surveyed using sub-cutaneous melanoma and orthotopic neuroblastoma xenograft models. D6 treated mice exhibited significantly reduced tumor growth compared to both control and curcumin treated ones (Melanoma: D6 vs control: P < 0.001 and D6 vs curcumin P < 0.01; Neuroblastoma: D6 vs both control and curcumin: P < 0.001).

Conclusions

Our data indicate D6 as a good candidate to develop new therapies against neural crest-derived tumors.
FRET microscopy autologous tumor lysate processing in mature dendritic cell vaccine therapy
Authors: Fiammenghi Laura , Ancarani Valentina , Rosales Tilman , Knutson Jay R , Petrini Massimiliano , Granato Anna Maria , Pancisi Elena , Ridolfi Laura , Ridolfi Ruggero , Riccobon Angela , Neyroz Paolo
Published: June 2010

Background

Antigen processing by dendritic cells (DC) exposed to specific stimuli has been well characterized in biological studies. Nonetheless, the question of whether autologous whole tumor lysates (as used in clinical trials) are similarly processed by these cells has not yet been resolved.

Methods

In this study, we examined the transfer of peptides from whole tumor lysates to major histocompatibility complex class II molecules (MHC II) in mature dendritic cells (mDC) from a patient with advanced melanoma. Tumor antigenic peptides-MHC II proximity was revealed by Förster Resonance Energy Transfer (FRET) measurements, which effectively extends the application of fluorescence microscopy to the molecular level (<100Å). Tumor lysates were labelled with Alexa-488, as the donor, and mDC MHC II HLA-DR molecules were labelled with Alexa-546-conjugated IgG, as the acceptor.

Results

We detected significant energy transfer between donor and acceptor-labelled antibodies against HLA-DR at the membrane surface of mDC. FRET data indicated that fluorescent peptide-loaded MHC II molecules start to accumulate on mDC membranes at 16 hr from the maturation stimulus, steeply increasing at 22 hr with sustained higher FRET detected up to 46 hr.

Conclusions

The results obtained imply that the patient mDC correctly processed the tumor specific antigens and their display on the mDC surface may be effective for several days. These observations support the rationale for immunogenic efficacy of autologous tumor lysates.
Patterns of pulmonary dysfunction in asbestos workers: a cross-sectional study
Authors: Abejie Belayneh A , Wang Xiaorong , Kales Stefanos N , Christiani David C
Published: June 2010

Background

Restrictive patterns of pulmonary function abnormalities associated with asbestos exposure are well described. Studies are less consistent, however, regarding the association of asbestos inhalation with airway dysfunction and obstructive impairment.

Methods

We compared pulmonary function test results between 277 chrysotile exposed workers (22% non-smokers) and 177 unexposed controls (50.3% non-smokers). Information on exposure and smoking were collected using a standardized questionnaire. Standardized spirometric and DCLO Measurement methods were utilized. CXRs were read based on ILO pneumoconiosis guidelines.

Results

Asbestos exposed subjects had significantly reduced FVC, FEV1, FEV1/FVC and DLCO. Restricting the analysis to non-smokers, asbestos workers still had about 3% lower FEV1/FVC ratio than controls, but this difference did not reach statistical significance. Among exposed workers, the presence of radiographic evidence of asbestosis further lowered FVC and DLCO but not FEV1/FVC compared to asbestos exposure without radiographic asbestosis. Additionally, smoking asbestos workers had significantly lower DLCO compared to non-smoking workers.

Conclusion

Asbestos exposure, especially when radiographic evidence of interstitial fibrosis from asbestosis is present, leads to significant decreases in FVC, FEV1 and the DLCO. However, asbestos exposure alone is not significantly associated with a reduction of the FEV1/FVC. Smoking-asbestos workers had significantly lower DLCO than their non-smoking counterparts. Whether asbestos interacts with smoking additively or synergistically on DLCO needs further investigation. Similarly, further studies are needed to assess the progression and clinical significance of asbestos induced airway dysfunction.
SEURAT: Visual analytics for the integrated analysis of microarray data
Authors: Gribov Alexander , Sill Martin , Lück Sonja , Rücker Frank , Döhner Konstanze , Bullinger Lars , Benner Axel , Unwin Antony
Published: June 2010

Background

In translational cancer research, gene expression data is collected together with clinical data and genomic data arising from other chip based high throughput technologies. Software tools for the joint analysis of such high dimensional data sets together with clinical data are required.

Results

We have developed an open source software tool which provides interactive visualization capability for the integrated analysis of high-dimensional gene expression data together with associated clinical data, array CGH data and SNP array data. The different data types are organized by a comprehensive data manager. Interactive tools are provided for all graphics: heatmaps, dendrograms, barcharts, histograms, eventcharts and a chromosome browser, which displays genetic variations along the genome. All graphics are dynamic and fully linked so that any object selected in a graphic will be highlighted in all other graphics. For exploratory data analysis the software provides unsupervised data analytics like clustering, seriation algorithms and biclustering algorithms.

Conclusions

The SEURAT software meets the growing needs of researchers to perform joint analysis of gene expression, genomical and clinical data.
Effect of multiple micronutrient supplementation on survival of HIV‐infected children in Uganda: a randomized, controlled trial
Authors: Ndeezi Grace , Tylleskär Thorkild , Ndugwa Christopher M , Tumwine James K
Published: June 2010

Background

Micronutrient deficiencies compromise the survival of HIV‐infected children in low‐income countries. We assessed the effect of multiple micronutrient supplementation on the mortality of HIV‐infected children in Uganda.

Methods

In a randomized, controlled trial, 847 children aged one to five years and attending HIV clinics in Uganda were stratified by antiretroviral therapy (ART, n = 85 versus no ART, n = 762). The children were randomized to six months of either: twice the recommended dietary allowance of 14 micronutrients as the intervention arm (vitamins A, B1, B2, niacin, B6, B12, C, D and E, folate, zinc, copper, iodine and selenium); or the standard recommended dietary allowance of six multivitamins (vitamins A, D2, B1, B2, C and niacin) as a comparative “standard‐of‐care” arm. Mortality was analyzed at 12 months of follow up using Kaplan Meier curves and the log rank test.

Results

Mortality at 12 months was 25 out of 426 (5.9%) children in the intervention arm and 28 out of 421 (6.7%) in the comparative arms: risk ratio 0.9 (95% CI 0.5 ‐ 1.5). Two out of 85 (2.4%) children in the ART stratum died compared with 51 out of 762 (6.7%) in the non‐ART stratum. Of those who died in the non‐ART stratum, 25 of 383 (6.5%) were in the intervention arm and 26 of 379 (6.9%) in the comparative arm; risk ratio 1.0 (95% CI 0.6 ‐ 1.6). There was no significant difference in survival at 12 months (p = 0.64, log rank test). In addition, there was no significant difference in mean weight‐for‐height at 12 months; 0.70 ± 1.43 (95% CI 0.52 ‐ 0.88) for the intervention versus 0.59 ± 1.15 (95% CI 0.45 ‐ 0.75) in the comparative arm. The mean CD4 cell count; 1024 ± 592 (95% CI 942 ‐ 1107) versus 1060 ± 553 (95% CI 985 ‐ 1136) was also similar between the two groups.

Conclusions

Twice the recommended dietary allowance of 14 micronutrients compared with a standard recommended dietary allowance of six multivitamins for six months was well tolerated, but it did not significantly alter mortality, growth or CD4 counts. Future intervention studies should carefully consider: (1) the composition and dosing of the supplements; and (2) the power needed to detect a difference between arms.

Trial Registration

ClinicalTrials.gov Identifier: NCT00122941
Preoperative diastolic function predicts the onset of left ventricular dysfunction following aortic valve replacement in high-risk patients with aortic stenosis
Authors: Licker Marc , Cikirikcioglu Mustafa , Inan Cidgem , Cartier Vanessa , Kalangos Afksendyios , Theologou Thomas , Cassina Tiziano , Diaper John
Published: June 2010

Introduction

Left ventricular (LV) dysfunction frequently occurs after cardiac surgery, requiring inotropic treatment and/or mechanical circulatory support. In this study, we aimed to identify clinical, surgical and echocardiographic factors that are associated with LV dysfunction during weaning from cardiopulmonary bypass (CPB) in high-risk patients undergoing valve replacement for aortic stenosis.

Methods

Perioperative data were prospectively collected in 108 surgical candidates with an expected operative mortality ≥9%. All anesthetic and surgical techniques were standardized. Reduced LV systolic function was defined by an ejection fraction <40%. Diastolic function of the LV was assessed using standard Doppler-derived parameters, tissue Doppler Imaging (TDI) and transmitral flow propagation velocity (Vp).

Results

Doppler-derived pulmonary flow indices and TDI could not be obtained in 14 patients. In the remaining 94 patients, poor systolic LV was documented in 14% (n = 12) and diastolic dysfunction in 84% of patients (n = 89), all of whom had Vp <50 cm/s. During weaning from CPB, 38 patients (40%) required inotropic and/or mechanical circulatory support. By multivariate regression analysis, we identified three independent predictors of LV systolic dysfunction: age (Odds ratio [OR] = 1.11; 95% confidence interval (CI), 1.01 to 1.22), aortic clamping time (OR = 1.04; 95% CI, 1.00 to 1.08) and Vp (OR = 0.65; 95% CI, 0.52 to 0.81). Among echocardiographic measurements, Vp was found to be superior in terms of prognostic value and reliability. The best cut-off value for Vp to predict LV dysfunction was 40 cm/s (sensitivity of 72% and specificity 94%). Patients who experienced LV dysfunction presented higher in-hospital mortality (18.4% vs. 3.6% in patients without LV dysfunction, P = 0.044) and an increased incidence of serious cardiac events (81.6 vs. 28.6%, P < 0.001).

Conclusions

This study provides the first evidence that, besides advanced age and prolonged myocardial ischemic time, LV diastolic dysfunction characterized by Vp ≤ 40 cm/sec identifies patients who will require cardiovascular support following valve replacement for aortic stenosis.
CSF-1, IGF-1, and the control of postnatal growth and development
Authors: Gow Deborah J , Sester David P , Hume David A
Published: June 2010

Review discusses macrophages as the major extrahepatic source of IGF-1, and how a surge of CSF-1 production contributes to the control of postnatal growth and organ maturation.

Growth hormone controls somatic growth in mammals by regulating the production of IGF-1, which is predominantly made by the liver. The development of cells within the MPS is controlled by the lineage-specific growth factor M-CSF (CSF-1). In this review, we summarize the role of CSF-1-dependent macrophages in somatic growth and organogenesis. We propose that macrophages are the major extrahepatic source of IGF-1 and that a surge of CSF-1 production contributes to the control of postnatal growth and organ maturation. Accordingly, CSF-1 may be considered a part of the GH/IGF-1 axis.
Hibernation: the immune system at rest?
Authors: Bouma Hjalmar R , Carey Hannah V , Kroese Frans G M
Published: June 2010

Review of mechanisms that might contribute to the fully reversible reduced immune function that is present during hibernation.

Mammalian hibernation consists of torpor phases when metabolism is severely depressed, and Tb can reach as low as approximately –2°C, interrupted by euthermic arousal phases. Hibernation affects the function of the innate and the adaptive immune systems. Torpor drastically reduces numbers of all types of circulating leukocytes. In addition, other changes have been noted, such as lower complement levels, diminished response to LPS, phagocytotic capacity, cytokine production, lymphocyte proliferation, and antibody production. Hibernation may therefore increase infection risk, as illustrated by the currently emerging WNS in hibernating bats. Unraveling the pathways that result in reduced immune function during hibernation will enhance our understanding of immunologic responses during extreme physiological changes in mammals.
Invasion of the leukocytes into the fetal-maternal interface during pregnancy
Authors: Gomez-Lopez Nardhy , Guilbert Larry J , Olson David M
Published: June 2010

Review of mechanisms of uterine leukocyte infiltration and the potential roles of each subpopulation of leukocytes in relation to pregnancy and parturition.

No other organ in the body undergoes such an invasion of selective cells (leukocytes) and release of homing molecules, CAMs, proinflammatory cytokines, and mediators or undergoes similar extensive remodeling of tissues over such a short period of time as the pregnant uterus. This is especially interesting, as an infectious process involving microorganisms does not exist in a healthy pregnancy and delivery. Furthermore, after delivery of the baby and placenta, the uterus involutes and returns to its normal monthly cycling, and most of the leukocytes are swept away or leave. In this review, we discuss leukocyte infiltration and recruitment and the potential roles of each subpopulation of leukocytes in relation to pregnancy and the problems of preterm birth, pre-eclampsia, and intrauterine growth restriction.
Probabilistic microearthquake location for reservoir monitoring
Authors: Xuan Ran , Sava Paul
Published: June 2010

Accurately locating microseismic events can be used to monitor fluid migration during reservoir production and hydrofracturing operations. This is usually done with sparse networks of seismic sensors located in boreholes or with denser surface arrays. The data used for microearthquake monitoring are corrupted by noise, which reduces the signal-to-noise ratio to values as low as 0.1. Monitoring methods based on traveltime picking of various wave modes (P or S) cannot deal with this level of noise and require extensive user interaction. An alternative class of methods uses time reversal to focus microearthquake information at the source position. These methods can handle noisier signals because they do not rely on event picking or recorded seismograms, but the methods are also costlier to run and still require picking locations where wavefields focus. We advocate the time-reversal technique within the general framework of Bayesian inversion. Given an assumption about the possible locations of microearthquakes, we use recorded data to evaluate the feasibilityof microearthquakes occurring at various locations in the earth. The method takes into account imaging imperfections caused by unknown components of the model or acquisition array aperture. We simulate wavefields corresponding to possible sources distributed in the model and evaluate their match with the wavefield reconstructed from the synthetic data recorded in the model. In this regard, the method operates like a pattern-recognition procedure and can exploit a wide variety of techniques designed for this purpose. We use simple crosscorrelation between simulated and reconstructed wavefields to take advantage of the speed and robustness of this technique. The wavefields reconstructed at various locations are used over time to scan the wavefield constructed from field data. Thus, our method can identify not only the position of the microearthquakes but also their origin times as well as the orientations of the fault planes characterizing the seismic sources. Maps of probability are the final outcome of this automated process, indicating the confidence of microearthquake occurrence at various positions and times.
Characterization of a C O2 gas vent using various geophysical and geochemical methods
Authors: Pettinelli Elena , Beaubien Stan E. , Zaja Annalisa , Menghini Antonio , Praticelli Nicola , Mattei Elisabetta , Di Matteo Andrea , Annunziatellis Aldo , Ciotoli Giancarlo , Lombardi Salvatore
Published: June 2010

An understanding of gas migration along faults is important in many geologic research fields, such as geothermal exploration, risk assessment, and, more recently, the geologic storage of man-made carbon dioxide [Formula: see text]. If these gases reach the surface, they typically are discharged to the atmosphere from small areas known as gas vents. In a study of an individual gas vent located in the extinct Latera caldera, central Italy, near-surface geochemical and geophysical surveys were conducted to define the spatial distribution of gas-induced effects in the first few meters of the soil and, by inference, the 3D structure and geometry of the associated gas-permeable fault. Grid surveys and detailed profiles were performed across this vent using time-domain reflectometry (TDR), ground-penetrating radar (GPR), frequency-domain electromagnetics (FDEM), electrical resistivity tomography (ERT), and gas geochemistry measurements. Detailed profilesurveys indicate that the leaking [Formula: see text] has changed the physical, chemical, and biological soil environment of the vent, resulting in significant spatial variations in parameters (e.g., water content and soil electric/dielectric properties) that influence geophysical measurement results. Despite the strong difference in vertical and lateral resolution and depth of investigation, all methods show the same general trends and similar relative variations in the measured physical parameters. TDR and GPR data highlight anomalous shallow lateral variations, whereas FDEM and ERT measurements identify the vertical extension of the anomalous zone. All methods highlight a north-northwest–south-southeast anomaly alignment that we associate with the main fault; FDEM and, to a lesser extent, [Formula: see text] flux also show elongation orthogonal to this direction, implying that the vent may occur at the intersection of two structures. Thus, different near-surface geophysical and geochemical methods can provide important information on faults and their gas-migration characteristics.
Target-oriented joint least-squares migration/inversion of time-lapse seismic data sets
Authors: Ayeni Gboyega , Biondi Biondo
Published: June 2010

Two related formulations are proposed for target-oriented joint least-squares migration/inversion of time-lapse seismic data sets. Time-lapse seismic images can be degraded when reservoir overburden is complex or when acquisition geometries significantly differ, because the migration operator does not compensate for the resulting amplitude and phase distortions. Under these circumstances, time-lapse amplitudes are poor indicators of production-related changes in reservoir properties. To correct for such image degradation, time-lapse imaging is posed as joint inverse problems that utilize concatenations of target-oriented approximations to the linear least-squares imaging Hessian. In both formulations, spatial and temporal constraints ensure inversion stability and geologically consistent time-lapse images. Using two numerical time-lapse data sets, we confirmed that these formulations can attenuate illumination artifacts caused by complex overburden or geometry differences, and that they yield better-quality images than obtainable with migration.