bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross-presentation by dendritic cells from live cells induces protective immune responses in vivo
Authors: Matheoud Diana , Perié Leila , Hoeffel Guillaume , Vimeux Lene , Parent Isabelle , Marañón Concepción , Bourdoncle Pierre , Renia Laurent , Prevost-Blondel Armelle , Lucas Bruno , Feuillet Vincent , Hosmalin Anne
Published: March 2010

Cross-presentation is an essential mechanism that allows dendritic cells (DCs) to efficiently present exogenous antigens to CD8+ T cells. Among cellular antigen sources, apoptotic cells are commonly considered as the best for cross-presentation by DCs. However, the potential of live cells as a source of antigen has been overlooked. Here we explored whether DCs were able to capture and cross-present antigens from live cells. DCs internalized cytosolic and membrane material into vesicles from metabolically labeled live cells. Using time-lapse confocal microscopy in whole spleens, we showed that DCs internalized material from live cells in vivo. After ovalbumin uptake from live cells, DCs cross-primed ovalbumin-specific naive OT-I CD8+ T cells in vitro. Injected into mice previously transferred with naive OT-I T cells, they also cross-primed in vivo, even in the absence of endogenous DCs able to present the epitope in the recipient mice. Interestingly, DCs induced stronger natural CD8+ T-cell responses and protection against a lethal tumor challenge after capture of antigens from live melanoma cells than from apoptotic melanoma cells. The potential for cross-presentation from live cells uncovers a new type of cellular intercommunication and must be taken into account for induction of tolerance or immunity against self, tumors, grafts, or pathogens.
How I treat hemochromatosis
Authors: Adams Paul C. , Barton James C.
Published: March 2010

Hemochromatosis is a common genetic disorder in which iron may progressively accumulate in the liver, heart, and other organs. The primary goal of therapy is iron depletion to normalize body iron stores and to prevent or decrease organ dysfunction. The primary therapy to normalize iron stores is phlebotomy. In this opinion article, we discuss the indications for and monitoring of phlebotomy therapy to achieve iron depletion, maintenance therapy, dietary and pharmacologic maneuvers that could reduce iron absorption, and the role of voluntary blood donation.
Improving pairwise sequence alignment accuracy using near-optimal protein sequence alignments
Authors: Sierk Michael L , Smoot Michael E , Bass Ellen J , Pearson William R
Published: March 2010

Background

While the pairwise alignments produced by sequence similarity searches are a powerful tool for identifying homologous proteins - proteins that share a common ancestor and a similar structure; pairwise sequence alignments often fail to represent accurately the structural alignments inferred from three-dimensional coordinates. Since sequence alignment algorithms produce optimal alignments, the best structural alignments must reflect suboptimal sequence alignment scores. Thus, we have examined a range of suboptimal sequence alignments and a range of scoring parameters to understand better which sequence alignments are likely to be more structurally accurate.

Results

We compared near-optimal protein sequence alignments produced by the Zuker algorithm and a set of probabilistic alignments produced by the probA program with structural alignments produced by four different structure alignment algorithms. There is significant overlap between the solution spaces of structural alignments and both the near-optimal sequence alignments produced by commonly used scoring parameters for sequences that share significant sequence similarity (E-values < 10-5) and the ensemble of probA alignments. We constructed a logistic regression model incorporating three input variables derived from sets of near-optimal alignments: robustness, edge frequency, and maximum bits-per-position. A ROC analysis shows that this model more accurately classifies amino acid pairs (edges in the alignment path graph) according to the likelihood of appearance in structural alignments than the robustness score alone. We investigated various trimming protocols for removing incorrect edges from the optimal sequence alignment; the most effective protocol is to remove matches from the semi-global optimal alignment that are outside the boundaries of the local alignment, although trimming according to the model-generated probabilities achieves a similar level of improvement. The model can also be used to generate novel alignments by using the probabilities in lieu of a scoring matrix. These alignments are typically better than the optimal sequence alignment, and include novel correct structural edges. We find that the probA alignments sample a larger variety of alignments than the Zuker set, which more frequently results in alignments that are closer to the structural alignments, but that using the probA alignments as input to the regression model does not increase performance.

Conclusions

The pool of suboptimal pairwise protein sequence alignments substantially overlaps structure-based alignments for pairs with statistically significant similarity, and a regression model based on information contained in this alignment pool improves the accuracy of pairwise alignments with respect to structure-based alignments.
Correcting for intra-experiment variation in Illumina BeadChip data is necessary to generate robust gene-expression profiles
Authors: Kitchen Robert R , Sabine Vicky S , Sims Andrew H , Macaskill E Jane , Renshaw Lorna , Thomas Jeremy S , van Hemert Jano I , Dixon J Michael , Bartlett John MS
Published: March 2010

Background

Microarray technology is a popular means of producing whole genome transcriptional profiles, however high cost and scarcity of mRNA has led many studies to be conducted based on the analysis of single samples. We exploit the design of the Illumina platform, specifically multiple arrays on each chip, to evaluate intra-experiment technical variation using repeated hybridisations of universal human reference RNA (UHRR) and duplicate hybridisations of primary breast tumour samples from a clinical study.

Results

A clear batch-specific bias was detected in the measured expressions of both the UHRR and clinical samples. This bias was found to persist following standard microarray normalisation techniques. However, when mean-centering or empirical Bayes batch-correction methods (ComBat) were applied to the data, inter-batch variation in the UHRR and clinical samples were greatly reduced. Correlation between replicate UHRR samples improved by two orders of magnitude following batch-correction using ComBat (ranging from 0.9833-0.9991 to 0.9997-0.9999) and increased the consistency of the gene-lists from the duplicate clinical samples, from 11.6% in quantile normalised data to 66.4% in batch-corrected data. The use of UHRR as an inter-batch calibrator provided a small additional benefit when used in conjunction with ComBat, further increasing the agreement between the two gene-lists, up to 74.1%.

Conclusion

In the interests of practicalities and cost, these results suggest that single samples can generate reliable data, but only after careful compensation for technical bias in the experiment. We recommend that investigators appreciate the propensity for such variation in the design stages of a microarray experiment and that the use of suitable correction methods become routine during the statistical analysis of the data.
Evidence of perturbations of cell cycle and DNA repair pathways as a consequence of human and murine NF1-haploinsufficiency
Authors: Pemov Alexander , Park Caroline , Reilly Karlyne M , Stewart Douglas R
Published: March 2010

Background

Neurofibromatosis type 1 (NF1) is a common monogenic tumor-predisposition disorder that arises secondary to mutations in the tumor suppressor gene NF1. Haploinsufficiency of NF1 fosters a permissive tumorigenic environment through changes in signalling between cells, however the intracellular mechanisms for this tumor-promoting effect are less clear. Most primary human NF1
+/- cells are a challenge to obtain, however lymphoblastoid cell lines (LCLs) have been collected from large NF1 kindreds. We hypothesized that the genetic effects of NF1-haploinsufficiency may be discerned by comparison of genome-wide transcriptional profiling in somatic, non-tumor cells (LCLs) from NF1-affected and -unaffected individuals. As a cross-species filter for heterogeneity, we compared the results from two human kindreds to whole-genome transcriptional profiling in spleen-derived B lymphocytes from age- and gender-matched Nf1
+/- and wild-type mice, and used gene set enrichment analysis (GSEA), Onto-Express, Pathway-Express and MetaCore tools to identify genes perturbed in NF1-haploinsufficiency.

Results

We observed moderate expression of NF1 in human LCLs and of Nf1 in CD19+ mouse B lymphocytes. Using the t test to evaluate individual transcripts, we observed modest expression differences in the transcriptome in NF1-haploinsufficient LCLs and Nf1-haploinsuffiicient mouse B lymphocytes. However, GSEA, Onto-Express, Pathway-Express and MetaCore analyses identified genes that control cell cycle, DNA replication and repair, transcription and translation, and immune response as the most perturbed in NF1-haploinsufficient conditions in both human and mouse.

Conclusions

Haploinsufficiency arises when loss of one allele of a gene is sufficient to give rise to disease. Haploinsufficiency has traditionally been viewed as a passive state. Our observations of perturbed, up-regulated cell cycle and DNA repair pathways may functionally contribute to NF1-haploinsufficiency as an "active state" that ultimately promotes the loss of the wild-type allele.
CoBaltDB: Complete bacterial and archaeal orfeomes subcellular localization database and associated resources
Authors: Goudenège David , Avner Stéphane , Lucchetti-Miganeh Céline , Barloy-Hubler Frédérique
Published: March 2010

Background

The functions of proteins are strongly related to their localization in cell compartments (for example the cytoplasm or membranes) but the experimental determination of the sub-cellular localization of proteomes is laborious and expensive. A fast and low-cost alternative approach isin silicoprediction, based on features of the protein primary sequences. However, biologists are confronted with a very large number of computational tools that use different methods that address various localization features with diverse specificities and sensitivities. As a result, exploiting these computer resources to predict protein localization accurately involves querying all tools and comparing every prediction output; this is a painstaking task. Therefore, we developed a comprehensive database, called CoBaltDB, that gathers all prediction outputs concerning complete prokaryotic proteomes.

Description

The current version of CoBaltDB integrates the results of 43 localization predictors for 784 complete bacterial and archaeal proteomes (2.548.292 proteins in total). CoBaltDB supplies a simple user-friendly interface for retrieving and exploring relevant information about predicted features (such as signal peptide cleavage sites and transmembrane segments). Data are organized into three work-sets ("specialized tools", "meta-tools" and "additional tools"). The database can be queried using the organism name, a locus tag or a list of locus tags and may be browsed using numerous graphical and text displays.

Conclusions

With its new functionalities, CoBaltDB is a novel powerful platform that provides easy access to the results of multiple localization tools and support for predicting prokaryotic protein localizations with higher confidence than previously possible. CoBaltDB is available athttp://www.umr6026.univ-rennes1.fr/english/home/research/basic/software/cobalten.
Symbiotic functioning and bradyrhizobial biodiversity of cowpea (Vigna unguiculataL. Walp.) in Africa
Authors: Pule-Meulenberg Flora , Belane Alphonsus K , Krasova-Wade Tatiana , Dakora Felix D
Published: March 2010

Background

Cowpea is the most important food grain legume in Sub-Saharan Africa. However, no study has so far assessed rhizobial biodiversity and/or nodule functioning in relation to strain IGS types at the continent level. In this study, 9 cowpea genotypes were planted in field experiments in Botswana, South Africa and Ghana with the aim of i) trapping indigenous cowpea root-nodule bacteria (cowpea "rhizobia") in the 3 countries for isolation, molecular characterisation using PCR-RFLP analysis, and sequencing of the 16S - 23S rDNA IGS gene, ii) quantifying N-fixed in the cowpea genotypes using the 15N natural abundance technique, and iii) relating the levels of nodule functioning (i.e. N-fixed) to the IGS types found inside nodules.

Results

Field measurements of N2 fixation revealed significant differences in plant growth, δ15N values, %Ndfa and amounts of N-fixed between and among the 9 cowpea genotypes in Ghana and South Africa. Following DNA analysis of 270 nodules from the 9 genotypes, 18 strain IGS types were found. Relating nodule function to the 18 IGS types revealed significant differences in IGS type N2-fixing efficiencies. Sequencing the 16S - 23S rDNA gene also revealed 4 clusters, with cluster 2 forming a distinct group that may be a new Bradyrhizobium species. Taken together, our data indicated greater biodiversity of cowpea bradyrhizobia in South Africa relative to Botswana and Ghana.

Conclusions

We have shown that cowpea is strongly dependant on N2 fixation for its N nutrition in both South Africa and Ghana. Strain IGS type symbiotic efficiency was assessed for the first time in this study, and a positive correlation was discernible where there was sole nodule occupancy. The differences in IGS type diversity and symbiotic efficiency probably accounts for the genotype × environment interaction that makes it difficult to select superior genotypes for use across Africa. The root-nodule bacteria nodulating cowpea in this study all belonged to the genus Bradyrhizobium. Some strains from Southern Africa were phylogenetically very distinct, suggesting a new Bradyrhizobium species.
Reference gene alternatives to Gapdh in rodent and human heart failure gene expression studies
Authors: Brattelid Trond , Winer Lisbeth H , Levy Finn Olav , Liestøl Knut , Sejersted Ole M , Andersson Kristin B
Published: March 2010

Background

Quantitative real-time RT-PCR (RT-qPCR) is a highly sensitive method for mRNA quantification, but requires invariant expression of the chosen reference gene(s). In pathological myocardium, there is limited information on suitable reference genes other than the commonly used Gapdh mRNA and 18S ribosomal RNA. Our aim was to evaluate and identify suitable reference genes in human failing myocardium, in rat and mouse post-myocardial infarction (post-MI) heart failure and across developmental stages in fetal and neonatal rat myocardium.

Results

The abundance of Arbp, Rpl32, Rpl4, Tbp, Polr2a, Hprt1, Pgk1, Ppia and Gapdh mRNA and 18S ribosomal RNA in myocardial samples was quantified by RT-qPCR. The expression variability of these transcripts was evaluated by the geNorm and Normfinder algorithms and by a variance component analysis method. Biological variability was a greater contributor to sample variability than either repeated reverse transcription or PCR reactions.

Conclusions

The most stable reference genes were Rpl32, Gapdh and Polr2a in mouse post-infarction heart failure, Polr2a, Rpl32 and Tbp in rat post-infarction heart failure and Rpl32 and Pgk1 in human heart failure (ischemic disease and cardiomyopathy). The overall most stable reference genes across all three species was Rpl32 and Polr2a. In rat myocardium, all reference genes tested showed substantial variation with developmental stage, with Rpl4 as was most stable among the tested genes.
The expression of TRMT2A, a novel cell cycle regulated protein, identifies a subset of breast cancer patients with HER2 over-expression that are at an increased risk of recurrence
Authors: Hicks David G , Janarthanan Bagi R , Vardarajan Ramya , Kulkarni Swati A , Khoury Thaer , Dim Daniel , Budd G Thomas , Yoder Brian J , Tubbs Raymond , Schreeder Marshall T , Estopinal Noel C , Beck Rodney A , Wang Yanling , Ring Brian Z , Seitz Robert S , Ross Douglas T
Published: March 2010

Background

Over-expression of HER2 in a subset of breast cancers (HER2+) is associated with high histological grade and aggressive clinical course. Despite these distinctive features, the differences in response of HER2+ patients to both adjuvant cytotoxic chemotherapy and targeted therapy (e.g. trastuzumab) suggests that unrecognized biologic and clinical diversity is confounding treatment strategies. Furthermore, the small but established risk of cardiac morbidity with trastuzumab therapy compels efforts towards the identification of biomarkers that might help stratify patients.

Methods

A single institution tissue array cohort assembled at the Clearview Cancer Institute of Huntsville (CCIH) was screened by immunohistochemistry staining using a large number of novel and commercially available antibodies to identify those with a univariate association with clinical outcome in HER2+ patients. Staining with antibody directed at TRMT2A was found to be strongly associated with outcome in HER2+ patients. This association with outcome was tested in two independent validation cohorts; an existing staining dataset derived from tissue assembled at the Cleveland Clinic Foundation (CCF), and in a new retrospective study performed by staining archived paraffin blocks available at the Roswell Park Cancer Institute (RPCI).

Results

TRMT2A staining showed a strong correlation with likelihood of recurrence at five years in 67 HER2+ patients from the CCIH discovery cohort (HR 7.0; 95% CI 2.4 to 20.1, p < 0.0004). This association with outcome was confirmed using 75 HER2+ patients from the CCF cohort (HR 3.6; 95% CI 1.3 to 10.2, p < 0.02) and 64 patients from the RPCI cohort (HR 3.4; 95% CI 1.3-8.9, p < 0.02). In bivariable analysis the association with outcome was independent of grade, tumor size, nodal status and the administration of conventional adjuvant chemotherapy in the CCIH and RPCI cohorts.

Conclusions

Studies from three independent single institution cohorts support TRMT2A protein expression as a biomarker of increased risk of recurrence in HER2+ breast cancer patients. These results suggest that TRMT2A expression should be further studied in the clinical trial setting to explore its predictive power for response to adjuvant cytotoxic chemotherapy in combination with HER2 targeted therapy.
Cross-national differences in clinically significant cannabis problems: epidemiologic evidence from 'cannabis-only' smokers in the United States, Mexico, and Colombia
Authors: Fiestas Fabian , Radovanovic Mirjana , Martins Silvia S , Medina-Mora Maria E , Posada-Villa Jose , Anthony James C
Published: March 2010

Background

Epidemiological studies show wide variability in the occurrence of cannabis smoking and related disorders across countries. This study aims to estimate cross-national variation in cannabis users' experience of clinically significant cannabis-related problems in three countries of the Americas, with a focus on cannabis users who may have tried alcohol or tobacco, but who have not used cocaine, heroin, LSD, or other internationally regulated drugs.

Methods

Data are from the World Mental Health Surveys Initiative and the National Latino and Asian American Study, with probability samples in Mexico (n = 4426), Colombia (n = 5,782) and the United States (USA; n = 8,228). The samples included 212 'cannabis only' users in Mexico, 260 in Colombia and 1,724 in the USA. Conditional GLM with GEE and 'exact' methods were used to estimate variation in the occurrence of clinically significant problems in cannabis only (CO) users across these surveyed populations.

Results

The experience of cannabis-related problems was quite infrequent among CO users in these countries, with weighted frequencies ranging from 1% to 5% across survey populations, and with no appreciable cross-national variation in general. CO users in Colombia proved to be an exception. As compared to CO users in the USA, the Colombia smokers were more likely to have experienced cannabis-associated 'social problems' (odds ratio, OR = 3.0; 95% CI = 1.4, 6.3; p = 0.004) and 'legal problems' (OR = 9.7; 95% CI = 2.7, 35.2; p = 0.001).

Conclusions

This study's most remarkable finding may be the similarity in occurrence of cannabis-related problems in this cross-national comparison within the Americas. Wide cross-national variations in estimated population-level cumulative incidence of cannabis use disorders may be traced to large differences in cannabis smoking prevalence, rather than qualitative differences in cannabis experiences. More research is needed to identify conditions that might make cannabis-related social and legal problems more frequent in Colombia than in the USA.
Intensity level for exercise training in fibromyalgia by using mathematical models
Authors: Lemos Maria Carolina D , Valim Valéria , Zandonade Eliana , Natour Jamil
Published: March 2010

Background

It has not been assessed before whether mathematical models described in the literature for prescriptions of exercise can be used for fibromyalgia syndrome patients. The objective of this paper was to determine how age-predicted heart rate formulas can be used with fibromyalgia syndrome populations as well as to find out which mathematical models are more accurate to control exercise intensity.

Methods

A total of 60 women aged 18-65 years with fibromyalgia syndrome were included; 32 were randomized to walking training at anaerobic threshold. Age-predicted formulas to maximum heart rate ("220 minus age" and "208 minus 0.7 × age") were correlated with achieved maximum heart rate (HRMax) obtained by spiroergometry. Subsequently, six mathematical models using heart rate reserve (HRR) and age-predicted HRMax formulas were studied to estimate the intensity level of exercise training corresponding to heart rate at anaerobic threshold (HRAT) obtained by spiroergometry. Linear and nonlinear regression models were used for correlations and residues analysis for the adequacy of the models.

Results

Age-predicted HRMax and HRAT formulas had a good correlation with achieved heart rate obtained in spiroergometry (r= 0.642;p< 0.05). For exercise prescription in the anaerobic threshold intensity, the percentages were 52.2-60.6% HRR and 75.5-80.9% HRMax. Formulas using HRR and the achieved HRMax showed better correlation. Furthermore, the percentages of HRMax and HRR were significantly higher for the trained individuals (p< 0.05).

Conclusion

Age-predicted formulas can be used for estimating HRMax and for exercise prescriptions in women with fibromyalgia syndrome. Karnoven's formula using heart rate achieved in ergometric test showed a better correlation. For the prescription of exercises in the threshold intensity, 52% to 60% HRR or 75% to 80% HRMax must be used in sedentary women with fibromyalgia syndrome and these values are higher and must be corrected for trained patients.
Phenotypic analysis of images of zebrafish treated with Alzheimer's γ-secretase inhibitors
Authors: Arslanova Dilyara , Yang Ting , Xu Xiaoyin , Wong Stephen T , Augelli-Szafran Corinne E , Xia Weiming
Published: March 2010

Background

Several γ-secretase inhibitors (GSI) are in clinical trials for the treatment of Alzheimer's disease (AD). This enzyme mediates the proteolytic cleavage of amyloid precursor protein (APP) to generate amyloid β protein, Aβ, the pathogenic protein in AD. The γ-secretase also cleaves Notch to generate Notch Intracellular domain (NICD), the signaling molecule that is implicated in tumorigenesis.

Results

We have developed a method to examine live zebrafish that were each treated with γ-secretase inhibitors (GSI), DAPT {N- [N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycinet-Butyl Ester}, Gleevec, or fragments of Gleevec. These compounds were first tested in a cell-based assay and the effective concentrations of these compounds that blocked Aβ generation were quantitated. The mortality of zebrafish, as a result of exposure to different doses of compound, was assessed, and any apoptotic processes were examined by TUNEL staining. We then used conventional and automatic microscopes to acquire images of zebrafish and applied algorithms to automate image composition and processing. Zebrafish were treated in 96- or 384-well plates, and the phenotypes were analyzed at 2, 3 and 5 days post fertilization (dpf). We identified that AD95, a fragment of Gleevec, effectively blocks Aβ production and causes specific phenotypes that were different from those treated with DAPT. Finally, we validated the specificity of two Notch phenotypes (pigmentation and the curvature of tail/trunk) induced by DAPT in a dose-dependent manner. These phenotypes were examined in embryos treated with GSIs or AD95 at increasing concentrations. The expression levels of Notch target geneher6were also measured byin situhybridization and the co-relationship between the levels of Notch inhibition by DAPT and AD95 and the severity of phenotypes were determined.

Conclusion

The results reported here of the effects on zebrafish suggest that this newly developed method may be used to screen novel GSIs and other leads for a variety of therapeutic indications.
Prevalence and risk profile of cervical human papillomavirus infection in Zhejiang Province, southeast China: a population-based study
Authors: Ye Jing , Cheng Xiaodong , Chen Xiaojing , Ye Feng , Lü Weiguo , Xie Xing
Published: March 2010

Background

Benign or malignant lesions caused by Human papillomavirus (HPV) produce considerable health burden worldwide. Since limited cross-protection would be offered between HPV types, heterogeneity in HPV type-specific distribution should be taken into account when predicting the effect of current prophylactic vaccines and forming the basic for the second-generation vaccines targeted to specific regions. Here, we investigated the prevalence of cervical HPV infection, as well as predictors concerned, in Zhejiang Province, southeast China.

Results

Totally 4987 cervical samples from five randomly chosen counties in Zhejiang Province were detected. The overall HPV prevalence was 13.3%. Established high-risk (HR) HPV prevalence was 10.2%. HPV-52 was the most prevalent type (3.1%), followed by HPV-16 (2.5%), -58 (2.1%), -68 (1.0%) and -81 (0.9%). HPV-16 or -18 were present in 3.1% of the detected samples, while 174 specimens (3.5%) were positive for any of HPV-6, -11, -16 and -18. The prevalence of HPV vaccine types was consistently low across age groups. Bimodal age distribution in HR-HPV, including established HR and probably HR-HPV, was observed, with a clear second peak in perimenopausal women. Multivariate unconditional logistic regression models revealed that partner's lifetime number of partners was the only common independent predictor of overall, established HR, established low-risk, single-type and multiple-type HPV infection in current study.

Conclusions

We have observed low prevalence of HPV vaccine types and relatively high prevalence of HPV-52 and -58 in our population. Our findings support universal "catch-up" vaccination of sexual experienced young women in Zhejiang Province, as well as enhance the hypothesis that the second-generation HPV prophylactic vaccines including HPV-52 and -58 may offer higher protection for women in China and other Asian areas. Furthermore, our data support close surveillance of perimenopausal women with HR-HPV infection.
Effect of the CB1 cannabinoid agonist WIN 55212-2 on the acquisition and reinstatement of MDMA-induced conditioned place preference in mice
Authors: Manzanedo Carmen , Rodríguez-Arias Marta , Daza-Losada Manuel , Maldonado Concepción , Aguilar María A , Miñarro José
Published: March 2010

Background

Numerous reports indicate that MDMA users consume other psychoactive drugs, among which cannabis is one of the most common. The aim of the present study was to evaluate, using the conditioned place preference, the effect of the cannabinoid agonist WIN 55,212-2 on the rewarding effects of MDMA in mice.

Methods

In the first experiment adolescent mice were initially conditioned with 1.25, 2.5 or 5 mg/kg of MDMA or 0.1 or 0.5 mg/kg of WIN and subsequently with both drugs. Reinstatement of the extinguished preference by priming doses was performed in the groups that showed CPP. In the second experiment, animals were conditioned with 2.5 or 5 mg/kg of MDMA and, after extinction, reinstatement of the preference was induced by 0.5 or 0.1 mg/kg of WIN.

Results

A low dose of WIN 55212-2 (0.1 mg/kg) increased the rewarding effects of low doses of MDMA (1.25 mg/kg), although a decrease in the preference induced by MDMA (5 and 2.5 mg/kg) was observed when the dose of WIN 55212-2 was raised (0.5 mg/kg). The CB1 antagonist SR 141716 also increased the rewarding effects of the lowest MDMA dose and did not block the effects of WIN. Animals treated with the highest WIN dose plus a non-neurotoxic dose of MDMA exhibited decreases of striatal DA and serotonin in the cortex. On the other hand, WIN 55212-2-induced CPP was reinstated by priming injections of MDMA, although WIN did not reinstate the MDMA-induced CPP.

Conclusions

These results confirm that the cannabinoid system plays a role in the rewarding effects of MDMA and highlights the risks that sporadic drug use can pose in terms of relapse to dependence. Finally, the potential neuroprotective action of cannabinoids is not supported by our data; on the contrary, they are evidence of the potential neurotoxic effect of said drugs when administered with MDMA.
Nocardia farcinica lung infection in a patient with cystic fibrosis: a case report
Authors: Bittar Fadi , Stremler Nathalie , Audié Jean-Pierre , Dubus Jean-Christophe , Sarles Jacques , Raoult Didier , Rolain Jean-Marc
Published: March 2010

Introduction

Respiratory tract infections are the major causes of morbidity and mortality in patients with cystic fibrosis. Nocardia are rarely implicated in these infections and few reports of the involvement of this species are found in the literature.

Case presentation

We describe a case of lung infection followed by chronic colonization of trimethoprim and sulfamethoxazole resistant Nocardia farcinica in a patient with cystic fibrosis. The chronic colonization of this uncommon bacterium in patients with cystic fibrosis was proved using a newly developed real-time polymerase chain reaction assay, which indicates that this bacterium, despite treatment, is difficult to eradicate.

Conclusion

Our case report confirms that this organism can be recovered in persons with cystic fibrosis. Its eradication is necessary especially if the patient is to undergo lung transplantation.
Comparison of mechanistic models in the initial rate enzymatic hydrolysis of AFEX-treated wheat straw
Authors: Brown Russell F , Agbogbo Frank K , Holtzapple Mark T
Published: March 2010

Background

Different mechanistic models have been used in the literature to describe the enzymatic hydrolysis of pretreated biomass. Although these different models have been applied to different substrates, most of these mechanistic models fit into two- and three-parameter mechanistic models. The purpose of this study is to compare the models and determine the activation energy and the enthalpy of adsorption of Trichoderma reesei enzymes on ammonia fibre explosion (AFEX)-treated wheat straw. Experimental enzymatic hydrolysis data from AFEX-treated wheat straw were modelled with two- and three-parameter mechanistic models from the literature. In order to discriminate between the models, initial rate data at 49°C were subjected to statistical analysis (analysis of variance and scatter plots).

Results

For three-parameter models, the HCH-1 model best fitted the experimental data; for two-parameter models Michaelis-Menten (M-M) best fitted the experimental data. All the three-parameter models fitted the data better than the two-parameter models. The best three models at 49°C (HCH-1, Huang and M-M) were compared using initial rate data at three temperatures (35°, 42° and 49°C). The HCH-1 model provided the best fit based on the F values, the scatter plot and the residual sum of squares. Also, its kinetic parameters were linear in Arrhenius/van't Hoff's plots, unlike the other models. The activation energy (Ea) is 47.6 kJ/mol and the enthalpy change of adsorption (ΔH) is -118 kJ/mol for T. reesei enzymes on AFEX-treated wheat straw.

Conclusion

Among the two-parameter models, Michaelis-Menten model provided the best fit compared to models proposed by Humphrey and Wald. For the three-parameter models, HCH-1 provided the best fit because the model includes a fractional coverage parameter (ϕ) which accounts for the number of reactive sites covered by the enzymes.
High survival and treatment success sustained after two and three years of first‐line ART for children in Cambodia
Authors: Isaakidis Petros , Raguenaud Marie‐Eve , Te Vantha , Tray Chhraing S , Akao Kazumi , Kumar Varun , Ngin Sopheak , Nerrienet Eric , Zachariah Rony
Published: March 2010

Background

Long‐term outcomes of antiretroviral therapy (ART) in children remain poorly documented in resource‐limited settings. The objective of this study was to assess two‐and three‐year survival, CD4 evolution and virological response among children on ART in a programmatic setting in Cambodia.

Methods

Children treated with first‐line ART for at least 24 months were assessed with viral load testing and genotyping. We used Kaplan‐Meier analysis for survival and Cox regression to identify risk factors associated with treatment failure.

Results

Of 1168 registered HIV‐positive children, 670 (57%) started ART between January 2003 and December 2007. Survival probability was 0.93 (95% CI: 0.91‐0.95) and 0.91 (95% CI: 0.88‐0.93) at 24 and 36 months after ART initiation, respectively. Median CD4 gain for children aged over five years was 704 cells/mm3 at 24 months and 737 at 36 months. Median CD4 percentage gain for children under five years old was 15.2% at 24 months and 15% at 36 months. One hundred and thirty children completed at least 24 months of ART, and 138 completed 36 months: 128 out of 268 (48%) were female. Median age at ART initiation was six years.

Overall, 22 children had viral loads of >1000 copies/ml (success ratio = 86% on intention‐to‐treat‐analysis) and 21 of 21 presented mutations conferring resistance mostly to lamivudine and non‐nucleoside reverse transcriptase inhibitors. Risk factors for failure after 24 and 36 months were CD4 counts below the threshold for severe immunosupression at those months respectively. Only two out of 22 children with viral loads of >1000 copies/ml met the World Health Organization immunological criteria for failure (sensitivity = 0.1).

Conclusions

Good survival, immunological restoration and viral suppression can be sustained after two to three years of ART among children in resource‐constrained settings. Increased access to routine virological measurements is needed for timely diagnosis of treatment failure.
Elevated osteoprotegerin is associated with abnormal ankle brachial indices in patients infected with HIV: a cross‐sectional study
Authors: Jang James J , Schwarcz Aron I , Amaez Daniel A , Woodward Mark , Olin Jeffrey W , Keller Marla J , Schecter Alison D
Published: March 2010

Background

Patients infected with HIV have an increased risk for accelerated atherosclerosis. Elevated levels of osteoprotegerin, an inflammatory cytokine receptor, have been associated with a high incidence of cardiovascular disease (including peripheral arterial disease, or PAD), acute coronary syndrome, and cardiovascular mortality. The objective of this study was to determine whether PAD is prevalent in an HIV‐infected population, and to identify an association with HIV‐specific and traditional cardiovascular risk factors, as well as levels of osteoprotegerin.

Methods

One hundred and two patients infected with HIV were recruited in a cross‐sectional study. To identify the prevalence of PAD, ankle‐brachial indices (ABIs) were measured. Four standard ABI categories were utilized: ≤ 0.90 (definite PAD); 0.91‐0.99 (borderline); 1.00‐1.30 (normal); and >1.30 (high). Medical history and laboratory measurements were obtained to determine possible risk factors associated with PAD in HIV‐infected patients.

Results

The prevalence of PAD (ABI ≤ 0.90) in a young HIV‐infected population (mean age: 48 years) was 11%. Traditional cardiovascular risk factors, including advanced age and previous cardiovascular history, as well as elevated C‐reactive protein levels, were associated with PAD. Compared with patients with normal ABIs, patients with high ABIs had significantly elevated levels of osteoprotegerin [1428.9 (713.1) pg/ml vs. 3088.6 (3565.9) pg/ml, respectively, p = 0.03].

Conclusions

There is a high prevalence of PAD in young HIV‐infected patients. A number of traditional cardiovascular risk factors and increased osteoprotegerin concentrations are associated with abnormal ABIs. Thus, early screening and aggressive medical management for PAD may be warranted in HIV‐infected patients.
Association between IL-18gene polymorphisms and biopsy-proven giant cell arteritis
Authors: Palomino-Morales Rogelio J , Vazquez-Rodriguez Tomas R , Torres Orlando , Morado Inmaculada C , Castañeda Santos , Miranda-Filloy Jose A , Callejas-Rubio Jose L , Fernandez-Gutierrez Benjamin , Gonzalez-Gay Miguel A , Martin Javier
Published: March 2010

Introduction

The objective was to investigate the potential implication of the IL18 gene promoter polymorphisms in the susceptibility to giant-cell arteritis (GCA).

Methods

In total, 212 patients diagnosed with biopsy-proven GCA were included in this study. DNA from patients and matched controls was obtained from peripheral blood. Samples were genotyped for the IL18-137 G>C (rs187238), the IL18-607 C>A (rs1946518), and the IL18-1297 T>C (rs360719) gene polymorphisms with polymerase chain reaction, by using a predesigned TaqMan allele discrimination assay.

Results

No significant association between the IL18-137 G>C polymorphism and GCA was found. However, the IL18 -607 allele A was significantly increased in GCA patients compared with controls (47.8% versus 40.9% in patients and controls respectively; P = 0.02; OR, 1.32; 95% CI, 1.04 to 1.69). It was due to an increased frequency of homozygosity for the IL18 -607 A/A genotype in patients with GCA (20.4%) compared with controls (13.4%) (IL18 -607 A/A versus IL18 -607 A/C plus IL18 -607 C/C genotypes: P = 0.04; OR, 1.59; 95% CI, 1.02 to 2.46). Also, the IL18-1297 allele C was significantly increased in GCA patients (30.7%) compared with controls (23.0%) (P = 0.003; OR, 1.48; 95% CI, 1.13 to 1.95). In this regard, an increased susceptibility to GCA was observed in individuals carrying the IL18-1297 C/C or the IL18-1297 C/T genotypes compared with those carrying the IL18-1297 T/T genotype (IL18-1297 C/C plus IL18-1297 T/C versus IL18-1297 T/T genotype in GCA patients compared with controls: P = 0.005; OR, 1.61; 95% CI, 1.15 to 2.25). We also found an additive effect of the IL18 -1297 and -607 polymorphisms with TLR4 Asp299Gly polymorphism. The OR for GCA was 1.95 for combinations of genotypes with one or two risk alleles, whereas carriers of three or more risk alleles have an OR of 3.7.

Conclusions

Our results show for the first time an implication of IL18 gene-promoter polymorphisms in the susceptibility to biopsy-proven GCA. In addition, an additive effect between the associated IL18 and TLR4 genetic variants was observed.
Generalized nonhyperbolic moveout approximation
Authors: Fomel Sergey , Stovas Alexey
Published: March 2010

Reflection moveout approximations are commonly used for velocity analysis, stacking, and time migration. A novel functional form for approximating the moveout of reflection traveltimes at large offsets is introduced. In comparison with the classic hyperbolic approximation, which uses only two parameters (zero-offset time and moveout velocity), this form involves five parameters that can be determined, in a known medium, from zero-offset computations and from tracing one nonzero-offset ray. It is called a generalized approximation because it reduces to some known three-parameter forms with a particular choice of coefficients. By testing the accuracy of the proposed approximation with analytical and numerical examples, the new approximation is shown to bring an improvement in accuracy of several orders of magnitude compared to known analytical approximations, which makes it as good as exact for many practical purposes.
Shear-wave seismic reflection studies of unconsolidated sediments in the near surface
Authors: Haines Seth S. , Ellefsen Karl J.
Published: March 2010

We have successfully applied of SH-wave seismic reflection methods to two different near-surface problems targeting unconsolidated sediments. At the former Fort Ord, where the water table is approximately [Formula: see text] deep, we imaged aeolian and marine aquifer and aquitard stratigraphy to a depth of approximately [Formula: see text]. We identified reflections from sand/clay and sand/silt interfaces and we mapped these interfaces along our transects. At an aggregate study site in Indiana, where the water table is at a depth of [Formula: see text], we imaged stratigraphy in alluvial sand and gravel, and observe a strong reflection from the [Formula: see text]-deep bedrock surface. In both cases, we exploited the high resolution potential of SH waves, their insensitivity to water content, and the possibility of reducing Love wave contamination by working along a roadway. We accomplished our results using only sledgehammer sources and simple data processing flows.
Neoadjuvant Treatment With Trastuzumab in HER2-Positive Breast Cancer: Results From the GeparQuattro Study
Authors: Untch Michael , Rezai Mahdi , Loibl Sibylle , Fasching Peter A. , Huober Jens , Tesch Hans , Bauerfeind Ingo , Hilfrich Jörn , Eidtmann Holger , Gerber Bernd , Hanusch Claus , Kühn Thorsten , du Bois Andreas , Blohmer Jens-Uwe , Thomssen Christoph , Dan Costa Serban , Jackisch Christian , Kaufmann Manfred , Mehta Keyur , von Minckwitz Gunter
Published: March 2010

Purpose

Trastuzumab, a humanized antibody against the human epidermal growth factor receptor type 2 (HER2), has shown high efficacy in breast cancer. We prospectively investigated its efficacy given simultaneously with anthracycline-taxane–based neoadjuvant chemotherapy.

Patients and Methods

Patients with operable or locally advanced, HER2-positive tumors were treated preoperatively with four cycles of epirubicin/cyclophosphamide followed by four cycles of docetaxel with or without capecitabine (EC-T[X]) and trastuzumab 6 mg/kg (with a loading dose of 8 mg/kg) every 3 weeks during all chemotherapy cycles. Patients with HER2-negative tumors treated in the same study with the same chemotherapy but without trastuzumab were used as a reference group.

Results

Of 1,509 participants, 445 had HER2-positive tumors treated with trastuzumab and chemotherapy. Pathologic complete response (pCR; defined as no invasive or in situ residual tumors in the breast) rate was 31.7%, which was 16% higher than that in the reference group (15.7%). HER2-positive patients without response to the first four cycles of EC showed an unexpectedly high pCR rate of 16.6% (3.3% in the reference group). Breast conservation rate was 63.1% and comparable to that of the reference group (64.7%). EC-T(X) plus trastuzumab was associated with more febrile neutropenia and conjunctivitis, but with a comparable short-term cardiac toxicity profile as the reference group.

Conclusion

This trial confirms that combining trastuzumab with anthracycline-taxane–based neoadjuvant chemotherapy results in a high pCR rate without clinically relevant early toxicity. Combination of chemotherapy with trastuzumab should be considered when neoadjuvant treatment is given to patients with HER2-positive breast cancer.
Do Radiation-Associated Soft Tissue Sarcomas Have the Same Prognosis As Sporadic Soft Tissue Sarcomas?
Authors: Gladdy Rebecca A. , Qin Li-Xuan , Moraco Nicole , Edgar Mark A. , Antonescu Cristina R. , Alektiar Kaled M. , Brennan Murray F. , Singer Samuel
Published: March 2010

Purpose

To determine the prognostic significance of histologic type in radiation-associated soft tissue sarcomas (RASs) and determine whether RASs are associated with an inferior prognosis compared with sporadic soft tissue sarcomas (STSs).

Patients and Methods

One hundred thirty primary RASs were identified from 7,649 STS patients from 1982 to 2007. Multivariate analysis of clinicopathologic factors for disease-specific survival (DSS) was performed for RASs, and a multivariate analysis of radiation exposure was also performed for RASs and sporadic sarcomas. A matched-cohort analysis was performed for radiation-associated and sporadic malignant fibrous histiocytoma (MFH).

Results

Most RASs were high grade (83%), deep (87%), and truncal (61.5%). The median interval between radiation therapy and RAS development was 10 years (range, 1.3 to 74 years), which varied significantly by histologic type (P = .003). The 5-year DSS was 58%, and independent predictors were size > 5 cm, margin positivity, and histologic type. Multivariate analysis of histologic types of primary, high-grade radiation-associated and sporadic STSs showed that RAS was associated with a worse DSS (hazard ratio, 1.7; range, 1.1 to 2.4; P = .007). For pleomorphic MFH—the most common RAS type—the 5-year DSS was 44% versus 66% in a matched cohort of sporadic MFH patients (P = .07). DSS was significantly worse in primary RAS malignant peripheral nerve sheath tumors (MPNSTs) compared with unmatched sporadic MPNSTs (P = .001).

Conclusion

Histologic type, margin status, and tumor size are the most important independent predictors of DSS in patients with RASs. DSS in patients with primary RAS is significantly worse compared with sporadic STS independent of sarcoma histologic type.
Lymph Node Staging by Positron Emission Tomography in Cervical Cancer: Relationship to Prognosis
Authors: Kidd Elizabeth A. , Siegel Barry A. , Dehdashti Farrokh , Rader Janet S. , Mutch David G. , Powell Matthew A. , Grigsby Perry W.
Published: March 2010

Purpose

A previous retrospective study demonstrated that positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET) was more sensitive than computed tomography for lymph node staging in patients with cervical cancer; the findings on FDG-PET were strongly associated with progression-free survival. Therefore, a prospective cohort study was initiated to evaluate FDG-PET lymph node staging in a larger patient population.

Patients and Methods

The study was conducted between July 2000 and March 2009. All 560 patients with cervical cancer underwent pretreatment FDG-PET lymph node staging. Treatment included surgery alone, surgery and postoperative radiation therapy, and definitive radiation or combination radiation and chemotherapy. PET findings were correlated with the risk of disease progression and with survival.

Results

Overall, 47% of patients had lymph node involvement by FDG-PET at diagnosis. The frequency of lymph node metastasis increased with clinical stage and was similar to that in historical surgical series. Within a stage, patients with PET-positive lymph nodes had significantly worse disease-specific survival than those with PET-negative lymph nodes (P < .001). Disease-specific survival was stratified into distinct groups based on the most distant level of PET-detected nodal disease (none, pelvic, para-aortic, or supraclavicular; P < .001). The hazard ratios for disease recurrence increased incrementally based on the most distant level of nodal disease: pelvic 2.40 (95% CI, 1.63 to 3.52), para-aortic 5.88 (95% CI, 3.80 to 9.09), and supraclavicular 30.27 (95% CI 16.56 to 55.34).

Conclusion

Nodal involvement detected by FDG-PET in cervical cancer relates to clinical stage, is comparable to historical data, and stratifies patient recurrence and survival outcomes.