bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence-Based Mini-Review: The Role of Alkylating Agents in the Initial Treatment of Chronic Lymphocytic Leukemia Patients with the 11q Deletion
Authors: Ding Wei , Ferrajoli Alessandra
Published: January 2011

A 55-year-old man presented with fever, night sweats, and weight loss of about 20 lbs. in the prior 6 months. Physical examination revealed multiple cervical, axillary, and inguinal lymphadenopathy. The spleen was enlarged. A complete blood count revealed leukocytosis with absolute lymphocytosis: 30,000/μL. Peripheral blood-flow cytometric analysis showed a clonal lymphocyte population with immunophenotypes positive for CD5, CD20(dim), and monotypic kappa light chain. Fluorescence in situ hybridization (FISH) analysis revealed del(11q22.3), but negative for t(11:14). What should be used to treat his chronic lymphocytic leukemia (CLL) disease?
Upcoming Diagnostic and Therapeutic Developments in Classical Hodgkin's Lymphoma
Authors: Blum Kristie A.
Published: January 2011

With improvements in therapy, increasing dose intensity, early recognition of toxicity, and enhanced supportive care, current outcomes in patients with classical Hodgkin's lymphoma (HL) may be superior to disease-free and overall survival (OS) predicted by existing prognostic models, including the International Prognostic Score (IPS). The addition of biologic markers to recognized clinical prognostic factors, including those of the IPS, may to improve patient risk stratification and guide therapy in the future. However, the identification of these markers has been problematic due to the lack of large, confirmatory prospective trials, reproducibility and feasibility of the assays, and failure to improve upon already recognized clinical risk factors. One biomarker in particular, CD68, present on tumor infiltrating macrophages and detectable by immunohistochemical staining, is significantly associated with both shortened progression-free and disease-specific survivals in patients with HL at diagnosis and at relapse. In addition, less than 5% CD68+ cells correlates with a 100% disease-specific survival in patients with early-stage HL. CD68 represents just one of the many prognostic markers that could eventually be used to risk-stratify therapy. In addition, biologic markers may not only serve as prognostic markers, but also as therapeutic targets in HL. This review examines current data using the IPS to determine patient outcome, discuss several potential biologic prognostic markers, and summarize new therapies that are currently in clinical development in HL.
Visualization and identification of the structures formed during early stages of fibrin polymerization
Authors: Chernysh Irina N. , Nagaswami Chandrasekaran , Weisel John W.
Published: January 2011

We determined the sequence of events and identified and quantitatively characterized the mobility of moving structures present during the early stages of fibrin-clot formation from the beginning of polymerization to the gel point. Three complementary techniques were used in parallel: spinning-disk confocal microscopy, transmission electron microscopy, and turbidity measurements. At the beginning of polymerization the major structures were monomers, whereas at the middle of the lag period there were monomers, oligomers, protofibrils (defined as structures that consisted of more than 8 monomers), and fibers. At the end of the lag period, there were primarily monomers and fibers, giving way to mainly fibers at the gel point. Diffusion rates were calculated from 2 different results, one based on sizes and another on the velocity of the observed structures, with similar results in the range of 3.8-0.1 μm2/s. At the gel point, the diffusion coefficients corresponded to very large, slow-moving structures and individual protofibrils. The smallest moving structures visible by confocal microscopy during fibrin polymerization were identified as protofibrils with a length of approximately 0.5 μm. The sequence of early events of clotting and the structures present are important for understanding hemostasis and thrombosis.
Babesias of red deer (Cervus elaphus) in Ireland
Authors: Zintl Annetta , Finnerty Eugene J , Murphy Thomas M , de Waal Theo , Gray Jeremy S
Published: January 2011

Blood samples were obtained from 38 wild red deer (Cervus elaphus) at two sites in Ireland and subjected to PCR analysis of the 18S rRNA gene followed by sequencing. Two fragments of the 18S rRNA gene were generated by two different PCR protocols and subsequent sequencing suggested that at least six of the deer were infected by a babesia that, in those loci, is indistinguishable from Babesia divergens, an important tick-borne pathogen of cattle and of zoonotic significance. Additionally, a B. odocoilei-like parasite was detected in three samples and a babesia that did not match any sequences in the GenBank database was found in five samples. Neither B. capreoli nor B. venatorum (EU1) were found. There have been several reports of B. divergens occurring in deer species, including red deer, roe deer (Capreolus capreolus) and reindeer (Rangifer tarandus). However, in view of recent re-sequencing of bovine-origin samples deposited previously in GenBank, it is unlikely that any of these sequences from deer are B. divergens. The present study describes the only deer piroplasm detected so far that shows complete identity with B. divergens, in just over half of the 18S rRNA gene. The entire gene of this deer parasite should be analysed and transmission experiments undertaken before the infectivity of B. divergens for red deer can be confirmed.
Epidemiology, radiology, and genetics of nicotine dependence in COPD
Authors: Kim Deog Kyeom , Hersh Craig P , Washko George R , Hokanson John E , Lynch David A , Newell John D , Murphy James R , Crapo James D , Silverman Edwin K ,   the COPD Gene Investigators
Published: January 2011

Background

Cigarette smoking is the principal environmental risk factor for developing COPD, and nicotine dependence strongly influences smoking behavior. This study was performed to elucidate the relationship between nicotine dependence, genetic susceptibility to nicotine dependence, and volumetric CT findings in smokers.

Methods

Current smokers with COPD (GOLD stage ≥ 2) or normal spirometry were analyzed from the COPDGene Study, a prospective observational study. Nicotine dependence was determined by the Fagerstrom test for nicotine dependence (FTND). Volumetric CT acquisitions measuring the percent of emphysema on inspiratory CT (% of lung <-950 HU) and gas trapping on expiratory CT (% of lung <-856 HU) were obtained. Genotypes for two SNPs in the CHRNA3/5 region (rs8034191, rs1051730) previously associated with nicotine dependence and COPD were analyzed for association to COPD and nicotine dependence phenotypes.

Results

Among 842 currently smoking subjects (335 COPD cases and 507 controls), 329 subjects (39.1%) showed high nicotine dependence. Subjects with high nicotine dependence had greater cumulative and current amounts of smoking. However, emphysema severity was negatively correlated with the FTND score in controls (ρ = -0.19, p < .0001) as well as in COPD cases (ρ = -0.18, p = 0.0008). Lower FTND score, male gender, lower body mass index, and lower FEV1 were independent risk factors for emphysema severity in COPD cases. Both CHRNA3/5 SNPs were associated with FTND in current smokers. An association of genetic variants in CHRNA3/5 with severity of emphysema was only found in former smokers, but not in current smokers.

Conclusions

Nicotine dependence was a negative predictor for emphysema on CT in COPD and control smokers. Increased inflammation in more highly addicted current smokers could influence the CT lung density distribution, which may influence genetic association studies of emphysema phenotypes.

Trial registration

ClinicalTrials (NCT): NCT00608764
Differential regulation drives plasticity in sex determination gene networks
Authors: MacCarthy Thomas , Seymour Robert M , Pomiankowski Andrew
Published: January 2011

Background

Sex determination networks evolve rapidly and have been studied intensely across many species, particularly in insects, thus presenting good models to study the evolutionary plasticity of gene networks.

Results

We study the evolution of an unlinked gene capable of regulating an existing diploid sex determination system. Differential gene expression determines phenotypic sex and fitness, dramatically reducing the number of assumptions of previous models. It allows us to make a quantitative evaluation of the full range of evolutionary outcomes of the system and an assessment of the likely contribution of sexual conflict to change in sex determination systems. Our results show under what conditions network mutations causing differential regulation can lead to the reshaping of sex determination networks.

Conclusion

The analysis demonstrates the complex relationship between mutation and outcome: the same mutation can produce many different evolved populations, while the same evolved population can be produced by many different mutations. Existing network structure alters the constraints and frequency of evolutionary changes, which include the recruitment of new regulators, changes in heterogamety, protected polymorphisms, and transitions to a new locus that controls sex determination.
Temporal transcriptomic response during arsenic stress in Herminiimonas arsenicoxydans
Authors: Cleiss-Arnold Jessica , Koechler Sandrine , Proux Caroline , Fardeau Marie-Laure , Dillies Marie-Agnès , Coppee Jean-Yves , Arsène-Ploetze Florence , Bertin Philippe N
Published: January 2011

Background

Arsenic is present in numerous ecosystems and microorganisms have developed various mechanisms to live in such hostile environments. Herminiimonas arsenicoxydans, a bacterium isolated from arsenic contaminated sludge, has acquired remarkable capabilities to cope with arsenic. In particular our previous studies have suggested the existence of a temporal induction of arsenite oxidase, a key enzyme in arsenic metabolism, in the presence of As(III).

Results

Microarrays were designed to compare gene transcription profiles under a temporal As(III) exposure. Transcriptome kinetic analysis demonstrated the existence of two phases in arsenic response. The expression of approximatively 14% of the whole genome was significantly affected by an As(III) early stress and 4% by an As(III) late exposure. The early response was characterized by arsenic resistance, oxidative stress, chaperone synthesis and sulfur metabolism. The late response was characterized by arsenic metabolism and associated mechanisms such as phosphate transport and motility. The major metabolic changes were confirmed by chemical, transcriptional, physiological and biochemical experiments. These early and late responses were defined as general stress response and specific response to As(III), respectively.

Conclusion

Gene expression patterns suggest that the exposure to As(III) induces an acute response to rapidly minimize the immediate effects of As(III). Upon a longer arsenic exposure, a broad metabolic response was induced. These data allowed to propose for the first time a kinetic model of the As(III) response in bacteria.
Ubiquitin-proteasome genes as targets for modulation of cisplatin sensitivity in fission yeast
Authors: Gatti Laura , Hoe Kwang L , Hayles Jacqueline , Righetti Sabina C , Carenini Nives , Bo Laura Dal , Kim Dong U , Park Han O , Perego Paola
Published: January 2011

Background

The ubiquitin(Ub)-proteasome pathway is implicated in the regulation of a variety of cellular functions and plays a major role in stress response in eukaryotic cells, by targeting misfolded and damaged proteins for degradation. In addition, in the presence of DNA damage, the Ub-proteasome system regulates proteins involved in sensing, repairing, and/or tolerating the damage. Antitumor agents such as cisplatin can activate the pathway, but the role of specific pathway components in cell sensitivity/response to the drug is not known. Since platinum compounds represent clinically relevant antitumor agents and a major limitation to their use is the development of drug resistance, there is an urgent need for identifying targets for improving their efficacy.

Results

In the present study, we performed a genome-wide screening for sensitivity to cisplatin using non-essential haploid deletion mutants of the fission yeastSchizosaccharomyces pombe, belonging to a collection of haploid strains constructed through homologous recombination. Using this approach, we identified three Ub-proteasome mutants exhibiting hypersensitivity to cisplatin (ubp16,ubc13andpmt3) and ten mutants (includingufd2,beta7 20S,rpt6/let1) resistant to the drug. In addition, the importance of lub1 gene emerged from the comparison between the present screening and gene expression profile data previously obtained in fission yeast.

Conclusions

The factors identified in the present study allowed us to highlight most finely the close relationship between the Ub-proteasome system and DNA damage response mechanisms, thus establishing a comprehensive framework of regulators likely relevant also in higher eukaryotes. Our results provide the proof of principle of the involvement of specific genes modulated by cisplatin treatment in cell response to the drug, suggesting their potential role as targets for modulating cisplatin sensitivity. In this regard, the prospective identification of novel targets for modulation of cisplatin sensitivity in an eukaryotic model organism appears particularly intriguing towards the discovery of strategies to overcome cisplatin resistance in human tumors.
Complementary monoclonal antibody-based dot ELISA for universal detection of H5 avian influenza virus
Authors: He Fang , Soejoedono Retno D , Murtini Sri , Goutama Michael , Kwang Jimmy
Published: January 2011

Background

Rapid diagnosis and surveillance for H5 subtype viruses are critical for the control of H5N1 infection.

Results

In this study, H5 Dot ELISA, a rapid test for the detection of avian H5N1 influenza virus, was developed with two complementary H5 monoclonal antibodies. HA sequencing of escape mutants followed by epitope mapping revealed that the two Mabs target the epitope component (189th amino acid) on the HA protein but are specific for different amino acids (189Lys or 189Arg). Gene alignment indicated that these two amino acids are the most frequent types on this position among all of the H5 AIV reported in GeneBank. These two H5 Mabs were used together in a dot ELISA to detect H5 viral antigen. The detection limit of the developed test for multiple clades of H5N1 viruses, including clades 0, 1, 2.1, 2.2, 2.3, 4, 7, and 8, was less than 0.5 hemagglutinin units. The specificity of the optimized dot ELISA was examined by using 100 H5 strains, including H5N1 HPAI strains from multiple clades, 36 non-H5N1 viruses, and 4 influenza B viruses. No cross-reactivity was observed for any of the non-H5N1 viruses tested. Among 200 random poultry samples, the test gave 100% positive results for all of the twelve RT-PCR-positive samples.

Conclusions

Considering that the test is convenient for field use, this H5 Dot ELISA can be used for on-site detection of H5N1 infection in clinical or environmental specimens and facilitate the investigation of H5N1 influenza outbreaks and surveillance in poultry.
Phylogenetic group- and species-specific oligonucleotide probes for single-cell detection of lactic acid bacteria in oral biofilms
Authors: Quevedo Beatrice , Giertsen Elin , Zijnge Vincent , Lüthi-Schaller Helga , Guggenheim Bernhard , Thurnheer Thomas , Gmür Rudolf
Published: January 2011

Background

The purpose of this study was to design and evaluate fluorescent in situ hybridization (FISH) probes for the single-cell detection and enumeration of lactic acid bacteria, in particular organisms belonging to the major phylogenetic groups and species of oral lactobacilli and to Abiotrophia/Granulicatella.

Results

As lactobacilli are known for notorious resistance to probe penetration, probe-specific assay protocols were experimentally developed to provide maximum cell wall permeability, probe accessibility, hybridization stringency, and fluorescence intensity. The new assays were then applied in a pilot study to three biofilm samples harvested from variably demineralized bovine enamel discs that had been carried in situ for 10 days by different volunteers. Best probe penetration and fluorescent labeling of reference strains were obtained after combined lysozyme and achromopeptidase treatment followed by exposure to lipase. Hybridization stringency had to be established strictly for each probe. Thereafter all probes showed the expected specificity with reference strains and labeled the anticipated morphotypes in dental plaques. Applied to in situ grown biofilms the set of probes detected only Lactobacillus fermentum and bacteria of the Lactobacillus casei group. The most cariogenic biofilm contained two orders of magnitude higher L. fermentum cell numbers than the other biofilms. Abiotrophia/Granulicatella and streptococci from the mitis group were found in all samples at high levels, whereas Streptococcus mutans was detected in only one sample in very low numbers.

Conclusions

Application of these new group- and species-specific FISH probes to oral biofilm-forming lactic acid bacteria will allow a clearer understanding of the supragingival biome, its spatial architecture and of structure-function relationships implicated during plaque homeostasis and caries development. The probes should prove of value far beyond the field of oral microbiology, as many of them detect non-oral species and phylogenetic groups of importance in a variety of medical conditions and the food industry.
Genetic variation of Glucose Transporter-1 (GLUT1) and albuminuria in 10,278 European Americans and African Americans: a case-control study in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Hsu Charles C , Kao Wenhong L , Steffes Michael W , Gambir Tejal , Brancati Frederick L , Heilig Charles W , Shuldiner Alan R , Boerwinkle Eric A , Coresh Josef
Published: January 2011

Background

Evidence suggests glucose transporter-1(GLUT1) genetic variation affects diabetic nephropathy and albuminuria. Our aim was to evaluate associations with albuminuria of six GLUT1 single nucleotide polymorphisms(SNPs), particularly XbaI and the previously associated Enhancer-2(Enh2) SNP.

Methods

A two-stage case-control study was nested in a prospective cohort study of 2156 African Americans and 8122 European Americans with urinary albumin-to-creatinine ratio(ACR). Cases comprised albuminuria(N = 825; ≥ 30 μg/mg) and macroalbuminuria(N = 173; ≥ 300 μg/mg). ACR < 30 μg/mg classified controls(n = 9453). Logistic regression and odds ratios(OR) assessed associations. The evaluation phase(stage 1, n = 2938) tested associations of albuminuria(n = 305) with six GLUT1 SNPs: rs841839, rs3768043, rs2297977, Enh2(rs841847) XbaI(rs841853), and rs841858. Enh2 was examined separately in the replication phase(stage 2, n = 7340) and the total combined sample (n = 10,278), with all analyses stratified by race and type 2 diabetes.

Results

In European Americans, after adjusting for diabetes and other GLUT1 SNPs in stage 1, Enh2 risk genotype(TT) was more common in albuminuric cases(OR = 3.37, P = 0.090) whereas XbaI (OR = 0.94, p = 0.931) and remaining SNPs were not. In stage 1, the Enh2 association with albuminuria was significant among diabetic European Americans(OR = 2.36, P = 0.025). In African Americans, Enh2 homozygosity was rare(0.3%); XbaI was common(18.0% AA) and not associated with albuminuria. In stage 2(n = 7,340), Enh2 risk genotype had increased but non-significant OR among diabetic European Americans(OR = 1.66, P = 0.192) and not non-diabetics(OR = 0.99, p = 0.953), not replicating stage 1. Combining stages 1 and 2, Enh2 was associated with albuminuria(OR 2.14 [1.20-3.80], P = 0.009) and macroalbuminuria(OR 2.69, [1.02-7.09], P = 0.045) in diabetic European Americans. The Enh2 association with macroalbuminuria among non-diabetic European Americans with fasting insulin(OR = 1.84, P = 0.210) was stronger at the highest insulin quartile(OR = 4.08, P = 0.040).

Conclusions

As demonstrated with type 1 diabetic nephropathy, the GLUT1 Enh2 risk genotype, instead of XbaI, may be associated with type 2 diabetic albuminuria among European Americans, though an association is not conclusive. The association among diabetic European Americans found in stage 1 was not replicated in stage 2; however, this risk association was evident after combining all diabetic European Americans from both stages. Additionally, our results suggest this association may extend to non-diabetics with high insulin concentrations. Rarity of the Enh2 risk genotype among African Americans precludes any definitive conclusions, although data suggest a risk-enhancing role.
A novel insight of sentinel lymph node concept based on 1-3 positive nodes in patients with pT1-2 gastric cancer
Authors: Huang Baojun , Wang Zhenning , Sun Zhe , Zhao Bo , Xu Huimian
Published: January 2011

Background

Sentinel node (SN) biopsy has been practiced in gastric cancer in recent years, and many studies focused on the distribution of solitary lymph node metastasis (SLM) to assess the pattern of SN. In fact, there is usually more than one SN existing in gastric cancer. The distribution of SNs needs to be further re-evaluated.

Methods

A total of 289 patients in pT1-2 stage with 1-3 positive nodes confined to same compartment were included in this study with informed consents. The primary lesion was solitary (≤ 5.0 cm in diameter) and D2 or D3 lymph node dissection had been performed. The location of metastatic lymph nodes was analyzed retrospectively.

Results

Most positive nodes occurred in N1 compartment, with frequency of 79.6% to 85.7% based on site of tumor. In the lower third of stomach, no. 6 was the most common metastatic site and no. 3 was the second; the order was reversed for SLM. With increasing depth of tumor invasion, a progressively augmented nodal involvement was shown. Nearly a half appeared transverse metastasis when the tumor located at the lesser or greater curvature. Among skip metastasis, no. 7, 8a, 9 and 11p were the most common metastatic sites and the prognosis was as similar as that of patients with N1 involved only.

Conclusions

The 1-3 positive nodes in the same compartment should be possible SNs, and most of which are restricted in N1 in pT1-2 gastric cancer. Transversal and 2 stations lymph node metastasis are common.
Bim and Mcl-1 exert key roles in regulating JAK2V617Fcell survival
Authors: Rubert Joëlle , Qian Zhiyan , Andraos Rita , Guthy Daniel A , Radimerski Thomas
Published: January 2011

Background

The JAK2V617F mutation plays a major role in the pathogenesis of myeloproliferative neoplasms and is found in the vast majority of patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia or from primary myelofibrosis. The V617F mutation is thought to provide hematopoietic stem cells and myeloid progenitors with a survival and proliferation advantage. It has previously been shown that activated JAK2 promotes cell survival by upregulating the anti-apoptotic STAT5 target gene Bcl-xL. In this study, we have investigated the role of additional apoptotic players, the pro-apoptotic protein Bim as well as the anti-apoptotic protein Mcl-1.

Methods

Pharmacological inhibition of JAK2/STAT5 signaling in JAK2V617F mutant SET-2 and MB-02 cells was used to study effects on signaling, cell proliferation and apoptosis by Western blot analysis, WST-1 proliferation assays and flow cytometry. Cells were transfected with siRNA oligos to deplete candidate pro- and anti-apoptotic proteins. Co-immunoprecipitation assays were performed to assess the impact of JAK2 inhibition on complexes of pro- and anti-apoptotic proteins.

Results

Treatment of JAK2V617F mutant cell lines with a JAK2 inhibitor was found to trigger Bim activation. Furthermore, Bim depletion by RNAi suppressed JAK2 inhibitor-induced cell death. Bim activation following JAK2 inhibition led to enhanced sequestration of Mcl-1, besides Bcl-xL. Importantly, Mcl-1 depletion by RNAi was sufficient to compromise JAK2V617F mutant cell viability and sensitized the cells to JAK2 inhibition.

Conclusions

We conclude that Bim and Mcl-1 have key opposing roles in regulating JAK2V617F cell survival and propose that inactivation of aberrant JAK2 signaling leads to changes in Bim complexes that trigger cell death. Thus, further preclinical evaluation of combinations of JAK2 inhibitors with Bcl-2 family antagonists that also tackle Mcl-1, besides Bcl-xL, is warranted to assess the therapeutic potential for the treatment of chronic myeloproliferative neoplasms.
Breast cancer care compared with clinical Guidelines: an observational study in France
Authors: Lebeau Marie , Mathoulin-Pélissier Simone , Bellera Carine , Tunon-de-Lara Christine , Daban Alain , Lipinski Francis , Jaubert Dominique , Ingrand Pierre , Migeot Virginie ,   the REPERES group
Published: January 2011

Background

Great variability in breast cancer (BC) treatment practices according to patient, tumour or organisation of care characteristics has been reported but the relation between these factors is not well known. In two French regions, we measured compliance with Clinical Practice Guidelines for non-metastatic BC care management and identified factors associated with non-compliance at clinical and organisational levels.

Methods

Eligible patients had invasive unilateral BC without distant metastases and at least two contacts with one of the two regional healthcare systems (2003-2004) in the first year after diagnosis. Medical data were collected from patient medical records in all public and private hospitals (99 hospitals).

The care process was defined by 20 criteria: clinical decisions for treatment and therapeutic procedures. Each criterion was classified according to level of compliance ("Compliant", "Justifiable" and "Not Compliant") and factors of non-compliance were identified (mixed effect logistic regression).

Results

926 women were included. Non-compliance with clinical decisions for treatment was associated with older patient age (OR 2.1; 95%CI: 1.3-3.6) and region (OR 3.0; 95%CI: 1.2-7.4). Non-compliance with clinical decisions for radiotherapy was associated with lymph node involvement or the presence of peritumoural vascular invasion (OR 1.5; 95%CI: 1.01-2.3) and non-compliance with overall treatment (clinical decisions for treatment + therapeutic procedures) was associated with the presence of positive lymph nodes (OR 2.0; 95%CI: 1.2-3.3), grade III versus grade I (OR 2.9; 95%CI: 1.4-6.2), and one region of care versus another (OR 3.5; 95%CI: 1.7-7.1). Finally, heterogeneity of compliance in overall treatment sequence was identified between local cancer units (p < 0.05).

Conclusion

This study provides interesting insights into factors of non-compliance in non-metastatic BC management and could lead to quality care improvements.
Elevated serum neutrophil elastase is related to prehypertension and airflow limitation in obese women
Authors: El-Eshmawy Mervat M , El-Adawy Eman H , Mousa Amany A , Zeidan Amany E , El-Baiomy Azza A , Abdel-Samie Elham R , Saleh Omayma M
Published: January 2011

Background

Neutrophil elastase level/activity is elevated in a variety of diseases such as atherosclerosis, systolic hypertension and obstructive pulmonary disease. It is unknown whether obese individuals with prehypertension also have elevated neutrophil elastase, and if so, whether it has a deleterious effect on pulmonary function. Objectives: To determine neutrophil elastase levels in obese prehypertensive women and investigate correlations with pulmonary function tests.

Methods

Thirty obese prehypertensive women were compared with 30 obese normotensive subjects and 30 healthy controls. The study groups were matched for age. Measurements: The following were determined: body mass index, waist circumference, blood pressure, lipid profile, high sensitivity C-reactive protein, serum neutrophil elastase, and pulmonary function tests including forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio.

Results

Serum neutrophil elastase concentration was significantly higher in both prehypertensive (405.8 ± 111.6 ng/ml) and normotensive (336.5 ± 81.5 ng/ml) obese women than in control non-obese women (243.9 ± 23.9 ng/ml); the level was significantly higher in the prehypertensive than the normotensive obese women. FEV1, FVC and FEV1/FVC ratio in both prehypertensive and normotensive obese women were significantly lower than in normal controls, but there was no statistically significant difference between the prehypertensive and normotensive obese women. In prehypertensive obese women, there were significant positive correlations between neutrophil elastase and body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, low density lipoprotein cholesterol, high sensitivity C-reactive protein and negative correlations with high density lipoprotein cholesterol, FEV1, FVC and FEV1/FVC.

Conclusion

Neutrophil elastase concentration is elevated in obese prehypertensive women along with an increase in high sensitivity C-reactive protein which may account for dyslipidemia and airflow dysfunction in the present study population.
Pharmacology podcasts: a qualitative study of non-medical prescribing students' use, perceptions and impact on learning
Authors: Meade Oonagh , Bowskill Dianne , Lymn Joanne S
Published: January 2011

Background

There is growing research on student use of podcasts in academic settings. However, there is little in-depth research focusing on student experience of podcasts, in particular in terms of barriers to, and facilitators of, podcast use and students' perceptions of the usefulness of podcasts as learning tools. This study aimed to explore the experiences of non-medical prescribing students who had access to podcasts of key pharmacology lectures as supplementary learning tools to their existing course materials.

Methods

Semi-structured interviews were carried out with seven non-medical prescribing students (average age = 43 years), all of whom were nurses, who had access to seven podcasts of key pharmacology lectures. These podcasts took the form of downloadable audio lecture recordings available through the virtual learning environment WebCT. Low, medium and high users of the podcasts took part in the interviews in order to access a variety of student experiences. Interview data was analysed using thematic template analysis to identify key themes surrounding student experience of podcast availability, particularly in relation to barriers to and facilitators of podcast use, and students' experiences of podcasts as a learning tool.

Results

Students used podcasts for a variety of reasons such as revisiting lectures, preparing for exams, to clarify or revise specific topics and, to a lesser extent, to catch up on a missed lecture. Barriers to podcast use centred mainly around technological issues. Lack of experience of the technology required to access podcasts proved a barrier for some students. A lack of access to suitable technology was also a reported barrier. Family assistance and I.T. assistance from the university helped facilitate students' use of the podcasts. Students found that using podcasts allowed them to have greater control over their learning and to gauge their learning needs, as well as helping them build their understanding of a complex topic.

Conclusions

Students used podcasts for a variety of reasons. Barriers to podcasts use were generally related to technological issues. Students often found that once assistance had been gained regarding these technological issues, they accessed the podcasts more easily. Students felt that access to podcasts added value to their learning materials by allowing them to better manage their learning and build their understanding. Podcasts represent a valuable additional learning tool for this specific group of older students.
Antimicrobial activity and mechanism of action of Nu-3, a protonated modified nucleotide
Authors: Cao Shanping , Sun Lun-Quan , Wang Ming
Published: January 2011

Background

"Nubiotics" are synthetic oligonucleotides and nucleotides with nuclease-resistant backbones, and are fully protonated for enhanced ability to be taken up by bacterial cells. Nu-3 [butyl-phosphate-5'-thymidine-3'-phosphate-butyl], one of the family members of Nubiotics was efficacious in the treatment of burn-wound infections by Pseudomonas aeruginosa in mice. Subsequent studies revealed that Nu-3 had a favorable toxicological profile for use as a pharmaceutical agent. This study evaluated the antibacterial activity of Nu-3 in vitro and its efficacy as a topical antibiotic. In addition, we investigated the possible mechanisms of Nu-3 action at the levels of DNA synthesis and bacterial membrane changes.

Methods

Antimicrobial minimum inhibitory concentrations (MIC) experiments with Nu-3 and controls were measured against a range of Gram-positive and Gram-negative bacteria, including some hospital isolates according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Analysis of the killing kinetics of Nu-3 was also performed against two strains (Staphylococcus aureus cvcc 2248 and Pseudomonas aeruginosa cvcc 5668). The mouse skin suture-wound infection model was used to evaluate the antibacterial activity of Nu-3. We used a 5-Bromo-2'-deoxy-uridine Labeling and Detection Kit III (Roche, Switzerland) to analyze DNA replication in bacteria according to the manufacturer's instruction. The BacLight™ Bacterial Membrane Potential Kit (Invitrogen) was used to measure the bacterial membrane potential in S. aureus.

Results

Nu-3 had a wide antibacterial spectrum to Gram-positive, Gram-negative and some resistant bacteria. The MIC values of Nu-3 against all tested MRSA and MSSA were roughly in a same range while MICs of Oxacillin and Vancomycin varied between the bacteria tested. In the mouse model of skin wound infection study, the treatment with 5% Nu-3 glycerine solution also showed comparable therapeutic effects to Ciprofloxacin Hydrochloride Ointment. While Nu-3 had no effect on DNA synthesis of the tested bacteria as demonstrated in a BrdU assay, it could cause bacterial cell membrane depolarization, as measured using a BacLight™ Bacterial Membrane Potential Kit.

Conclusions

These results provide additional experimental data that are consistent with the hypothesis that Nu-3 represents a new class of antibacterial agents for treating topical infections and acts via a different mechanism from conventional antibiotics.
Reflections on the ethics of recruiting foreign-trained human resources for health
Authors: Runnels Vivien , Labonté Ronald , Packer Corinne
Published: January 2011

Background

Developed countries' gains in health human resources (HHR) from developing countries with significantly lower ratios of health workers have raised questions about the ethics or fairness of recruitment from such countries. By attracting and/or facilitating migration for foreign-trained HHR, notably those from poorer, less well-resourced nations, recruitment practices and policies may be compromising the ability of developing countries to meet the health care needs of their own populations. Little is known, however, about actual recruitment practices. In this study we focus on Canada (a country with a long reliance on internationally trained HHR) and recruiters working for Canadian health authorities.

Methods

We conducted interviews with health human resources recruiters employed by Canadian health authorities to describe their recruitment practices and perspectives and to determine whether and how they reflect ethical considerations.

Results and discussion

We describe the methods that recruiters used to recruit foreign-trained health professionals and the systemic challenges and policies that form the working context for recruiters and recruits. HHR recruiters' reflections on the global flow of health workers from poorer to richer countries mirror much of the content of global-level discourse with regard to HHR recruitment. A predominant market discourse related to shortages of HHR outweighed discussions of human rights and ethical approaches to recruitment policy and action that consider global health impacts.

Conclusions

We suggest that the concept of corporate social responsibility may provide a useful approach at the local organizational level for developing policies on ethical recruitment. Such local policies and subsequent practices may inform public debate on the health equity implications of the HHR flows from poorer to richer countries inherent in the global health worker labour market, which in turn could influence political choices at all government and health system levels.
Etiopathology of chronic tubular, glomerular and renovascular nephropathies: Clinical implications
Authors: López-Novoa José M , Rodríguez-Peña Ana B , Ortiz Alberto , Martínez-Salgado Carlos , López Hernández Francisco J
Published: January 2011

Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e. no functional alterations are evident), continue through renal dysfunction and ends up in renal failure. At this point, kidney transplant or dialysis (renal replacement therapy, RRT) becomes necessary to prevent death derived from the inability of the kidneys to cleanse the blood and achieve hydroelectrolytic balance. Worldwide, nearly 1.5 million people need RRT, and the incidence of CKD has increased significantly over the last decades. Diabetes and hypertension are among the leading causes of end stage renal disease, although autoimmunity, renal atherosclerosis, certain infections, drugs and toxins, obstruction of the urinary tract, genetic alterations, and other insults may initiate the disease by damaging the glomerular, tubular, vascular or interstitial compartments of the kidneys. In all cases, CKD eventually compromises all these structures and gives rise to a similar phenotype regardless of etiology. This review describes with an integrative approach the pathophysiological process of tubulointerstitial, glomerular and renovascular diseases, and makes emphasis on the key cellular and molecular events involved. It further analyses the key mechanisms leading to a merging phenotype and pathophysiological scenario as etiologically distinct diseases progress. Finally clinical implications and future experimental and therapeutic perspectives are discussed.
Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages
Authors: Lässer Cecilia , Seyed Alikhani Vesta , Ekström Karin , Eldh Maria , Torregrosa Paredes Patricia , Bossios Apostolos , Sjöstrand Margareta , Gabrielsson Susanne , Lötvall Jan , Valadi Hadi
Published: January 2011

Background

Exosomes are 30-100 nm membrane vesicles of endocytic origin produced by numerous cells. They can mediate diverse biological functions, including antigen presentation. Exosomes have recently been shown to contain functional RNA, which can be delivered to other cells. Exosomes may thus mediate biological functions either by surface-to-surface interactions with cells, or by the delivery of functional RNA to cells. Our aim was therefore to determine the presence of RNA in exosomes from human saliva, plasma and breast milk and whether these exosomes can be taken up by macrophages.

Method

Exosomes were purified from human saliva, plasma and breast milk using ultracentrifugation and filtration steps. Exosomes were detected by electron microscopy and examined by flow cytometry. Flow cytometry was performed by capturing the exosomes on anti-MHC class II coated beads, and further stain with anti-CD9, anti-CD63 or anti-CD81. Breast milk exosomes were further analysed for the presence of Hsc70, CD81 and calnexin by Western blot. Total RNA was detected with a Bioanalyzer and mRNA was identified by the synthesis of cDNA using an oligo (dT) primer and analysed with a Bioanalyzer. The uptake of PKH67-labelled saliva and breast milk exosomes by macrophages was examined by measuring fluorescence using flow cytometry and fluorescence microscopy.

Results

RNA was detected in exosomes from all three body fluids. A portion of the detected RNA in plasma exosomes was characterised as mRNA. Our result extends the characterisation of exosomes in healthy humans and confirms the presence of RNA in human saliva and plasma exosomes and reports for the first time the presence of RNA in breast milk exosomes. Our results also show that the saliva and breast milk exosomes can be taken up by human macrophages.

Conclusions

Exosomes in saliva, plasma and breast milk all contain RNA, confirming previous findings that exosomes from several sources contain RNA. Furthermore, exosomes are readily taken up by macrophages, supporting the notion that exosomal RNA can be shuttled between cells.
The democratic fallacy in matters of clinical opinion: implications for analysing cause-of-death data
Authors: Byass Peter
Published: January 2011

Arriving at a consensus between multiple clinical opinions concerning a particular case is a complex issue - and may give rise to manifestations of the democratic fallacy, whereby a majority opinion is misconstrued to represent some kind of "truth" and minority opinions are somehow "wrong". Procedures for handling multiple clinical opinions in epidemiological research are not well established, and care is needed to avoid logical errors. How to handle physicians' opinions on cause of death is one important domain of concern in this respect. Whether multiple opinions are a legal requirement, for example ahead of cremating a body, or used for supposedly greater rigour, for example in verbal autopsy interpretation, it is important to have a clear understanding of what unanimity or disagreement in findings might imply, and of how to aggregate case data accordingly.

In many settings where multiple physicians have interpreted verbal autopsy material, an over-riding goal of arriving at a single cause of death per case has been applied. In many instances this desire to constrain findings to a single cause per case has led to methodologically awkward devices such as "TB/AIDS" as a single cause. This has also usually meant that no sense of disagreements or uncertainties at the case level is taken forward into aggregated data analyses, and in many cases an "indeterminate" cause may be recorded which actually reflects a lack of agreement rather than a lack of data on possible cause(s).

In preparing verbal autopsy material for epidemiological analyses and public health interpretations, the possibility of multiple causes of death per case, and some sense of any disagreement or uncertainty encountered in interpretation at the case level, need to be captured and incorporated into overall findings, if evidence is not to be lost along the way. Similar considerations may apply in other epidemiological domains.
Identification of critical residues of influenza neuraminidase in viral particle release
Authors: Tisoncik Jennifer R , Guo Ying , Cordero Katie S , Yu Jia , Wang Jianwei , Cao Youjia , Rong Lijun
Published: January 2011

Background

Influenza neuraminidase (NA) is essential for virus release from its host cells and it is one of the targets for structure-based antiviral drug design.

Results

In this report, we established a pseudoviral particle release assay to study NA function, which is based on lentiviral particles pseudotyped with influenza glycoproteins HA and NA as a surrogate system. Through an extensive molecular analysis, we sought to characterize important residues governing NA function. We identified five residues of NA, 234, 241, 257, 286 and 345, four of which (except 345) map away from the active site of NA when projected onto the three-dimensional structure of avian influenza H5N1 NA, and substitutions of these residues adversely affected the NA-mediated viral particle release, suggesting that these residues are critical for NA enzymatic activity.

Conclusion

Through extensive chimeric and mutational analyses, we have identified several residues, which map away from the active site and are critical for NA function. These findings provide new insights into NA-mediated pseudoviral particle release and may have important implications in drug design and therapeutics against influenza infection.
Short distance movement of genomic negative strands in a host and nonhost for Sugarcane mosaic virus (SCMV)
Authors: Chaves-Bedoya Giovanni , Espejel Fulgencio , Alcalá-Briseño Ricardo I , Hernández-Vela Juan , Silva-Rosales Laura
Published: January 2011

Background

In order to obtain an initial and preliminary understanding of host and nonhost resistance in the initial step of potyvirus replication, both positive and negative Sugarcane mosaic virus (SCMV) strands where traced in inoculated and systemic leaves in host and nonhost resistant maize and sugarcane for one Mexican potyviral isolate (SCMV-VER1). Intermediary replication forms, such as the negative viral strand, seem to only move a short distance as surveyed by RT-PCR analysis and ELISA in different leaves. Virus purification was also done in leaves and stems.

Results

Susceptible maize plants allowed for viral SCMV replication, cell-to-cell, and long distance movement, as indicated by the presence of the coat protein along the plant. In the host resistant maize plants for the SCMV-VER1 isolate, the virus was able to establish the disease though the initial steps of virus replication, as detected by the presence of negative strands, in the basal area of the inoculated leaves at six and twelve days post inoculation. The nonhost sugarcane for SCMV-VER1 and the host sugarcane for SCMV-CAM6 also allowed the initial steps of viral replication for the VER1 isolate in the local inoculated leaf. SCMV-VER1 virions could be extracted from stems of susceptible maize with higher titers than leaves.

Conclusion

Nonhost and host resistance allow the initial steps of potyvirus SCMV replication, as shown by the negative strands' presence. Furthermore, both hosts allow the negative viral strands' local movement, but not their systemic spread through the stem. The presence of larger amounts of extractable virions from the stem (as compared to the leaves) in susceptible maize lines suggests their long distance movement as assembled particles. This will be the first report suggesting the long distance movement of a monocot potyvirus as a virion.