bluuebunny/crossref_metadata_2025 huggingface dataset:
Conceptualizing the management and consumption of live music in urban space
Authors: Oakes Steve , Warnaby Gary
Published: December 2011

This paper examines how live music performed outdoors contributes to an overall urban servicescape capable of transforming perceptions of urban environments. A broad spectrum of outdoor musical performance is discussed ranging from major festivals to busking. The benefits of live music in urban space are highlighted in terms of benefits to the local economy and widening arts engagement. Key issues are discussed within the context of the wider place marketing literature, and it is proposed that the role of music in the marketing of specifically urban places may be conceptualized in terms of three distinct continua – managed/spontaneous, spectacular/mundane, and exclusive/inclusive. As jazz has been consistently identified as an urban genre, each continuum is discussed with reference to jazz performances within the context of a specific urban space – St. Ann’s Square in Manchester
On the intersection of marketing history and marketing theory
Authors: Hunt Shelby D.
Published: December 2011

Can historical research contribute to marketing theory? This essay argues ‘yes.’ The essay begins by reviewing the conventional view of marketing theory. Then, it discusses the nature of historical research, proposes how marketing history and theory intersect, and provides two examples of how historical method has been used to advance marketing theory.
The double helix of marketing
Authors: Sheth Jagdish N.
Published: December 2011

This brief note explores the complementary relationship between the history of both marketing thought and marketing practice and the development of marketing theory, a relationship best described as a double helix.
Energy efficiency of alternative lighting control systems
Authors: Chiogna M , Mahdavi A , Albatici R , Frattari A
Published: December 2011

Due to new European standards and requirements for energy performance in non-residential buildings, it is important to explore and quantify the benefits of intelligent (automated) energy-efficient operating systems relative to conventional (manual) systems. This paper explores the energy performance of an automated lighting control system under realistic conditions in two groups of lecture rooms that have the same shape, dimensions and exposure. The results demonstrate that the use of automated systems for electric lighting control can improve the energy performance of the system between 40% and 65% depending on the complexity of the system and the parameters under control.
Modelling the spectral sensitivity of the human circadian system
Authors: Rea MS , Figueiro MG , Bierman A , Hamner R
Published: December 2011

It is now well established that the spectral, spatial, temporal and absolute sensitivities of the human circadian system are very different from those of the human visual system. Although qualitative comparisons between the human circadian and visual systems can be made, there still remains some uncertainty in quantitatively predicting exactly how the circadian system will respond to different light exposures reaching the retina. This paper discusses attempts to model the spectral sensitivity of the circadian system. Each of the models discussed here varies in terms of its complexity and its consideration of retinal neuroanatomy and neurophysiology. Future testing to validate or improve any of these computational models will require a targeted hypothesis, as well as a suitably high level of experimental control before one model can be rejected in favour of another. Until specific hypotheses are formulated and tested, it would be premature to recommend international acceptance of any model or system of circadian photometry.
Radiofrequency-Assisted Liver Resection With a Comb-Shaped Bipolar Device Versus Clamp Crushing
Authors: Galizia Gennaro , Castellano Paolo , Pinto Margherita , Zamboli Anna , Orditura Michele , De Vita Ferdinando , Pignatelli Carlo , Lieto Eva
Published: December 2011

Background. In liver surgery, clamp-crushing (CC) procedure has been shown to be the most efficient system for liver transection. Recently, it has been suggested that radiofrequency-assisted liver resection (RFALR) may be more advantageous, but sufficient evidence has yet to be accumulated. Method. The control group was constituted by 32 patients undergoing CC liver transection. The study group included 13 patients undergoing RFALR with a new fully automated radiofrequency generator supplying a comb-shaped bipolar multielectrode device. Results. RFALR allowed a faster hepatic transection and reduced both surgical time and intraoperative blood loss. RFALR was the only independent prognostic indicator of bleeding during liver transection. No significant liver damage and postoperative complications, particularly biliary leakage and stenosis, were experienced in the RFALR group. Conclusion. Compared with the CC procedure, this bipolar device was shown to be safe and effective in liver resections, allowing a very clean surgical field without increase of postoperative complications.
Just Despots: The Cultural Construction of Imperial Constitutionalism
Authors: Benton Lauren
Published: December 2011

This article explores the significance of widespread debates in empires about the exercise of arbitrary power. As particularly evident in the decades around the turn of the nineteenth century, colonial conflicts often centered on the nature and scope of the legal prerogatives of middling authorities. The focus on the proper relation of multiple authorities within composite polities was accompanied by claims about particular configurations of rights, by references to divisible sovereignty, and by legal strategies that appealed to the intervention of imperial sovereigns in the exercise of judicial power within private or subordinate jurisdictions. The result was an intimate connection between persistent references to petty despotism and an emerging framework for imperial constitutional politics.
A condition- and age-based replacement model using delay time modelling
Authors: Lipi T F , Lim J-H , Zuo M J , Wang W
Published: December 2011

To make realistic maintenance decisions, it is important that maintenance managers make their preventive replacement decisions based on observations of the condition of their equipment. This study addresses a condition- and age-based replacement decision problem using the complete history of measured condition observations to minimize long-run average cost, maximize long-run average availability, or both. A stochastic filtering process (SFP) is used to estimate the residual lifetime distribution conditional on the history of observed condition information. A long-run average cost model and a long-run average availability model are analysed in order to determine the theorems necessary for calculating the optimum replacement time. To minimize the cost and maximize availability, a multiobjective decision frontier is proposed that will help maintenance managers deal with trade-offs between the two objectives. Finally, numerical examples are presented for each scenario to show the effectiveness of the methods proposed.
Les matrones et la réduction de la mortalité maternelle, une contribution au débat
Authors: Petitet Pascale Hancart
Published: December 2011

Résumé

Avec le présupposé que la biomédecine était capable de prévenir la majorité des morts maternelles, l’une des recommandations formulées en 1987 par l’Initiative Maternité Sans Risque était de former des matrones. Ces formations réalisées durant trois décennies sont souvent décrites comme étant un échec. Néanmoins, elles n’ont guère pris en compte l’hétérogénéité des statuts sociaux et pratiques des matrones, ni remis en question certaines méthodes pédagogiques essentiellement didactiques et souvent inappropriées. Ainsi, le débat relatif à la pertinence de ces formations est loin d’être clos. Dans cette perspective, l’ouvrage collectif L’art des matrones revisité. Naissances contemporaines en question dirigé par Pascale Hancart Petitet (2011) rassemble neuf contributions d’auteur(e)s dont l’objectif n’est nullement de remettre en cause les effets bénéfiques de la biomédicalisation de l’accouchement mais de montrer, comment, et pourquoi, se construisent les pratiques des matrones et les discours dont elles sont l’objet actuellement.
Ipilimumab: its potential in non-small cell lung cancer
Authors: Tomasini Pascale , Khobta Nataliya , Greillier Laurent , Barlesi Fabrice
Published: December 2011

Ipilimumab is a fully human monoclonal antibody that enhances antitumor immunity by way of cytotoxic T-lymphocyte antigen 4 blockade. It has already been approved by the US Food and Drug Administration for the treatment of metastatic melanoma and is being investigated for treating other solid tumors such as renal cell, prostate and lung cancers. This review details the potential of ipilimumab in the management of non-small cell lung cancer (NSCLC). In particular, ipilimumab showed promising results in a first-line NSCLC phase II study combining carboplatin/paclitaxel chemotherapy with concurrent or phased ipilimumab. The median immune-related progression-free survival was 5.68 months for the phased ipilimumab arm versus 4.63 months for chemotherapy alone (hazard ratio [HR] = 0.68, p = 0.026) and 5.52 months for the concurrent ipilimumab arm versus 4.63 months for chemotherapy alone (HR = 0.77, p = 0.094). The main adverse events were immune related, such as hypophysitis, enterocolitis, and hyperthyroidism. These adverse events may be improved with high-dose glucocorticoids and may be correlated with tumor response. Phase III studies are ongoing. Future studies may investigate ipilimumab in the management of early stage lung cancer. Strategies for potential translational research studies are also discussed to identify prognostic and predictive biomarkers for the use of ipilimumab in the treatment of patients with NSCLC.
Functional heterogeneity of human effector CD8+ T cells
Authors: Takata Hiroshi , Naruto Takuya , Takiguchi Masafumi
Published: December 2011

Effector CD8+ T cells are believed to be terminally differentiated cells having cytotoxic activity and the ability to produce effector cytokines such as INF-γ and TNF-α. We investigated the difference between CXCR1+ and CXCR1− subsets of human effector CD27−CD28−CD8+ T cells. The subsets expressed cytolytic molecules similarly and exerted substantial cytolytic activity, whereas only the CXCR1− subset had IL-2 productivity and self-proliferative activity and was more resistant to cell death than the CXCR1+ subset. These differences were explained by the specific up-regulation of CAMK4, SPRY2, and IL-7R in the CXCR1− subset and that of pro-apoptotic death-associated protein kinase 1 (DAPK1) in the CXCR1+ subset. The IL-2 producers were more frequently found in the IL-7R+ subset of the CXCR1− effector CD8+ T cells than in the IL-7R− subset. IL-7/IL-7R signaling promoted cell survival only in the CXCR1− subset. The present study has highlighted a novel subset of effector CD8+ T cells producing IL-2 and suggests the importance of this subset in the homeostasis of effector CD8+ T cells.
R-Ras is required for murine dendritic cell maturation and CD4+ T-cell priming
Authors: Singh Gobind , Hashimoto Daigo , Yan Xiaocai , Helft Julie , Park Patricia J.-Y. , Ma Ge , Qiao Rui F. , Kennedy Colin R. , Chen Shu-Hsia , Merad Miriam , Chan Andrew M.
Published: December 2011

R-Ras is a member of the RAS superfamily of small GTP-binding proteins. The physiologic function of R-Ras has not been fully elucidated. We found that R-Ras is expressed by lymphoid and nonlymphoid tissues and drastically up-regulated when bone marrow progenitors are induced to differentiate into dendritic cells (DCs). To address the role of R-Ras in DC functions, we generated a R-Ras-deficient mouse strain. We found that tumors induced in Rras−/− mice formed with shorter latency and attained greater tumor volumes. This finding has prompted the investigation of a role for R-Ras in the immune system. Indeed, Rras−/− mice were impaired in their ability to prime allogeneic and antigen-specific T-cell responses. Rras−/− DCs expressed lower levels of surface MHC class II and CD86 in response to lipopolysaccharide compared with wild-type DCs. This was correlated with a reduced phosphorylation of p38 and Akt. Consistently, R-Ras–GTP level was increased within 10 minutes of lipopolysaccharide stimulation. Furthermore, Rras−/− DCs have attenuated capacity to spread on fibronectin and form stable immunologic synapses with T cells. Altogether, these findings provide the first demonstration of a role for R-Ras in cell-mediated immunity and further expand on the complexity of small G-protein signaling in DCs.
Responses to second-line tyrosine kinase inhibitors are durable: an intention-to-treat analysis in chronic myeloid leukemia patients
Authors: Milojkovic Dragana , Apperley Jane F. , Gerrard Gareth , Ibrahim Amr R. , Szydlo Richard , Bua Marco , Reid Alistair , Rezvani Katayoun , Foroni Letizia , Goldman John , Marin David
Published: December 2011

Second-generation tyrosine kinase inhibitors (2G-TKIs) are effective at inducing complete cytogenetic responses (CCyRs) in approximately half of chronic myeloid leukemia patients treated while still in the chronic phase and after failing imatinib. It is less clear whether these responses are durable. In the present study, we report the clinical outcome of 119 patients who received a 2G-TKI as second-line treatment while still in the chronic phase. In an intention-to-treat analysis, the 4-year probabilities of overall and event-free survival were 81.9% and 35.3%, respectively. Sixty-two patients discontinued the initial 2G-TKI because of resistance or intolerance. To further explore the durability of cytogenetic responses, irrespective of the need for a third-line TKI, we used the concept of “current CCyR-survival” (c-CCyRS). The c-CCyRS at 4 years was 54.4%. After introduction of a 2G-TKI, 77 patients had a 3-month BCR-ABL1/ABL1 transcript ratio of ≤ 10% and had significantly superior overall survival (91.3% vs 72.1%, P = .02), event-free survival (49.3% vs 13.0%, P < .001), and c-CCyRS (67.2% vs 11.2%, P = .0001) compared with the 33 patients with ratios > 10%. The 3-month molecular response was the only independent predictor for overall survival. Using an intention-to-treat analysis, we have shown that the responses to second-line therapies are durable. Patients destined to fare poorly can be identified early during therapy.
A multifaceted analysis of HIV-1 protease multidrug resistance phenotypes
Authors: Doherty Kathleen M , Nakka Priyanka , King Bracken M , Rhee Soo-Yon , Holmes Susan P , Shafer Robert W , Radhakrishnan Mala L
Published: December 2011

Background

Great strides have been made in the effective treatment of HIV-1 with the development of second-generation protease inhibitors (PIs) that are effective against historically multi-PI-resistant HIV-1 variants. Nevertheless, mutation patterns that confer decreasing susceptibility to available PIs continue to arise within the population. Understanding the phenotypic and genotypic patterns responsible for multi-PI resistance is necessary for developing PIs that are active against clinically-relevant PI-resistant HIV-1 variants.

Results

In this work, we use globally optimal integer programming-based clustering techniques to elucidate multi-PI phenotypic resistance patterns using a data set of 398 HIV-1 protease sequences that have each been phenotyped for susceptibility toward the nine clinically-approved HIV-1 PIs. We validate the information content of the clusters by evaluating their ability to predict the level of decreased susceptibility to each of the available PIs using a cross validation procedure. We demonstrate the finding that as a result of phenotypic cross resistance, the considered clinical HIV-1 protease isolates are confined to ~6% or less of the clinically-relevant phenotypic space. Clustering and feature selection methods are used to find representative sequences and mutations for major resistance phenotypes to elucidate their genotypic signatures. We show that phenotypic similarity does not imply genotypic similarity, that different PI-resistance mutation patterns can give rise to HIV-1 isolates with similar phenotypic profiles.

Conclusion

Rather than characterizing HIV-1 susceptibility toward each PI individually, our study offers a unique perspective on the phenomenon of PI class resistance by uncovering major multidrug-resistant phenotypic patterns and their often diverse genotypic determinants, providing a methodology that can be applied to understand clinically-relevant phenotypic patterns to aid in the design of novel inhibitors that target other rapidly evolving molecular targets as well.
Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension
Authors: Rabieyousefi Moloud , Soroosh Pejman , Satoh Kimio , Date Fumiko , Ishii Naoto , Yamashita Masahiro , Oka Masahiko , McMurtry Ivan F , Shimokawa Hiroaki , Nose Masato , Sugamura Kazuo , Ono Masao
Published: December 2011

Background

Pulmonary hypertension (PH) refers to a spectrum of diseases with elevated pulmonary artery pressure. Pulmonary arterial hypertension (PAH) is a disease category that clinically presents with severe PH and that is histopathologically characterized by the occlusion of pulmonary arterioles, medial muscular hypertrophy, and/or intimal fibrosis. PAH occurs with a secondary as well as a primary onset. Secondary PAH is known to be complicated with immunological disorders. The aim of the present study is to histopathologically and genetically characterize a new animal model of PAH and clarify the role of OX40 ligand in the pathogenesis of PAH.

Results

Spontaneous onset of PAH was stably identified in mice with immune abnormality because of overexpression of the tumor necrosis factor (TNF) family molecule OX40 ligand (OX40L). Histopathological and physical examinations revealed the onset of PAH-like disorders in the C57BL/6 (B6) strain of OX40L transgenic mice (B6.TgL). Comparative analysis performed using different strains of transgenic mice showed that this onset depends on the presence of OX40L in the B6 genetic background. Genetic analyses demonstrated a susceptibility locus of a B6 allele to this onset on chromosome 5. Immunological analyses revealed that the excessive OX40 signals in TgL mice attenuates expansion of regulatory T cells the B6 genetic background, suggesting an impact of the B6 genetic background on the differentiation of regulatory T cells.

Conclusion

Present findings suggest a role for the OX40L-derived immune response and epistatic genetic effect in immune-mediated pathogenesis of PAH.
Genome-wide transcriptome analysis of gametophyte development in Physcomitrella patens
Authors: Xiao Lihong , Wang Hui , Wan Ping , Kuang Tingyun , He Yikun
Published: December 2011

Background

Regulation of gene expression plays a pivotal role in controlling the development of multicellular plants. To explore the molecular mechanism of plant developmental-stage transition and cell-fate determination, a genome-wide analysis was undertaken of sequential developmental time-points and individual tissue types in the model moss Physcomitrella patens because of the short life cycle and relative structural simplicity of this plant.

Results

Gene expression was analyzed by digital gene expression tag profiling of samples taken from P. patens protonema at 3, 14 and 24 days, and from leafy shoot tissues at 30 days, after protoplast isolation, and from 14-day-old caulonemal and chloronemal tissues. In total, 4333 genes were identified as differentially displayed. Among these genes, 4129 were developmental-stage specific and 423 were preferentially expressed in either chloronemal or caulonemal tissues. Most of the differentially displayed genes were assigned to functions in organic substance and energy metabolism or macromolecule biosynthetic and catabolic processes based on gene ontology descriptions. In addition, some regulatory genes identified as candidates might be involved in controlling the developmental-stage transition and cell differentiation, namely MYB-like, HB-8, AL3, zinc finger family proteins, bHLH superfamily, GATA superfamily, GATA and bZIP transcription factors, protein kinases, genes related to protein/amino acid methylation, and auxin, ethylene, and cytokinin signaling pathways.

Conclusions

These genes that show highly dynamic changes in expression during development in P. patens are potential targets for further functional characterization and evolutionary developmental biology studies.
Genetic mechanisms underlying the methylation level of anthocyanins in grape (Vitis viniferaL.)
Authors: Fournier-Level Alexandre , Hugueney Philippe , Verriès Clotilde , This Patrice , Ageorges Agnès
Published: December 2011

Background

Plant color variation is due not only to the global pigment concentration but also to the proportion of different types of pigment. Variation in the color spectrum may arise from secondary modifications, such as hydroxylation and methylation, affecting the chromatic properties of pigments. In grapes (Vitis viniferaL.), the level of methylation modifies the stability and reactivity of anthocyanin, which directly influence the color of the berry. Anthocyanin methylation, as a complex trait, is controlled by multiple molecular factors likely to involve multiple regulatory steps.

Results

In a Syrah × Grenache progeny, two QTLs were detected for variation in level of anthocyanin methylation. The first one, explaining up to 27% of variance, colocalized with a cluster of Myb-type transcription factor genes. The second one, explaining up to 20% of variance, colocalized with a cluster ofO-methyltransferase coding genes (AOMT). In a collection of 32 unrelated cultivars,MybAandAOMTexpression profiles correlated with the level of methylated anthocyanin. In addition, the newly characterizedAOMT2gene presented two SNPs associated with methylation level. These mutations, probably leading to a structural change of the AOMT2 protein significantly affected the enzyme specific catalytic efficiency for the 3'-O-methylation of delphinidin 3-glucoside.

Conclusion

We demonstrated that variation in methylated anthocyanin accumulation is susceptible to involve both transcriptional regulation and structural variation. We report here the identification of novel AOMT variants likely to cause methylated anthocyanin variation. The integration of QTL mapping and molecular approaches enabled a better understanding of how variation in gene expression and catalytic efficiency of the resulting enzyme may influence the grape anthocyanin profile.
Genetic and functional evaluation of the role of CXCR1 and CXCR2 in susceptibility to visceral leishmaniasis in north-east India
Authors: Mehrotra Sanjana , Fakiola Michaela , Oommen Joyce , Jamieson Sarra E , Mishra Anshuman , Sudarshan Medhavi , Tiwary Puja , Rani Deepa Selvi , Thangaraj Kumarasamy , Rai Madhukar , Sundar Shyam , Blackwell Jenefer M
Published: December 2011

Background

IL8RA and IL8RB, encoded by CXCR1 and CXCR2, are receptors for interleukin (IL)-8 and other CXC chemokines involved in chemotaxis and activation of polymorphonuclear neutrophils (PMN). Variants at CXCR1 and CXCR2 have been associated with susceptibility to cutaneous and mucocutaneous leishmaniasis in Brazil. Here we investigate the role of CXCR1/CXCR2 in visceral leishmaniasis (VL) in India.

Methods

Three single nucleotide polymorphisms (SNPs) (rs4674259, rs2234671, rs3138060) that tag linkage disequilibrium blocks across CXCR1/CXCR2 were genotyped in primary family-based (313 cases; 176 nuclear families; 836 individuals) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association between CXCR1/CXCR2 variants and VL. Quantitative RT/PCR was used to compare CXCR1/CXCR2 expression in mRNA from paired splenic aspirates taken before and after treatment from 19 VL patients.

Results

Family-based analysis using FBAT showed association between VL and SNPs CXCR1_rs2234671 (Z-score = 2.935, P = 0.003) and CXCR1_rs3138060 (Z-score = 2.22, P = 0.026), but not with CXCR2_rs4674259. Logistic regression analysis of the case-control data under an additive model of inheritance showed association between VL and SNPs CXCR2_rs4674259 (OR = 1.15, 95%CI = 1.01-1.31, P = 0.027) and CXCR1_rs3138060 (OR = 1.25, 95%CI = 1.02-1.53, P = 0.028), but not with CXCR1_rs2234671. The 3-locus haplotype T_G_C across these SNPs was shown to be the risk haplotype in both family- (TRANSMIT; P = 0.014) and population- (OR = 1.16, P = 0.028) samples (combined P = 0.002). CXCR2, but not CXCR1, expression was down regulated in pre-treatment compared to post-treatment splenic aspirates (P = 0.021).

Conclusions

This well-powered primary and replication genetic study, together with functional analysis of gene expression, implicate CXCR2 in determining outcome of VL in India.
Ocular fundus pathology and chronic kidney disease in a Chinese population
Authors: Gao Bixia , Zhu Ling , Pan Yingzi , Yang Shuwen , Zhang Luxia , Wang Haiyan
Published: December 2011

Background

Previous study indicated a high prevalence of ocular fundus pathology among patients with chronic kidney disease (CKD), while the relationship between them has never been explored in a Chinese Population.

Methods

This cross-sectional study included 9 670 participants enrolled in a medical screening program. Ocular fundus examination was performed by ophthalmologists using ophthalmoscopes. The presence of eGFR less than 60 mL/min/1.73 m2 and/or proteinuria was defined as CKD.

Results

Compared to participants without CKD, participants with CKD had higher prevalence of retinopathy (28.5% vs. 16.3%, P < 0.001), glaucoma suspect (3.1% vs. 1.8%, P = 0.004), age-related macular degeneration (1.7% vs. 0.9%, P = 0.01) and overall eye pathology (32.0% vs. 19.4%, P < 0.001). After adjusting for potential confounders, the odds ratio of proteinuria for overall eye pathology and retinopathy was 1.29 (95% confidence interval [CI] 1.07-1.55) and 1.37 (95% CI 1.12-1.67), respectively. The results were robust after excluding participants with hypertension or with diabetes.

Conclusions

Ocular fundus pathology is common among Chinese patients with CKD. Regular eye exam among persons with proteinuria is warranted.
Vaccination against 2009 pandemic H1N1 in a population dynamical model of Vancouver, Canada: timing is everything
Authors: Conway Jessica M , Tuite Ashleigh R , Fisman David N , Hupert Nathaniel , Meza Rafael , Davoudi Bahman , English Krista , van den Driessche P , Brauer Fred , Ma Junling , Meyers Lauren Ancel , Smieja Marek , Greer Amy , Skowronski Danuta M , Buckeridge David L , Kwong Jeffrey C , Wu Jianhong , Moghadas Seyed M , Coombs Daniel , Brunham Robert C , Pourbohloul Babak
Published: December 2011

Background

Much remains unknown about the effect of timing and prioritization of vaccination against pandemic (pH1N1) 2009 virus on health outcomes. We adapted a city-level contact network model to study different campaigns on influenza morbidity and mortality.

Methods

We modeled different distribution strategies initiated between July and November 2009 using a compartmental epidemic model that includes age structure and transmission network dynamics. The model represents the Greater Vancouver Regional District, a major North American city and surrounding suburbs with a population of 2 million, and is parameterized using data from the British Columbia Ministry of Health, published studies, and expert opinion. Outcomes are expressed as the number of infections and deaths averted due to vaccination.

Results

The model output was consistent with provincial surveillance data. Assuming a basic reproduction number = 1.4, an 8-week vaccination campaign initiated 2 weeks before the epidemic onset reduced morbidity and mortality by 79-91% and 80-87%, respectively, compared to no vaccination. Prioritizing children and parents for vaccination may have reduced transmission compared to actual practice, but the mortality benefit of this strategy appears highly sensitive to campaign timing. Modeling the actual late October start date resulted in modest reductions in morbidity and mortality (13-25% and 16-20%, respectively) with little variation by prioritization scheme.

Conclusion

Delays in vaccine production due to technological or logistical barriers may reduce potential benefits of vaccination for pandemic influenza, and these temporal effects can outweigh any additional theoretical benefits from population targeting. Careful modeling may provide decision makers with estimates of these effects before the epidemic peak to guide production goals and inform policy. Integration of real-time surveillance data with mathematical models holds the promise of enabling public health planners to optimize the community benefits from proposed interventions before the pandemic peak.
Structural comparison of tRNA m1A58 methyltransferases revealed different molecular strategies to maintain their oligomeric architecture under extreme conditions
Authors: Guelorget Amandine , Barraud Pierre , Tisné Carine , Golinelli-Pimpaneau Béatrice
Published: December 2011

Background

tRNA m1A58 methyltransferases (TrmI) catalyze the transfer of a methyl group from S-adenosyl-L-methionine to nitrogen 1 of adenine 58 in the T-loop of tRNAs from all three domains of life. The m1A58 modification has been shown to be essential for cell growth in yeast and for adaptation to high temperatures in thermophilic organisms. These enzymes were shown to be active as tetramers. The crystal structures of five TrmIs from hyperthermophilic archaea and thermophilic or mesophilic bacteria have previously been determined, the optimal growth temperature of these organisms ranging from 37°C to 100°C. All TrmIs are assembled as tetramers formed by dimers of tightly assembled dimers.

Results

In this study, we present a comparative structural analysis of these TrmIs, which highlights factors that allow them to function over a large range of temperature. The monomers of the five enzymes are structurally highly similar, but the inter-monomer contacts differ strongly. Our analysis shows that bacterial enzymes from thermophilic organisms display additional intermolecular ionic interactions across the dimer interfaces, whereas hyperthermophilic enzymes present additional hydrophobic contacts. Moreover, as an alternative to two bidentate ionic interactions that stabilize the tetrameric interface in all other TrmI proteins, the tetramer of the archaeal P. abyssi enzyme is strengthened by four intersubunit disulfide bridges.

Conclusions

The availability of crystal structures of TrmIs from mesophilic, thermophilic or hyperthermophilic organisms allows a detailed analysis of the architecture of this protein family. Our structural comparisons provide insight into the different molecular strategies used to achieve the tetrameric organization in order to maintain the enzyme activity under extreme conditions.
Modest effect on plaque progression and vasodilatory function in atherosclerosis-prone mice exposed to nanosized TiO2
Authors: Mikkelsen Lone , Sheykhzade Majid , Jensen Keld A , Saber Anne T , Jacobsen Nicklas R , Vogel Ulla , Wallin Håkan , Loft Steffen , Møller Peter
Published: December 2011

Background

There is growing evidence that exposure to small size particulate matter increases the risk of developing cardiovascular disease.

Methods

We investigated plaque progression and vasodilatory function in apolipoprotein E knockout (ApoE
-/-) mice exposed to TiO2. ApoE
-/- mice were intratracheally instilled (0.5 mg/kg bodyweight) with rutile fine TiO2 (fTiO2, 288 nm), photocatalytic 92/8 anatase/rutile TiO2 (pTiO2, 12 nm), or rutile nano TiO2 (nTiO2, 21.6 nm) at 26 and 2 hours before measurement of vasodilatory function in aorta segments mounted in myographs. The progression of atherosclerotic plaques in aorta was assessed in mice exposed to nanosized TiO2 (0.5 mg/kg bodyweight) once a week for 4 weeks. We measured mRNA levels of Mcp-1, Mip-2, Vcam-1, Icam-1 and Vegf in lung tissue to assess pulmonary inflammation and vascular function. TiO2-induced alterations in nitric oxide (NO) production were assessed in human umbilical vein endothelial cells (HUVECs).

Results

The exposure to nTiO2 was associated with a modest increase in plaque progression in aorta, whereas there were unaltered vasodilatory function and expression levels of Mcp-1, Mip-2, Vcam-1, Icam-1 and Vegf in lung tissue. The ApoE

-/-
mice exposed to fine and photocatalytic TiO2 had unaltered vasodilatory function and lung tissue inflammatory gene expression. The unaltered NO-dependent vasodilatory function was supported by observations in HUVECs where the NO production was only increased by exposure to nTiO2.

Conclusion

Repeated exposure to nanosized TiO2 particles was associated with modest plaque progression in ApoE

-/-
mice. There were no associations between the pulmonary TiO2 exposure and inflammation or vasodilatory dysfunction.
Reproducible hairy root transformation and spot-inoculation methods to study root symbioses of pea
Authors: Clemow Scott R , Clairmont Lindsey , Madsen Lene H , Guinel Frédérique C
Published: December 2011

Pea has lagged behind other model legumes in the molecular study of nodulation and mycorrhizae-formation because of the difficulty to transform its roots and its poor growth on agar plates. Here we describe for pea 1) a transformation technique which permits the complementation of two known non-nodulating pea mutants, 2) a rhizobial inoculation method which allows the study of early cellular events giving rise to nodule primordia, and 3) a targeted fungal inoculation method which allows us to study short segments of mycorrhizal roots assured to be infected. These tools are certain to advance our knowledge of pea root symbioses.
Virtual 3D tumor marking-exact intraoperative coordinate mapping improve post-operative radiotherapy
Authors: Essig Harald , Rana Majeed , Meyer Andreas , Eckardt André M , Kokemueller Horst , von See Constantin , Lindhorst Daniel , Tavassol Frank , Ruecker Martin , Gellrich Nils-Claudius
Published: December 2011

The quality of the interdisciplinary interface in oncological treatment between surgery, pathology and radiotherapy is mainly dependent on reliable anatomical three-dimensional (3D) allocation of specimen and their context sensitive interpretation which defines further treatment protocols. Computer-assisted preoperative planning (CAPP) allows for outlining macroscopical tumor size and margins. A new technique facilitates the 3D virtual marking and mapping of frozen sections and resection margins or important surgical intraoperative information. These data could be stored in DICOM format (Digital Imaging and Communication in Medicine) in terms of augmented reality and transferred to communicate patient's specific tumor information (invasion to vessels and nerves, non-resectable tumor) to oncologists, radiotherapists and pathologists.
Frequency of Th17 CD20+ cells in the peripheral blood of rheumatoid arthritis patients is higher compared to healthy subjects
Authors: Eggleton Paul , Bremer Edwin , Tarr Joanna M , de Bruyn Marco , Helfrich Wijnand , Kendall Alexandra , Haigh Richard C , Viner Nick J , Winyard Paul G
Published: December 2011

Introduction

Rheumatoid arthritis (RA) is considered a T cell driven autoimmune disease, therefore, the ability of B cell depleting biologics, e.g., anti-CD20 antibodies, to alleviate RA is unclear. This study examined the proportions of IL-17-secreting lymphocytes in the blood of healthy subjects and RA patients and determined if Th17 cells belong to a CD20+ subset of T cells.

Methods

Fluorescence-activated cell sorting and confocal microscopy verified CD3, CD4/CD8 and CD20-staining of T cells. IL-17 secretion was determined using a commercial assay.

Results

In healthy subjects and RA patients blood, the median percentage of total CD20+ lymphocytes was similar (7.5%; n = 6 and 10.3%; n = 9, respectively) and comprised predominantly of B cells (~ 86%). However, 2-4% of CD3+ T cells from both healthy subjects (n = 7) and RA (n = 8) individuals co-expressed CD20. The peripheral blood of healthy subjects contained few IL-17-secreting CD20+ T cells (< 0.1%; n = 6). In contrast, in RA blood a median and interquartile range % of, 24.2%; IQR 28.5 of IL-17-secreting T cells were CD20+ (n = 9; p = 0.02).

Conclusions

In the blood of RA patients, a greater proportion of Th17 cells are of a CD20+ phenotype compared to healthy individuals. These cells may represent an additional target for anti-CD20 therapies.
Malaria therapy in HIV: drug interactions between nevirapine and quinine
Authors: Uriel A , Lewthwaite P
Published: December 2011

We report the case of an HIV-positive Nigerian man on antiretroviral therapy (ART) with an undetectable viral load who presented with rigors, fever and back pain after returning to the UK from a three-week trip to Nigeria. Infection with Plasmodium falciparum malaria was confirmed and treatment with quinine commenced together with amoxicillin/clavulanic acid and clarithromycin for possible respiratory infection. At the time of admission the patient could not remember the names of his ART medications. After 24 hours his parasitaemia had increased from 1% to 2.5% and his clinical condition had deteriorated. At this point, his ART was identified as abacavir, lamivudine and nevirapine. The Liverpool HIV-drug interactions website was checked for drug interactions. It recommends caution in the co-administration of both clarithromycin and quinine with nevirapine. Quinine is metabolized by CYP34A and exposure is likely to be decreased by induction of these enzymes in patients taking nevirapine. Given the clinical deterioration the patient was switched to Malarone® (atovoquone/ proguanil) which has no clinically significant interactions with nevirapine. He responded to treatment and was discharged home after 48 hours. This case highlights the importance of knowing the potential drug interactions with ART and the importance of checking for such interactions when prescribing new medications.
Changes in HIV testing rates among patients with tuberculosis in a large multiethnic city in the UK
Authors: Thomas William S , Taylor R , Barrett S , Janmohamed K
Published: December 2011

Screening for HIV in patients with tuberculosis (TB) is essential, as HIV/TB co-infection has an adverse prognosis. We compared HIV testing practices in 2005 and 2008/09 in the Birmingham and Solihull region of the UK and evaluated the trends before and after the implementation of the British HIV Association (BHIVA) HIV testing guidelines (2008). A total of 371 TB patients in 2005 and 407 in 2008/09 were included. Demographics across both cohorts were similar. HIV testing increased from 14% in 2005 to 43% in 2008/09. Patients aged ≥55 years and Asian patients were less likely to be tested in 2005 and those aged ≥35 years in 2008/09. An increased rate of HIV testing was seen in all patient categories in 2008/09 compared with 2005. The odds of being tested was high in black African patients (compared with white ethnicity) in both years and increased among black Africans and African Caribbeans between both time points, albeit with wide confidence intervals (CIs). No significant difference in HIV testing was found in 2008/09 before and after the publication of the BHIVA guidelines. This study underlines the importance of continued efforts to minimize the significant gaps in HIV testing rates in TB services.
Acute HIV infection: a misleading presentation
Authors: Gentile M , Baldini F , Garbuglia A R , Sciarrone M R , Grisetti S , Giancola M L
Published: December 2011

Detecting acute HIV infection is important, but often the infection is difficult to recognize. We report the case of a 23-year-old man with persistent genital ulceration; all microbiological examinations from the ulcers were negative. HIV-1/2 antibodies were positive, but the HIV-1 Western blot (WB) was indeterminate and HIV-1 p24 antigen was persistently negative, with a low HIV-1 RNA level. One month later, the genital ulcerations disappeared and the WB test showed complete seroconversion; nonetheless HIV p24 antigen remained negative and HIV-RNA was persistently low. HIV-1 proviral DNA was detected by nested polymerase chain reaction (PCR) from the initial ulcers swabs. This case was notable due to genital ulceration being the only sign of primary HIV infection. Furthermore, the serological pattern was unusual, and HIV-RNA was unexpectedly low. This underlines the importance of screening for HIV being infection in the setting of sexually transmitted infections (STIs), and also in cases of atypical STI-like presentations.
Oral cavity and extra-oral plasmablastic lymphomas in AIDS patients: report of five cases and review of the literature
Authors: Corti M , Villafañe M F , Bistmans A , Campitelli A , Narbaitz M , Baré P
Published: December 2011

Plasmablastic lymphoma (PBL) is a distinct disease entity of the diffuse large B-cell lymphoma, which often occurs in HIV-positive patients. The immunophenotype of this lymphoid neoplasm is characterized by the presence of plasma cell-associated markers VS38c and CD138 antigens and the absence of B-cell markers such as CD20 and CD45. The most frequent site of involvement is the oral cavity and the jaw, while several reports describe the development of PBL in extra-oral sites including the lymph nodes, the anal canal, the soft tissue, the skin and the gastrointestinal tract as less frequent. Epstein−Barr virus is often associated with PBL pathogenesis and the neoplastic cells contain this virus genome. Here we review the epidemiological, clinical, immunological, histopathological and virological characteristics and their prognosis and outcome in a series of five patients with diagnoses of HIV/AIDS and PBL.
Optimization of oxygen delivery in a Jehovah's Witness with severe anaemia after postpartum haemorrhage
Authors: Simmons LaVone , Stephenson-Famy Alyssa , Easterling Thomas
Published: December 2011

The delivery of a 25-year-old Jehovah's Witness was complicated by postpartum haemorrhage with a nadir haematocrit of 3%. To improve oxygen delivery without blood transfusion, FiO2 was increased to maximize dissolved oxygen delivery. Central venous oxygen saturation was used to assess tissue oxygenation. When blood products are refused, successful management of severe anaemia is possible with supportive medical care to achieve haemostasis, optimize oxygen delivery and promote haematopoiesis.
Clofarabine in the Treatment of Newly Diagnosed Acute Myeloid Leukemia in Older Adults
Authors: Tran Huyentran , Yang Daisy
Published: December 2011

OBJECTIVE:

To review the literature evaluating the efficacy and tolerability of clofarabine, a second-generation purine nucleoside analogue, for the treatment of previously untreated acute myeloid leukemia (AML) in older adults.

DATA SOURCE:

A literature search of the PubMed database (1972-October 2011) using the search terms clofarabine and acute myeloid leukemia was performed.

STUDY SELECTION AND DATA EXTRACTION:

All relevant English-language articles were reviewed, and clinical trials with patients aged 50 years or older who were newly diagnosed with AML were included.

DATA SYNTHESIS:

Two studies evaluating clofarabine as monotherapy and 2 studies evaluating clofarabine in combination with cytarabine were reviewed. Clofarabine demonstrated activity in older adults with previously untreated AML. Response rates and median overall survival (OS) for patients receiving clofarabine were similar to those reported for conventional intensive chemotherapy regimens. Responses to the 2 types of treatment remained similar in the presence of unfavorable prognostic factors, such as secondary AML or adverse cytogenetics. Although clofarabine was associated with a lower induction mortality rate versus intensive chemotherapy regimens, a significant percentage of patients experienced severe complications, including sepsis. Compared to single-agent clofarabine, response rates and median OS were higher for clofarabine combined with cytarabine.

CONCLUSIONS:

Based on published data, adverse effect profiles, and cost, clofarabine may be an appropriate alternative to intensive chemotherapy regimens in certain subsets of older patients with newly diagnosed AML. These include patients with a baseline decreased performance status or history of cardiovascular disease who may not tolerate anthracyclines, which are typically a component of most intensive chemotherapy regimens. Additional randomized controlled trials are needed to directly compare the efficacy of clofarabine with that of intensive chemotherapy regimens and to evaluate the potential benefit of combining clofarabine with cytarabine.
Sedation and Analgesia Usage in Severe Pandemic H1N1 (2009) Infection: A Comparison to Respiratory Failure Secondary to Other Infectious Pneumonias
Authors: Olafson Kendiss , Ramsey Clare D , Ariano Robert E , Stasiuk Allison , Siddiqui Faisal , Wong Davie , Guinn Aaron , Braun Joel , Kumar Anand , Zarychanski Ryan
Published: December 2011

BACKGROUND:

During the 2009 H1N1 pandemic (pH1N1), patients requiring mechanical ventilation for respiratory failure received high doses of sedation and analgesia.

OBJECTIVE:

To examine sedation and analgesia use among patients with respiratory failure due to severe pH1N1 infection compared to other infectious pneumonias.

METHODS:

In this observational cohort study of intensive care unit (ICU) patients with respiratory failure, we compared doses of sedatives and analgesics administered to patients with pH1N1, non-pH1N1 viral pneumonia, and adult respiratory distress syndrome (ARDS) secondary to bacterial pneumonia, on days 1, 3, 7, 14, and 28 of ICU admission. Cumulative drug use, daily drug use, and weight-adjusted medication doses were examined.

RESULTS:

The study population consisted of 37 patients with pH1N1 infection, 22 patients with non-pH1N1 viral pneumonia, and 46 patients with ARDS secondary to bacterial pneumonia. To achieve similar levels of sedation using the Richmond Agitation Sedation Scale, patients with pH1N1 were administered the highest cumulative median doses of fentanyl (11, 230 μg; interquartile range [IQR] 3240-21, 000), compared to 2400 μg (IQR 130-7130) in viral pneumonia and 2880 μg (IQR 600-6950) in ARDS (p < 0.001). Patients with pH1N1 were also administered the highest cumulative median doses of midazolam at 820 mg (IQR 330-1160), compared to 160 mg (IQR 20-390) in viral pneumonia and 160 mg (IQR 20-480 mg) in ARDS (p < 0.001). The pH1N1 group received the highest median daily fentanyl and midazolam doses on all study days. The pH1N1 group did not differ significantly in cumulative propofol dose compared with the other 2 study groups.

CONCLUSIONS:

Sedative and analgesic use may be uniquely higher in critically ill patients with pH1N1 infection compared to patients with other infectious pneumonias. This finding may be important for resource planning in future pandemics. Further study is required to explore the underlying mechanisms for potentially higher sedative and analgesic requirements in this patient population.