bluuebunny/crossref_metadata_2025 huggingface dataset:
Congenital Narrowing of a Pulmonary Vein: Slit‐like Pulmonary Vein Ostium
Authors: TAN JESSICA , RIVANDI ALI HOSSEINI , SAWHNEY NAVINDER , FELD GREGORY , KARIMI AFSHIN
Published: May 2011

We report the case of a 60‐year‐old female with a history of refractory paroxysmal atrial fibrillation. Preablation contrast enhanced pulmonary vein computed tomography (CT) scan demonstrated a slit‐like narrowing of the left inferior pulmonary vein ostium. The narrowing measured approximately 3 mm, with poststenotic dilation. The patient had no prior history of ablation. The patient subsequently underwent segmental antral isolation of all four pulmonary veins and cavo‐tricuspid isthmus ablation with bidirectional block. The diagnosis of preexisting congenital pulmonary vein stenosis had an impact on the type of ablation procedure performed (antral rather than ostial) and will affect the interpretation of postablation CT scans. (PACE 2013; 36:e150–e152)
Mothers’ attitudes towards perinatal autopsy after stillbirth
Authors: HOLSTE CAROLA , PILO CHRISTINA , PETTERSSON KARIN , RÅDESTAD INGELA , PAPADOGIANNAKIS NIKOS
Published: May 2011

We investigated mothers’ attitudes to autopsy of their stillborn baby and their experiences concerning information and treatment in relation to their loss in an observational study. Data were collected by postal questionnaires and telephone calls. Fifty‐four of 72 mothers (76%) replied. Fifty‐one (94%) received information from a physician about the possibility of having an autopsy; three (6%) did not get any information. The autopsy rate was 83% (n= 45). Thirty‐six of 45 (80%) received adequate information about results. Twenty‐five (56%) were pleased with how results were presented. Eleven (24%) were positive about individual contact with the pathologist who performed the autopsy. Fifty‐one (94%) stated that their decision concerning autopsy was right. Mothers do not regret their decision concerning perinatal autopsy but they do not always receive thorough and timely information concerning autopsy and its results. Personal contact with the perinatal pathologist might help with specific questions both before and after autopsy.
Swedish randomized controlled trial of cardiotocography only versus cardiotocography plus ST analysis of fetal electrocardiogram revisited: analysis of data according to standard versus modified intention‐to‐treat principle
Authors: AMER‐WÅHLIN ISIS , KJELLMER INGEMAR , MARŠÁL KAREL , OLOFSSON PER , ROSÉN KARL GUSTAF
Published: May 2011

Objective. To undertake a renewed analysis of data from the previously published Swedish randomized controlled trial on intrapartum fetal monitoring with cardiotocography (CTG‐only) vs. CTG plus ST analysis of fetal electrocardiogram (CTG+ST), using current standards of intention‐to‐treat (ITT) analysis and to compare the results with those of the modified ITT (mITT) and per protocol analyses. Methods. Renewed extraction of data from the original database including all cases randomized according to primary case allocation (n=5 049). Main outcome measure. Metabolic acidosis in umbilical artery at birth (pH <7.05, base deficit in extracellular fluid >12.0mmol/l) including samples of umbilical vein blood or neonatal blood if umbilical artery blood was missing. Results. The metabolic acidosis rates were 0.66% (17 of 2 565) and 1.33% (33 of 2 484) in the CTG+ST and CTG‐only groups, respectively [relative risk (RR) 0.50; 95% confidence interval (CI) 0.28–0.88; p=0.019]. The original mITT gave RR 0.47, 95%CI 0.25–0.86 (p=0.015), mITT with correction for 10 previously misclassified cases RR 0.48, 95%CI 0.24–0.96 (p=0.038) and per protocol analysis RR 0.40, 95%CI 0.20–0.80 (p=0.009). The level of significance of the difference in metabolic acidosis rates between the two groups remained unchanged in all analyses. Conclusion. Re‐analysis of data according to the ITT principle showed that regardless of the method of analysis, the Swedish randomized controlled trial maintained its ability to demonstrate a significant reduction in metabolic acidosis rate when using CTG+ST analysis for fetal surveillance in labor.
SUPERVISION REGIMES, RISK, AND OFFICIAL REACTIONS TO PAROLEE DEVIANCE*
Authors: GRATTET RYKEN , LIN JEFFREY , PETERSILIA JOAN
Published: May 2011

Parolee deviance has emerged as a central issue in policy debates about crime and punishment in American society as well as in scholarship on “mass incarceration.” Although the prevailing approach to studying parolees conceives of parole violations as outcomes of individual propensities toward criminal behavior (i.e., criminogenic risk), we consider how indicators of individual risk and characteristics of formal social control systems combine to account for reported parole violations. Using data on California parolees, we examine the effects of parolees’ personal characteristics, their criminal histories, and the social organization of supervision on parole violations. We advance the notion of a “supervision regime”—a legal and organizational structure that shapes the detection and reporting of parolee deviance. Three components of a supervision regime are explored: 1) the intensity of supervision, 2) the capacity of the regime to detect parolee deviance, and 3) the tolerance of parole officials for parolee deviance. We find that personal characteristics and offense histories are predictive of parole violations. However, we also find that introducing supervision factors reduces the effects of offense history variables on violation risk, suggesting that the violation risks of serious, violent, and sexual offenders are partially explainable through the heightened supervision to which they are subject. In addition, we find that supervision intensity and tolerance are generally predictive of violation risk. Capacity effects are present but weak. We conclude with a discussion of how the supervision regimes concept illuminates the gap between macro‐ and micro‐analyses of social control.
Probing the Deep: Theory and History
Authors: Beadie Nancy
Published: May 2011

Professor Tamura, in her paper “Narrative History and Theory,” poses an issue with which I have lately wrestled. She reviews, first of all, some of the challenges to the tradition of narrative history presented by “social-scientifically oriented historians” like Fernand Braudel and “analytic philosophers” like Hayden White in the 1960s and 1970s, and then goes on to note that more recently, a turn to narrative among social scientists and a use of theory by historians suggests the possibility of combining narrative and theory in historical work. Overall, Professor Tamura expresses a sanguine view of the prospects for such integration. While narrative “provides a causal account and allows us to relive events,” theory “allows us to analyze more effectively the forces that are beneath the surface.” My own efforts to write a history of education in the early Republican era that moves back and forth between telling the stories of ordinary people and using social capital theory to analyze the place of schooling in larger patterns of social, economic, and political change, lead me to share Professor Tamura's interest in the possibilities, and at the same time to identify some of the challenges, of such work.
Reflections on History, Education, and Social Theories
Authors: Franklin V. P.
Published: May 2011

Historians need social theories to conduct their research whether they are acknowledged or not. Positivist social theories underpinned the professionalization of the writing of history as well as the establishment of the social sciences as “disciplines,” in the late nineteenth and early twentieth centuries. August Comte's “science of society” and theories of evolution were attractive to U.S. historians and other researchers dealing with rapid social and economic changes taking place under the banner of American and Western “progress.” Progressive and “pragmatic” approaches were taken in dealing with the social wreckage created by the expanding industrialization, increasing urbanization, and huge influx of southern and eastern European immigrants. In addition, social theories and philosophical trends also served as the ideological underpinning for historians writing about the “white man's burden” that was said to have brought European and American “civilization” to the indigenous peoples in Asia, Africa, the Americas, and the islands of the Pacific who came to be dominated by military might with collaboration from local elites.
Photocatalytic Reduction of CO2 over Cu‐TiO2/Molecular Sieve 5A Composite
Authors: Srinivas Basavaraju , Shubhamangala Ballamoole , Lalitha Kannekanti , Anil Kumar Reddy Police , Durga Kumari Valluri , Subrahmanyam Machiraju , De Bhudev Ranjan
Published: May 2011

TiO2 and different Cu wt% loaded TiO2 (TC0.5–5.0), 10 wt% TC2.0 supported on molecular sieve 5A (10 wt% TC2.0/MS) were prepared by impregnation and solid‐state dispersion methods. The photocatalysts prepared were characterized using XRD, SEM, and UV–Vis DRS, TEM, XPS spectroscopy techniques. Photocatalytic reduction of CO2 in water and alkaline solution are investigated in a batch reactor. The yield of oxalic acid increased notably when TC was supported on molecular sieve. The Cu‐TiO2 supported on molecular sieve catalyst promotes the charge separation that leads to an increase in the selective formation of oxalic acid in addition to methanol, acetic acid and traces of methane. The product formation is due to the high adsorption of CO2, water and product shape selectivity of the composite photocatalyst. The maximum yield of oxalic acid was found to be 65.6 μg h−1 g−1 per cat using 0.2 N NaOH containing solution over 10 wt% TC2.0/MS photocatalyst. The difference in the photocatalytic activity is related to its physicochemical properties.
First evidence of mineralization of petroleum asphaltenes by a strain of Neosartorya fischeri
Authors: Uribe‐Alvarez Cristina , Ayala Marcela , Perezgasga Lucia , Naranjo Leopoldo , Urbina Héctor , Vazquez‐Duhalt Rafael
Published: May 2011

A fungal strain isolated from a microbial consortium growing in a natural asphalt lake is able to grow in purified asphaltenes as the only source of carbon and energy. The asphaltenes were rigorously purified in order to avoid contamination from other petroleum fractions. In addition, most of petroporphyrins were removed. The 18S rRNA and β‐tubulin genomic sequences, as well as some morphologic characteristics, indicate that the isolate is Neosartorya fischeri. After 11 weeks of growth, the fungus is able to metabolize 15.5% of the asphaltenic carbon, including 13.2% transformed to CO2. In a medium containing asphaltenes as the sole source of carbon and energy, the fungal isolate produces extracellular laccase activity, which is not detected when the fungus grow in a rich medium. The results obtained in this work clearly demonstrate that there are microorganisms able to metabolize and mineralize asphaltenes, which is considered the most recalcitrant petroleum fraction.
Sunitinib, a Receptor Tyrosine Kinase Inhibitor, Increases Blood Pressure in Rats without Associated Changes in Cardiac Structure and Function
Authors: Blasi E. , Heyen J. , Patyna S. , Hemkens M. , Ramirez D. , John‐Baptiste A. , Steidl‐Nichols J. , McHarg A.
Published: June 2011

Background: Sunitinib, a multi‐tyrosine kinase inhibitor has demonstrated clinical activity in advanced renal cell carcinoma and imatinib‐resistant/intolerant gastrointestinal stromal tumor. It has been associated with manageable hypertension and other unique toxicities. Aims: Two nonclinical studies were conducted to determine if sunitinib has direct/indirect effects on cardiac structure/function that may be related to hypertension at clinically relevant exposures. Materials & Methods: Rats received once‐daily vehicle or sunitinib 1 or 10 mg/kg/day (n = 10/group) orally for 4 weeks, followed by 2 weeks off treatment then a 2‐week rechallenge. Blood pressure (BP) and heart rate (HR) were continuously acquired and echocardiograms were obtained weekly. Effects of sunitinib and its metabolite (0.003–0.3 μM) were also evaluated in guinea pig isolated Langendorff‐perfused hearts (n = 4–6 hearts/group). Results: Sunitinib 10 mg/kg/day produced significant (P < 0.05) hemodynamic changes: 24 h average BP increased during initial dosing/rechallenge, with rebound hypotension during the off‐treatment period; 24 h average HR increased during the off‐treatment period, and decreased during rechallenge; no changes in cardiac structure/function were observed. In guinea pig isolated hearts, neither sunitinib nor its metabolite had direct effects on contractility, HR or left ventricular pressure. Discussion & Conclusion: These studies demonstrate that sunitinib/metabolite had no direct effects on cardiac function ex vivo, and that therapeutically relevant concentrations of sunitinib dosed on a “clinical schedule” increased BP in rats without adverse changes in cardiac structure/function.
Biodiversity information goes public: GBIF at your service
Authors: Telenius Anders
Published: June 2011

Abstract To the benefit of taxonomists, systematists, ecologists, conservationists and the interested general public community GBIF (the Global Biodiversity Information Facility) now offers more than 280 million records from biological and geological collections and observation data bases worldwide. Taxonomic revisions, phylogenetic analyses, large scale ecological modelling, and decisionmaking in conservation and planning issues are simplified and may be based on better background knowledge than ever before using the central GBIF portal athttp://www.gbif.org/or regional portals hosted by the different GBIF‐nodes.
Aggregatibacter actinomycetemcomitans leukotoxin is post‐translationally modified by addition of either saturated or hydroxylated fatty acyl chains
Authors: Fong K.P. , Tang H.‐Y. , Brown A.C. , Kieba I.R. , Speicher D.W. , Boesze‐Battaglia K. , Lally E.T.
Published: June 2011

Aggregatibacter actinomycetemcomitans, a common inhabitant of the human upper aerodigestive tract, produces a repeat in toxin (RTX), leukotoxin (LtxA). The LtxA is transcribed as a 114‐kDa inactive protoxin with activation being achieved by attachment of short chain fatty acyl groups to internal lysine residues. Methyl esters of LtxA that were isolated from A. actinomycetemcomitans strains JP2 and HK1651 and subjected to gas chromatography/mass spectrometry contained palmitoyl (C16:0, 27–29%) and palmitolyl (C16:1 cis Δ9, 43–44%) fatty acyl groups with smaller quantities of myristic (C14:0, 14%) and stearic (C18:0, 12–14%) fatty acids. Liquid chromatography/mass spectrometry of tryptic peptides from acylated and unacylated recombinant LtxA confirmed that Lys562 and Lys687 are the sites of acyl group attachment. During analysis of recombinant LtxA peptides, we observed peptide spectra that were not observed as part of the RTX acylation schemes of either Escherichia coliα‐hemolysin or Bordetella pertussis cyclolysin. Mass calculations of these spectra suggested that LtxA was also modified by the addition of monohydroxylated forms of C14 and C16 acyl groups. Multiple reaction monitoring mass spectrometry identified hydroxymyristic and hydroxypalmitic acids in wild‐type LtxA methyl esters. Single or tandem replacement of Lys562 and Lys687 with Arg blocks acylation, resulting in a >75% decrease in cytotoxicity when compared with wild‐type toxin, suggesting that these post‐translational modifications are playing a critical role in LtxA‐mediated target cell cytotoxicity.
Pseudoeffective and nef classes on abelian varieties
Authors: Debarre Olivier , Ein Lawrence , Lazarsfeld Robert , Voisin Claire
Published: June 2011

We study the cones of pseudoeffective and nef cycles of higher codimension on the self product of an elliptic curve with complex multiplication, and on the product of a very general abelian surface with itself. In both cases, we find for instance the existence of nef classes that are not pseudoeffective, answering in the negative a question raised by Grothendieck in correspondence with Mumford. We also discuss several problems and questions for further investigation.
Aerothermodynamics of
a High-Pressure Turbine Blade With Very High Loading and Vortex
Generators
Authors: Gomes Reinaldo
A. , Niehuis Reinhard
Published: May 2011

AITEB-2 is a project where aerothermal challenges of modern high pressure turbine designs are analyzed. One of the scopes of the project is to allow for new gas turbine designs with less parts and lighter jet engines by increasing the blade pitch and therefore the aerodynamic blade loading. For transonic profiles, this leads to very high velocities on the suction side and shock induced separation is likely to occur. The total pressure loss increase due to flow separation and strong shocks, as well as the underturning of the flow, limits the increase of the blade pitch. In this paper, experiments using a linear turbine blade cascade with high aerodynamic loading are presented. The blade pitch is increased such that at design conditions, a strong separation occurs on the suction side. The experiments were run at high subsonic exit Mach numbers and at Reynolds numbers of 390,000 and 800,000. In order to reduce the flow separation and the aerodynamic losses, air jet vortex generators are used, which create streamwise vortices prior to the separation start. Since in high pressure turbine blades film cooling is widely used, also the influence of film cooling both with and without using vortex generators is analyzed. Film cooling is provided on the suction side by two rows of cylindrical holes. This paper provides an analysis of the influence of different main flow conditions, film cooling, and vortex generators on total pressure loss, heat transfer and film cooling effectiveness. The experiments show that the vortex generators, as well as the film cooling reduce flow separation and total pressure losses. The effects are also seen in the local heat transfer, especially with enhanced heat transport in the region with flow separation. The cases presented in this paper deal with complex flow phenomena, which are challenging to be predicted with modern numerical tools correctly. Therefore, the experimental data serve as a comprehensive database for validation of simulation tools in the AITEB-2 project.
Geometrical Uncertainty and Film Cooling: Fillet Radii
Authors: Montomoli Francesco , Massini Michela , Salvadori Simone , Martelli Francesco
Published: May 2011

This study presents an investigation of the impact of filleted edge variations on heat transfer. In real gas turbines, sharp edges are an approximation because of manufacturing tolerances and/or geometrical modifications occurring during operation. The value of fillet radius is not exactly known a priori. It can be assumed that a specific radius occurs with a probability following a probabilistic distribution. For this reason, the effect of variation of the filleted edge on internal channel of a film cooling configuration has been studied numerically using an in house solver. The hole exit is fanshaped and the feeding duct axis and the main stream are perpendicular to each other. A response surface has been generated, varying the internal Mach number of coolant and the pressure ratio range between coolant and main gas. Four fillet radii for the internal duct have been analyzed, r/D=0.0–5%. A Gaussian distribution for the fillet radius has been assumed. Using the overmentioned distributions, it is possible to obtain the probabilistic functions of corresponding discharge coefficient Cd and adiabatic effectiveness η. The overall variation of Cd and η can be more than 10% the value without fillet. Furthermore, the differences on Cd due to the uncertainties on fillet radius are bigger than those obtained due to modifying the exit duct shape (i.e., from cylindrical to fanshaped). This paper shows that the effect of variation of fillet radii must be included in numerical simulations. This has direct consequences on LES and DNS simulations, which normally include sharp corners or mean radii. A probabilistic approach must be included in the analysis of the results and the equivalent fillet radius must be assumed instead.
A HIF-Regulated VHL-PTP1B-Src Signaling Axis Identifies a Therapeutic Target in Renal Cell Carcinoma
Authors: Suwaki Natsuko , Vanhecke Elsa , Atkins Katelyn M. , Graf Manuela , Swabey Katherine , Huang Paul , Schraml Peter , Moch Holger , Cassidy Amy Mulick , Brewer Daniel , Al-Lazikani Bissan , Workman Paul , De-Bono Johann , Kaye Stan B. , Larkin James , Gore Martin. E. , Sawyers Charles L. , Nelson Peter , Beer Tomasz M. , Geng Hao , Gao Lina , Qian David Z. , Alumkal Joshi J. , Thomas Gary , Thomas George V.
Published: June 2011

Signaling through the VHL-PTP1B-Src pathway in renal cell carcinomas may determine sensitivity to Src inhibitors and provide a basis for treatment planning.
MF59 Adjuvant Enhances Diversity and Affinity of Antibody-Mediated Immune Response to Pandemic Influenza Vaccines
Authors: Khurana Surender , Verma Nitin , Yewdell Jonathan W. , Hilbert Anne Katrin , Castellino Flora , Lattanzi Maria , Del Giudice Giuseppe , Rappuoli Rino , Golding Hana
Published: June 2011

Adjuvant use improves the quality and quantity of the immune response to pandemic influenza vaccines.
T Cell Monitoring of Chemotherapy in Experimental Rat Tuberculosis
Authors: Foo Damian Guang , Tay Hui Chien , Siew Jie Yee , Singhal Amit , Camacho Luis , Bifani Pablo , Dartois Véronique , Hervé Maxime
Published: June 2011

Mycobacterium tuberculosis
is the causative agent of a pulmonary epidemic that is estimated to infect one-third of the world's population and that has an increased incidence of multidrug resistance. The evaluation of new chemical entities against
M. tuberculosis
is hampered by the lack of biological tools to help predict efficacy, from early drug development to clinical trials. As the rat is the animal species of choice in the pharmaceutical industry, we have developed a rat model of acute and chronic phases of
M. tuberculosis
infection for drug efficacy testing. In this model, we have evaluated the impact of tuberculosis drugs on T cell response using the enzyme-linked immunospot assay methodology. Infected rats treated with isoniazid (INH) or rifampin (RIF) responded to therapy, the potency of which was comparable to that seen in the mouse. Peripheral blood mononuclear cells from infected rats produced gamma interferon (IFN-γ) in response to RD-1 antigens, such as the 6-kDa early secretory antigen target (ESAT-6) and the 10-kDa culture filtrate protein (CFP-10). A decrease in IFN-γ spot-forming cells (SFCs) was consistently observed in response to drug treatment. In both the acute- and chronic-phase models, the T cell response was more sensitive to ESAT-6 than to CFP-10. The SFC count in response to ESAT-6 appears to be an indicator of bacterial killing in the rat. Collectively, our data suggest that the ESAT-6 response could be used as a potential surrogate of drug efficacy in the rat and that such a readout could help shorten drug testing during preclinical development.
Novel Method for Simultaneous Quantification of Phenotypic Resistance to Maturation, Protease, Reverse Transcriptase, and Integrase HIV Inhibitors Based on 3′Gag(p2/p7/p1/p6)/PR/RT/INT-Recombinant Viruses: a Useful Tool in the Multitarget Era of Antiretroviral Therapy
Authors: Weber Jan , Vazquez Ana C. , Winner Dane , Rose Justine D. , Wylie Doug , Rhea Ariel M. , Henry Kenneth , Pappas Jennifer , Wright Alison , Mohamed Nizar , Gibson Richard , Rodriguez Benigno , Soriano Vicente , King Kevin , Arts Eric J. , Olivo Paul D. , Quiñones-Mateu Miguel E.
Published: June 2011

Twenty-six antiretroviral drugs (ARVs), targeting five different steps in the life cycle of the human immunodeficiency virus type 1 (HIV-1), have been approved for the treatment of HIV-1 infection. Accordingly, HIV-1 phenotypic assays based on common cloning technology currently employ three, or possibly four, different recombinant viruses. Here, we describe a system to assess HIV-1 resistance to all drugs targeting the three viral enzymes as well as viral assembly using a single patient-derived, chimeric virus. Patient-derived p2-INT (gag-p2/NCp7/p1/p6/pol-PR/RT/IN) products were PCR amplified as a single fragment (3,428 bp) or two overlapping fragments (1,657 bp and 2,002 bp) and then recombined into a vector containing a near-full-length HIV-1 genome with theSaccharomyces cerevisiaeuracil biosynthesis gene (URA3) replacing the 3,428 bp p2-INT segment (Dudley et al., Biotechniques 46:458–467, 2009). P2-INT-recombinant viruses were employed in drug susceptibility assays to test the activity of protease (PI), nucleoside/nucleotide reverse transcriptase (NRTI), nonnucleoside reverse transcriptase (NNRTI), and integrase strand-transfer (INSTI) inhibitors. Using a single standardized test (ViralARTS HIV), this new technology permits the rapid and automated quantification of phenotypic resistance for all known and candidate antiretroviral drugs targeting all viral enzymes (PR, RT, including polymerase and RNase H activities, and IN), some of the current and potential assembly inhibitors, and any drug targeting Pol or Gag precursor cleavage sites (relevant for PI and maturation inhibitors) This novel assay may be instrumental (i) in the development and clinical assessment of novel ARV drugs and (ii) to monitor patients failing prior complex treatment regimens.
Tripropeptin C Blocks the Lipid Cycle of Cell Wall Biosynthesis by Complex Formation with Undecaprenyl Pyrophosphate
Authors: Hashizume Hideki , Sawa Ryuichi , Harada Shigeko , Igarashi Masayuki , Adachi Hayamitsu , Nishimura Yoshio , Nomoto Akio
Published: June 2011

Tripropeptin C (TPPC) is a naturally occurring cyclic lipodepsipeptide antibiotic produced by aLysobactersp. TPPC exhibits potent antibacterial activity against methicillin-resistantStaphylococcus aureus(MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistantStreptococcus pneumoniae. This antibiotic also inhibits the incorporation ofN-acetylglucosamine into the peptidoglycan ofS. aureusat a 50% inhibitory concentration (IC50) of 0.7 μM, which is proportional to its MIC (0.87 μM; equivalent to 1.0 μg/ml). Treatment of exponential-phaseS. aureuscells with TPPC resulted in accumulation of UDP-MurNAc-pentapeptide in the cytoplasm. The antimicrobial activity of TPPC was weakened by the addition of prenyl pyrophosphates but not by prenyl phosphates, UDP-linked sugars, or the pentapeptide of peptidoglycan. The direct interaction between TPPC and undecaprenyl pyrophosphate (C55-PP) was observed by mass spectrometry and thin-layer chromatography analysis, indicating that TPPC can potentially inhibit C55-PP phosphatase activity, which plays a crucial role in the lipid cycle of peptidoglycan synthesis. As expected, TPPC inhibits this enzymatic reaction at an IC50of 0.03 to 0.1 μMin vitro, as does bacitracin. From the analysis of accumulation of lipid carrier-related compounds, TPPC was found to cause the accumulation of C55-PPin situ, leading to the accumulation of a glycine-containing lipid intermediate. This suggested that the TPPC/C55-PP complex also inhibits the transglycosylation step or flippase activity, adding to the inhibition of C55-PP dephosphorylation. This mode of action is different from that of currently available drugs such as vancomycin, daptomycin, and bacitracin.
Single Mutations in HIV Integrase Confer High-Level Resistance to Raltegravir in Primary Human Macrophages
Authors: Marsden Matthew D. , Avancena Patricia , Kitchen Christina M. R. , Hubbard Trish , Zack Jerome A.
Published: June 2011

CD4+T cells and macrophages are the primary target cells for HIVin vivo, and antiretroviral drugs can vary in their ability to inhibit the infection of these different cell types. Resistance pathways to the HIV integrase inhibitor raltegravir have previously been investigated in T cells. Primary raltegravir resistance mutations, most often at integrase amino acid position 148 or 155, afford some resistance to the drug. The acquisition of pathway-specific secondary mutations then provides higher-level resistance to viruses infecting T cells. We show here that during macrophage infection, the presence of a single primary raltegravir resistance mutation (Q148H, Q148R, N155H, or N155S) is sufficient to provide resistance to raltegravir comparable to that seen in viruses expressing both primary and secondary mutations in costimulated CD4+T cells. These data implicate macrophages as a potentialin vivoreservoir that may facilitate the development of resistance to raltegravir. Notably, the newer integrase inhibitor MK-2048 effectively suppressed the infection of all raltegravir-resistant viruses in both T cells and macrophages, indicating that more recently developed integrase inhibitors are capable of inhibiting infection in both major HIV cellular reservoirs, even in patients harboring raltegravir-resistant viruses.
In Vitro
Efficacy of Antibiotics Commonly Used To Treat Human Plague against Intracellular
Yersinia pestis
Authors: Wendte Jered M. , Ponnusamy Duraisamy , Reiber Deanna , Blair Jeffrey L. , Clinkenbeard Kenneth D.
Published: June 2011

Yersinia pestis
initiates infection as a facultative intracellular parasite in host macrophages; however, little is known about the efficacy of antibiotics commonly used to treat human plague against intracellular
Y. pestis
. Intracellular minimal bactericidal concentrations (MBCs) were determined using a high-throughput broth microdilution assay in which human THP-1 macrophage-like cells were infected with
Y. pestis
strain KIM6-2053.1+ and exposed to 2-fold serial dilutions of antibiotics for 24 h in 96-well plates. The numbers of CFU, upon which minimal bactericidal concentrations were based, were determined by counting “microcolonies” in wells of 96-well plates following lysis of tissue culture cells to release surviving
Y. pestis
, replica dilution, and plating in soft tryptic soy broth agar. For THP-1 cells, streptomycin and ciprofloxacin had comparable efficacies for intra- and extracellular
Y. pestis
, but the MBCs for chloramphenicol, gentamicin, doxycycline, and amoxicillin were two-, three-, four-, and five 2-fold serial dilutions greater, respectively, for intracellular than for extracellular
Y. pestis
. During the initial stage of plague, intracellular
Y. pestis
may be less susceptible to antibiotic killing by particular antibiotics recommended for treatment of plague, such as gentamicin or doxycycline, whereas others, such as streptomycin and ciprofloxacin, may have similar efficacies against extracellular or intracellular
Y. pestis
. This may be of particular importance in the selection of antibiotics for prophylactic treatment in the case of a bioterrorism event.
Expression of Toll-Like Receptor 4 and Downstream Effectors in Selected Cecal Cell Subpopulations of Chicks Resistant or Susceptible to Salmonella Carrier State
Authors: Chaussé Anne-Marie , Grépinet Olivier , Bottreau Elisabeth , Le Vern Yves , Menanteau Pierrette , Trotereau Jérome , Robert Vincent , Wu Zhiguang , Kerboeuf Dominique , Beaumont Catherine , Velge Philippe
Published: June 2011

Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharide from Gram-negative bacteria, plays a major role in resistance of mice and humans to
Salmonella
infection. In chickens,
Salmonella
may establish a carrier state whereby bacteria are able to persist in the host organism without triggering clinical signs. Based on cellular morphological parameters, we developed a method, without using antibodies, to separate three cecal cell subpopulations: lymphocytes, enterocytes, and a population encompassing multiple cell types. We analyzed the mRNA expression of TLR4, interleukin-1β (IL-1β), IL-8, IL-12, and lipopolysaccharide-induced tumor necrosis factor alpha factor (LITAF) in cecal subpopulations of chicks from inbred lines resistant or susceptible to the carrier state infected with
Salmonella enterica
serovar Enteritidis. The results showed that resistance to the carrier state in chicks is associated with a larger percentage of lymphocytes and with higher levels of expression of TLR4 and IL-8 at homeostasis in the three cell subpopulations, as well as with a higher level of expression of LITAF in lymphocytes during the carrier state. In contrast to the early phase of infection, the carrier state is characterized by no major cell recruitment differences between infected and noninfected animals and no significant modification in terms of TLR4, IL-1β, IL-8, IL-12, and LITAF expression in all cell subpopulations measured. However, TLR4 expression increased in the lymphocytes of chicks from the susceptible line, reaching the same level as that in infected chicks from the resistant line. These observations suggest that the carrier state is characterized by a lack of immune activation and highlight the interest of working at the level of the cell population rather than that of the organ.
Efficacy of a Conjugate Vaccine Containing Polymannuronic Acid and Flagellin against Experimental Pseudomonas aeruginosa Lung Infection in Mice
Authors: Campodónico Victoria L. , Llosa Nicolas J. , Bentancor Leticia V. , Maira-Litran Tomas , Pier Gerald B.
Published: June 2011

Vaccines that could effectively prevent
Pseudomonas aeruginosa
pulmonary infections in the settings of cystic fibrosis (CF) and nosocomial pneumonia could be exceedingly useful, but to date no effective immunotherapy targeting this pathogen has been successfully developed for routine use in humans. Evaluations using animals and limited human trials of vaccines and their associated immune effectors against different
P. aeruginosa
antigens have suggested that antibody to the conserved surface polysaccharide alginate, as well as the flagellar proteins, often give high levels of protection. However, alginate itself does not elicit protective antibody in humans, and flagellar vaccines containing the two predominant serotypes of this antigen may not provide sufficient coverage against variant flagellar types. To evaluate if combining these antigens in a conjugate vaccine would be potentially efficacious, we conjugated polymannuronic acid (PMA), containing the blocks of mannuronic acid conserved in all
P. aeruginosa
alginates, to type a flagellin (FLA) and evaluated immunogenicity, opsonic killing activity, and passive protective efficacy in mice. The PMA-FLA conjugate was highly immunogenic in mice and rabbits and elicited opsonic antibodies against mucoid but not nonmucoid
P. aeruginosa
, but nonetheless rabbit antibody to PMA-FLA showed evidence of protective efficacy against both types of this organism in a mouse lung infection model. Importantly, the PMA-FLA conjugate vaccine did not elicit antibodies that neutralized the Toll-like receptor 5 (TLR5)-activating activity of flagellin, an important part of innate immunity to flagellated microbial pathogens. Conjugation of PMA to FLA appears to be a promising path for developing a broadly protective vaccine against
P. aeruginosa
.
Antibodies in Action: Role of Human Opsonins in Killing Salmonella enterica Serovar Typhi
Authors: Lindow Janet C. , Fimlaid Kelly A. , Bunn Janice Y. , Kirkpatrick Beth D.
Published: June 2011

Although vaccines have been available for over a century, a correlate of protection for typhoid fever has yet to be identified. Antibodies are produced in response to typhoid infection and vaccination and are generally used as the gold standard for determining vaccine immunogenicity, even though their role in clearance ofSalmonella entericaserovar Typhi infections is poorly defined. Here, we describe the first functional characterization ofS.Typhi-specific antibodies following vaccination with a new vaccine, M01ZH09 (Ty2 ΔaroCΔssaV). We determined that postvaccination sera increased the uptake of wild-typeS.Typhi by human macrophages up to 2.3-fold relative to prevaccination (day 0) or placebo samples. These results were recapitulated using immunoglobulins purified from postvaccination serum, demonstrating that antibodies were largely responsible for increases in uptake. Imaging verified that macrophages internalized 2- to 9.5-fold moreS.Typhi when the bacteria were opsonized with postvaccination sera than when the bacteria were opsonized with day 0 or placebo sera. Once inside macrophages, the survival ofS.Typhi was reduced as much as 50% when opsonized with postvaccination sera relative to day 0 or placebo serum samples. Lastly, bactericidal assays indicated that antibodies generated postvaccination were recognized by complement factors and assisted in killingS.Typhi: mean postvaccination bactericidal antibody titers were higher at all time points than placebo and day 0 titers. These data clearly demonstrate that there are at least two mechanisms by which antibodies facilitate killing ofS.Typhi. Future work could lead to improved immunogenicity tests associated with vaccine efficacy and the identification of correlates of protection against typhoid fever.
The clinic embraces all aspects of SEM from ‘exercise on prescription’ and ‘functional rehabilitation programmes’ to specialist image guided spinal injections
Authors: Petrides Simon
Published: June 2011

Simon is a Musculoskeletal and Sports physician and Director of the Blackberry Clinic in Milton Keynes. Simon has a special interest in prolotherapy injections as an adjunct to intense rehabilitation programmes for unremitting low back pain (LBP).

This has culminated in successful treatment of many elite athletes and footballers.

Most clinical trials on the treatment have shown significant benefits but no prominent trials have used patients with specific back pain diagnoses using selective block injections to determine which patients are most likely to benefit.

Rowing has a LBP incidence of 100% and over 20 GB rowers have been successfully treated using this technique.

The lecture will summarise his experience in the use of prolotherapy in these athlete.
Benefits and challenges of collaborative research: lessons from supportive and palliative care
Authors: Payne Sheila , Seymour Jane , Molassiotis Alex , Froggatt Katherine , Grande Gunn , Lloyd-Williams Mari , Foster Claire , Wilson Roger , Rolls Liz , Todd Chris , Addington-Hall Julia
Published: May 2011

Objective

To describe the processes of establishing and running the Cancer Experiences Collaborative (CECo), and reflect upon the benefits and challenges of undertaking collaborative research in supportive and palliative care.

Design

A descriptive analysis of a 5-year research collaborative initiated in 2006.

Setting

Research groups at the Universities of Lancaster, Liverpool, Manchester, Nottingham and Southampton, England.

Participants

26 UK organisations including the four largest hospices in England, hospital cancer centres, Help the Hospices (a national charity supporting independent hospices) and user representatives.

Findings

The aim of CECo was to enhance the value, quality and productivity of scientific research in supportive and palliative care, and to increase research capacity and improve the coordination of collaborative research. Three programmatic themes of research were established: (i) innovative approaches to complex symptoms, (ii) planning for the care of older adults towards the end of life and (iii) research methodology including narrative approaches. Four benefits and challenges are highlighted: strategic leadership and management structures for cross-institutional work, working in multidisciplinary groups and linking research with practice settings, capacity building, and user involvement.

Conclusions

The activities of CECo have resulted in significant benefits with an increase in good quality research studies that have led to the production of a significant number of peer-reviewed papers, and learning between academics, clinicians and users, which has contributed to raising the standards of supportive and palliative care research. However, the future of such research initiatives is fragile, with concerns about the sustainability of collaboration in the face of diminishing resources.
Palliative care services for advanced non-malignant lung diseases in Taiwan
Authors: Chan T T , Lin M S , Yu C J , Hsu J Y , Wang J D , Yan Y H , Partridge M , Chen C R
Published: May 2011

Although hospice services has been available for cancer patients for 20 years in Taiwan, that for non-malignant diseases was started only since September, 2009. How well clinicians in this country are prepared for this challenge is unknown. A questionnaire was completed by 149 mostly respiratory clinicians (including 41 physicians, 65 nurses, 36 respiratory therapists,) in three large hospitals from northern, central and southern Taiwan. Although hospice inpatient, outpatient and home care services were provided by all 3 hospitals, only 24–35% of clinicians reported easy access of these services. Fifty percent of physicians had referred patients at risk of respiratory failure to palliative care team, and the main reasons of non-referral were resource factors and no request by patients. Only 8.1% of all respondents had explicit policies and procedures of end-of-life care for patients with non-malignant lung diseases in their hospitals. Such policies or procedures were thought to be developed by the hospice team in 8.1%, and by pulmonologist or intensivist in 6.7%. For COPD patients, majority of physicians suggested discussion of end-of-life issues when patients were in severe disease (GOLD stage III), less than 100 m in 6-min walking test, after 2 to 3 admissions or ER visits for acute exacerbations in the past year, or after 1 respiratory failure attack. Almost all of them considered current palliative care for non-malignant lung disease patients having a long way to go to meet their needs. Among others, professional recruitment and development, public education and medical practice guidelines were those most urgently expected.
ACP: more than burial or cremation!
Authors: Loney J , Willoughby J , Miller H , Russell S , Loney J
Published: May 2011

Three care home educators worked across nine care homes in East, North and West Hertfordshire to provide an End of Life Care Education Programme to care homes.

496 staff took part in the education programme. (Isabel Hospice Project: 150 participants in 3 homes, Peace Hospice Project: 155 participants in 4 homes, Hospice of St Francis Project: 191 participants in 2 homes).

Each education programme although designed differently contained the same education content and themes as well as measuring the education activity and impact of that education:

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Clarification of advance care planning terminology and documentation.

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Awareness of services and team working across organizations.

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Identification of residents at the end of life.

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Symptom control and assessment.

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Communication skills.

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Cultural care.

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Manager support for the end of life ethos.

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Support in policy writing.

The education programme resulted in:

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An increase in the skills, confidence and competence of care home staff with the advance care planning process.

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Significant increase in the preferred place of care being achieved through the use of advance care planning with the residents.

The three programmes focused on identifying, developing and sustaining the care home staff skills and confidence, thus enabling proactive advance care planning in the care home setting.

This demonstrated that a flexible, learner centred and systematic approach to education can make a difference.
On Your Marks, Get Set, Go! Piloting Advance Care Planning Education
Authors: Russell S , Fowler C
Published: May 2011

In 2009, Mount Vernon Cancer Network piloted four 1 day experiential advance care planning (ACP) workshops in four locations facilitated by two educators. The training the trainer model was considered early in order to increase the availability of ACP facilitators across MVCN. Participants to the 1 day workshops were invited to attend a ½ day ‘Teaching Advance Care Planning’.

51 participants attended the workshops:

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45% Community Matrons, District, Respiratory Specialist Nurses, Care Home Staff

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18% palliative care education roles

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15% hospice care

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12% Clinical Nurse Specialists in Palliative Care

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6% hospice social workers

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4% associate specialist/GP assistant roles.

The participants confidence increased significantly following attendance at the workshops: Pre Post

Confidence in explaining ACP 54% 100%.

What a statement of wishes and preferences is 33% 93%.

What an advance decision to refuse treatment is 24% 91%.

When lasting power of attorney (welfare) is used 15% 87%.

A ‘Teaching Advance Care Planning’ ½ day interactive workshop discussed the rationale for the 1 day course, signposting to relevant resources and information about the wider evidence base for advance care planning. Participants brought to the sessions the type of sessions, target audience and timings that they planned to deliver training to. Draft lesson plans and resources were produced during the workshop for them to take away to practice. Delivery methods and interactive exercises were also discussed and offered. The education model was further developed and delivered in 2010.
Creating interest in ACP in a health group setting
Authors: Denson J , McKinnon A , Scammell S , Dickins C , Meehan L
Published: May 2011

In 2009 Barwon Health's Chronic Heart Failure (CHF) team commenced promoting the opportunity of Advanced Care Planning (ACP) to clients in our 12 week group programs. Prior to 2009, ACP information was provided to clients individually when time permitted.

The team was interested in exploring if this new approach led to a greater willingness to engage in discussion about ACP.

Midway into a program the Cardiac Nurse provides a leaflet and information about ACP to all participants and partners. In the following weeks the Social Worker speaks to each client about his/her interest or questions. The discussions can then continue with Social Worker, client and family and any existing legal documents the client has are checked.

There has been a marked increase both in information clients received about ACP and follow-up discussions. 51 of 99 clients and partners discussed ACP with the Social Worker and 37 plans completed with a high client satisfaction rate.

This approach is innovative because the ACP information is initially offered with health related information when clients are relaxed within the group, familiar with the team and have an increased understanding of their heart condition. The process is connected with their weekly program attendance and moves at the client's pace. It is acceptable to clients, timely and leads to greater willingness to engage in the ACP process. We believe the approach can be used for many health group programs and has the potential to increase the participation in ACP within the community health population.
Advance Care Planning (ACP) within a palliative approach for residential aged care
Authors: Hudson R
Published: May 2011

In a unique collaboration between palliative care and aged care the Australian government produced Guidelines for a palliative approach in residential aged care, endorsed by the National Health & Medical Research Council in 2006. Specific guidelines for Advance Care Planning (ACP) fit within the broader palliative approach with its emphasis on holistic assessment early in the course of life-threatening disease. Replacing ad hoc arrangements for offering end-of-life choices, the guidelines emphasise systematic implementation, regular education and ongoing assessment. The ACP component is clearly linked to many of the other 76 guidelines, demonstrating the role of ACP in the broader framework of goal setting and care planning.

Two brief, contrasting case studies exemplify the successful application of the guidelines for (a) a very physically frail, mentally alert older person and (b) a person with advanced dementia and other co-morbidities. Noting the families' reports and the endorsement of professional colleagues, aged care workers enjoyed pride and satisfaction from seeing the guidelines at work. The challenge remains, however, to ensure consistency in the application of the guidelines over a sustained period of time.

When advance care planning in care homes is based on endorsed guidelines drawn from the best available evidence, the end-of-life experience for older persons, families, and care staff can be transformed.