The neuraminidase activity of influenza A virus determines the strain-specific sensitivity to neutralization by respiratory mucus.

IMPORTANCE: The respiratory tract of humans is constantly exposed to potentially harmful agents, such as small particles or pathogens, and thus requires protective measures. Respiratory mucus that lines the airway epithelia plays a major role in the prevention of viral infections by limiting the mobility of viruses, allowing subsequent mucociliary clearance. Understanding the interplay between respiratory mucus and viruses can help elucidate host and virus characteristics that enable the initiation of infection. Here, we tested a panel of primary influenza A viruses of avian or human origin for their sensitivity to mucus derived from primary human airway cultures and found that differences between virus strains can be mapped to viral neuraminidase activity. We also show that binding of influenza A viruses to decoy receptors on highly glycosylated mucus components constitutes the major inhibitory function of mucus against influenza A viruses.

Broad and Dynamic Diversification of Infectious Hepatitis C Virus in a Cell Culture Environment.

Previous studies documented that long-term hepatitis C virus (HCV) replication in human hepatoma Huh-7.5 cells resulted in viral fitness gain, expansion of the mutant spectrum, and several phenotypic alterations. In the present work, we show that mutational waves (changes in frequency of individual mutations) occurred continuously and became more prominent as the virus gained fitness. They were accompanied by an increasing proportion of heterogeneous genomic sites that affected 1 position in the initial HCV population and 19 and 69 positions at passages 100 and 200, respectively. Analysis of biological clones of HCV showed that these dynamic events affected infectious genomes, since part of the fluctuating mutations became incorporated into viable genomes. While 17 mutations were scored in 3 biological clones isolated from the initial population, the number reached 72 in 3 biological clones from the population at passage 200. Biological clones differed in their responses to antiviral inhibitors, indicating a phenotypic impact of viral dynamics. Thus, HCV adaptation to a specific constant environment (cell culture without external influences) broadens the mutant repertoire and does not focus the population toward a limited number of dominant genomes. A retrospective examination of mutant spectra of foot-and-mouth disease virus passaged in cell cultures suggests a parallel behavior here described for HCV. We propose that virus diversification in a constant environment has its basis in the availability of multiple alternative mutational pathways for fitness gain. This mechanism of broad diversification should also apply to other replicative systems characterized by high mutation rates and large population sizes.IMPORTANCE The study shows that extensive replication of an RNA virus in a constant biological environment does not limit exploration of sequence space and adaptive options. There was no convergence toward a restricted set of adapted genomes. Mutational waves and mutant spectrum broadening affected infectious genomes. Therefore, profound modifications of mutant spectrum composition and consensus sequence diversification are not exclusively dependent on environmental alterations or the intervention of population bottlenecks.

Energetics and solvation structure of a dihalogen dopant (I2) in (4)He clusters.

The energetics and structure of small HeNI2 clusters are analyzed as the size of the system changes, with N up to 38. The full interaction between the I2 molecule and the He atoms is based on analytical ab initio He-I2 potentials plus the He-He interaction, obtained from first-principle calculations. The most stable structures, as a function of the number of solvent He atoms, are obtained by employing an evolutionary algorithm and compared with CCSD(T) and MP2 ab initio computations. Further, the classical description is completed by explicitly including thermal corrections and quantum features, such as zero-point-energy values and spatial delocalization. From quantum PIMC calculations, the binding energies and radial/angular probability density distributions of the thermal equilibrium state for selected-size clusters are computed at a low temperature. The sequential formation of regular shell structures is analyzed and discussed for both classical and quantum treatments.

Full-dimensional quantum calculations of the dissociation energy, zero-point, and 10 K properties of H7+/D7+ clusters using an ab initio potential energy surface.

Diffusion Monte Carlo (DMC) and path-integral Monte Carlo computations of the vibrational ground state and 10 K equilibrium state properties of the H7 (+)/D7 (+) cations are presented, using an ab initio full-dimensional potential energy surface. The DMC zero-point energies of dissociated fragments H5 (+)(D5 (+))+H2(D2) are also calculated and from these results and the electronic dissociation energy, dissociation energies, D0, of 752 ± 15 and 980 ± 14 cm(-1) are reported for H7 (+) and D7 (+), respectively. Due to the known error in the electronic dissociation energy of the potential surface, these quantities are underestimated by roughly 65 cm(-1). These values are rigorously determined for first time, and compared with previous theoretical estimates from electronic structure calculations using standard harmonic analysis, and available experimental measurements. Probability density distributions are also computed for the ground vibrational and 10 K state of H7 (+) and D7 (+). These are qualitatively described as a central H3 (+)/D3 (+) core surrounded by "solvent" H2/D2 molecules that nearly freely rotate.

Full-dimensional (15-dimensional) ab initio analytical potential energy surface for the H7+ cluster.

Full-dimensional ab initio potential energy surface is constructed for the H(7)(+) cluster. The surface is a fit to roughly 160,000 interaction energies obtained with second-order MöllerPlesset perturbation theory and the cc-pVQZ basis set, using the invariant polynomial method [B. J. Braams and J. M. Bowman, Int. Rev. Phys. Chem. 28, 577 (2009)]. We employ permutationally invariant basis functions in Morse-type variables for all the internuclear distances to incorporate permutational symmetry with respect to interchange of H atoms into the representation of the surface. We describe how different configurations are selected in order to create the database of the interaction energies for the linear least squares fitting procedure. The root-mean-square error of the fit is 170 cm(-1) for the entire data set. The surface dissociates correctly to the H(5)(+) + H(2) fragments. A detailed analysis of its topology, as well as comparison with additional ab initio calculations, including harmonic frequencies, verify the quality and accuracy of the parameterized potential. This is the first attempt to present an analytical representation of the 15-dimensional surface of the H(7)(+) cluster for carrying out dynamics studies.

Changes in body composition and mitochondrial DNA in HIV-1-infected patients switching to fixed-dose abacavir/lamivudine or tenofovir/emtricitabine: a substudy of the BICOMBO trial.

BACKGROUND: Fat distribution, bone mineral density (BMD) and mitochondrial DNA (mtDNA) may improve, in the long-term, after switching from nucleoside reverse transcriptase inhibitors (NRTIs) to fixed-dose abacavir (ABC)/lamivudine (3TC) or tenofovir (TDF)/emtricitabine (FTC). METHODS: This was a prospective, randomized, open-label, multicentre substudy of the BICOMBO trial in which virologically suppressed patients had their NRTIs switched to ABC/3TC or TDF/FTC. Whole-body dual-energy X-ray absorptiometry (DXA) was used to measure limb, trunk and total body fat and total BMD. Lumbar and hip DXA scans were used to measure lumbar and hip BMD. Fat mass ratio (FMR; % trunk fat/% leg fat by whole-body DXA) was used to assess fat distribution. mtDNA was measured in peripheral blood mononuclear cells (PBMCs). Parameters of interest were measured at baseline, 48 and 96 weeks, and were compared between treatment groups. RESULTS: Of 56 patients included, 45 (20 ABC/3TC and 25 TDF/FTC) completed the substudy. After 96 weeks, ABC/3TC (+756 g, +12.1%) and TDF/FTC (+337 g, +7.6%) led to non-significantly different increases in limb fat (P=0.60). By contrast, trunk fat showed a significant increase (P=0.04) with ABC/3TC (+1,184 g, +10.6%) relative to TDF/FTC (-370 g, -4.2%). Median (IQR) FMR remained unchanged with ABC/3TC (-0.01 [-0.16-0.06]; P=0.23), but it decreased significantly with TDF/FTC (-0.13 [-0.30-0.00]; P=0.007). Total BMD and mtDNA significantly increased after 96 weeks, without differences between groups. CONCLUSIONS: Switching from NRTIs to either ABC/3TC or TDF/FTC led to similar increases in limb fat, BMD and PBMC mtDNA after 96 weeks.

Low-density lipoprotein size and lipoprotein-associated phospholipase A2 in HIV-infected patients switching to abacavir or tenofovir.

BACKGROUND: The aim of this study was to assess changes in the size and cholesterol content of low-density lipoproteins (LDL) and changes in lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in HIV-infected patients switching to tenofovir + emtricitabine (TDF+FTC) or abacavir + lamivudine (ABC+3TC). METHODS: This was a substudy of a multicentre randomized trial comparing TDF+FTC with ABC+3TC-based regimens in patients with virological suppression. Fasting lipids and apolipoproteins (apo), LDL size and cholesterol content and Lp-PLA2 activity were measured at baseline and at week 48. RESULTS: A total of 62 patients, naive for the compared drugs, were included. At baseline, groups were comparable except for total Lp-PLA2 activity (P=0.047) and for a tendency towards the use of a major baseline thymidine analogue in the TDF+FTC arm (25 versus 18 patients; P=0.054). In the ABC+3TC arm a significant increase in total cholesterol (0.64 mmol/l; P=0.003), high-density lipoprotein cholesterol (HDL-c, 0.13 mmol/l; P=0.031), triglycerides (0.39 mmol/l; P=0.036), apo A-I (0.12 g/l; P=0.006), apo B (0.16 g/l; P=0.015) and non-HDL-c (0.50 mmol/l; P=0.009) concentrations was observed at week 48 compared with the TDF+FTC treatment arm. In addition, an increase in the cholesterol content of small, dense LDL subfractions (0.48 mmol/l; P=0.003) and a decrease in LDL size (-2.6 nm; P=0.011) was observed in the ABC arm without changes in the TDF patients. Total PLA2, LDL-PLA2 and HDL-PLA2 activity decreased in the TDF arm, but multivariate analysis showed baseline PLA2 values and previous use of thymidine analogues as the factors associated with these changes. Estimated cardiovascular risk did not change in either arm. CONCLUSIONS: A more atherogenic LDL profile, including a decrease in LDL size, was found in the ABC group and not in TDF patients.

Internal proton transfer and H2 rotations in the H5(+) cluster: a marked influence on its thermal equilibrium state.

Classical and path integral Monte Carlo (CMC, PIMC) "on the fly" calculations are carried out to investigate anharmonic quantum effects on the thermal equilibrium structure of the H5(+) cluster. The idea to follow in our computations is based on using a combination of the above-mentioned nuclear classical and quantum statistical methods, and first-principles density functional (DFT) electronic structure calculations. The interaction energies are computed within the DFT framework using the B3(H) hybrid functional, specially designed for hydrogen-only systems. The global minimum of the potential is predicted to be a nonplanar configuration of C(2v) symmetry, while the next three low-lying stationary points on the surface correspond to extremely low-energy barriers for the internal proton transfer and to the rotation of the H2 molecules, around the C2 axis of H5(+), connecting the symmetric C(2v) minima in the planar and nonplanar orientations. On the basis of full-dimensional converged PIMC calculations, results on the quantum vibrational zero-point energy (ZPE) and state of H5(+) are reported at a low temperature of 10 K, and the influence of the above-mentioned topological features of the surface on its probability distributions is clearly demonstrated.

Community associated methicillin-resistant Staphylococcus aureus in HIV-infected patients.

Until recently, methicillin-resistant Staphylococcus aureus was considered an uncommon community pathogen, almost exclusively associated with healthcare exposure. Over the last decade, however, methicillin-resistant S. aureus infection, particularly skin and soft tissue infection, has emerged in healthy individuals with no traditional risk factors for its acquisition. Several risk factors, including certain lifestyle behaviors, have been associated with community-acquired methicillin-resistant S. aureus colonization and infection. Regardless of other concurrent risk factors, HIV-infected patients have an increased risk for acquiring this pathogen. This article summarizes the current knowledge regarding associated risk factors, clinical manifestations, and management of community-acquired methicillin-resistant Staphylococcus aureus infections in HIV-infected patients.

Toward a realistic density functional theory potential energy surface for the H5+ cluster.

The potential energy surface of H(5)(+) is characterized using density functional theory. The hypersurface is evaluated at selected configurations employing different functionals, and compared with results obtained from ab initio CCSD(T) calculations. The lowest ten stationary points (minima and saddle-points) on the surface are located, and the features of the short-, intermediate-, and long-range intermolecular interactions are also investigated. A detailed analysis of the surface's topology, and comparisons with extensive CCSD(T) results, as well as a recent ab initio analytical surface, shows that density functional theory calculations using the B3(H) functional represent very well all aspects studied on the H(5)(+) potential. These include the tiny energy difference between the minimum at 1-C(2v) configuration and the 2-D(2d) one corresponding to the transition state for the proton transfer between the two equivalent C(2v) minima, and also the correct asymptotic behavior of the long-range interactions. The calculated binding energy and dissociation enthalpies compare very well with previous benchmark coupled-cluster ab initio data, and with experimental data available. Based on these results the use of such approach to perform first-principles molecular dynamics simulations could provide reliable information regarding the dynamics of protonated hydrogen clusters.

Visceral Leishmaniasis treated with antimonials/paromomycin followed by itraconazole/miltefosine after standard therapy failures in a human immunodeficiency virus-infected patient.

Visceral leishmaniasis is an opportunistic infection that affects human immunodeficiency virus-infected persons in leishmaniasis-endemic areas. The standard treatment may not be effective and relapses are common. We report the case of a human immunodeficiency virus-1-infected patient who had several relapses of visceral leishmaniasis after treatment with standard therapies and responded to a combined therapy.

Abacavir-based therapy does not affect biological mechanisms associated with cardiovascular dysfunction.

OBJECTIVE: To assess the effects of initiating abacavir-containing therapy on plasma lipids and cardiovascular biomarkers. DESIGN: Sub-study of the BICOMBO study in which participants were randomized to switch their nucleoside backbone to either abacavir/lamivudine or tenofovir/emtricitabine. METHODS: We assessed 48-week changes in fasting lipids and several biomarkers including serum high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), osteoprotegerin, interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), selectin E and P, adiponectin, insulin, and D-dimer in otherwise healthy, virologically suppressed HIV-infected patients randomly switched to abacavir/lamivudine or tenofovir/emtricitabine with no history of cardiovascular disease, no prior abacavir or tenofovir use, and no virological failure or AIDS during follow-up. RESULTS: Eighty (46 abacavir/lamivudine and 34 tenofovir/emtricitabine) patients were included. Baseline characteristics were similar between groups and between patients in the sub-study vs. those not. There were no significant differences in baseline lipids and markers between groups. Although total (6.5 vs. -6.7%, P < 0.0001) and low-density lipoprotein (LDL) (8.6 vs. -9.1%, P = 0.004) cholesterol increased significantly in the abacavir/lamivudine group relative to the tenofovir/emtricitabine group, we found no significant changes in the biomarkers: CRP (-3.9 vs. 0.0%), MCP-1 (5.9 vs. 4.0%), osteoprotegerin (5.1 vs. -2.8%), IL-6 (0.0 vs. 0.0%), IL-10 (0.0 vs. 0.0%), TNF-alpha (0.0 vs. 0.0%), ICAM-1 (6.6 vs. 5.2%), VCAM-1 (0.02 vs. -0.01%), selectin E (-0.4 vs. 7.8%), selectin P (4.6 vs. 12.6%), insulin (-2.5 vs. 8.8%), adiponectin (-2.2 vs. 15.4%), and D-dimer (0.0 vs. 0.0%) (P > or = 0.12 for all comparisons). CONCLUSION: Abacavir/lamivudine increased total and LDL cholesterol compared with tenofovir/emtricitabine, but it did not cause inflammation, endothelial dysfunction, insulin resistance, or hypercoagulability in virologically suppressed HIV-infected patients.

A simplification trial switching from nucleoside reverse transcriptase inhibitors to once-daily fixed-dose abacavir/lamivudine or tenofovir/emtricitabine in HIV-1-infected patients with virological suppression.

BACKGROUND: Data comparing abacavir/lamivudine versus tenofovir/emtricitabine in antiretroviral-naive patients are controversial. We compared 48-week efficacy and safety of these combinations as substitutes of nucleosides in patients with virological suppression. METHODS: We randomly assigned 333 HIV-1-infected patients on lamivudine-containing triple regimens with <200 copies per milliliter for at least 6 months to switch their nucleosides to either abacavir/lamivudine (n = 167) or tenofovir/emtricitabine (n = 166). The primary outcome was treatment failure ["switching = failure" intention to treat (ITT) analysis, noninferiority margin 12.5%]. Secondary outcomes were time to treatment failure, virological failure, adverse events, and changes in CD4 count, fasting plasma lipids, lipodystrophy, body fat, bone mineral density, and renal function. RESULTS: Treatment failure occurred in 32 patients (19%) on abacavir/lamivudine and 22 patients (13%) on tenofovir/emtricitabine [difference 5.9%; (95% confidence interval -2.1% to 14.0%), P = 0.06]. Four patients in the abacavir/lamivudine group versus none in the tenofovir/emtricitabine group developed virological failure [difference 2.4; (95% confidence interval 0.05 to 6.0), P = 0.04]. Twenty-three patients (14%) assigned to abacavir/lamivudine and 10 (6%) to tenofovir/lamivudine experienced grade 3 or 4 adverse effects (P = 0.03). CD4 counts and plasma lipids showed higher increments in the abacavir/lamivudine group than in the tenofovir/emtricitabine group. CONCLUSIONS: In HIV-1-infected patients with virological suppression, abacavir/lamivudine did not meet the noninferiority outcome for treatment efficacy compared with tenofovir/emtricitabine.

Lopinavir/ritonavir: a protease inhibitor for HIV-1 treatment.

BACKGROUND: Lopinavir is a protease inhibitor with high specificity for HIV-1 protease formulated with ritonavir. Numerous clinical trials have shown that lopinavir/ritonavir (LPV/r) is highly effective as a component of highly active antiretroviral therapy (HAART) regimens for HIV-1 infection. OBJECTIVE: In this article we provide an overview of the properties of LPV/r and the experience with its use in HIV-infected adults and adolescents. METHODS: We reviewed the literature and selected the most important published articles on LPV/r and the latest posters/communications presented in conferences, with particular attention to the clinical efficacy and tolerability of LPV/r in HIV-1 infected patients. CONCLUSION: LPV/r is highly effective as a component of HAART regimens for HIV-1 infection. There is considerable experience with the drug in both treatment-naive and treatment-experienced patients. In general, LPV/r is well tolerated and its high genetic barrier to resistance favours long-term efficacy.

Diseño de un observatorio de Equidad en Calidad de Vida y Salud para Bogotá / Design of an observatory of equity as life and health for Bogota

El artículo recoge los resultados del trabajo realizado por el Grupo de Protección Social del Centro de Investigaciones para el Desarrollo (CID) de la Facultad de Ciencias Económicas de la Universidad Nacional de Colombia, en el marco del Convenio interadministrativo con la Secretaría Distrital de Salud (SDS), para la elaboración de una propuesta de diseño de un observatorio de equidad en calidad de vida y salud para Bogotá. Con tal propósito se realizó una revisión minuciosa del debate internacional y nacional sobre el tema de la equidad en salud, como punto de partida para la formulación de un enfoque teórico para el observatorio. Adicionalmente se revisó la experiencia de los observatorios de equidad en salud de las ciudades de Londres, Bruselas y Montreal, como referentes internacionales para el diseño. Con base en lo anterior, se elaboró una propuesta de diseño del observatorio que incluye el enfoque teórico adoptado, los objetivos, los procesos centrales, los métodos y la estructura básica de operación. Tratándose de un diseño, la operación del observatorio será el resultado de nuevas decisiones institucionales, si se considera que la propuesta presentada aquí tiene lugar, importancia y viabilidad para el futuro de la ciudad.

The article summarizes the results of the work done by the Social Protection Group of the Development Investigation Center (CID) of the Faculty of Economic Sciences of the National University of Colombia, according to the interadministrative agreement with the District Secretary of Health (SDS), for the elaboration of a design proposal for an observatory for equity in quality of life and health in Bogotá. With this in mind, they undertook a minute review of national and international debates on the subject of equity in health, as a point of departure for the formulation of a theoretical basis for the observatory. Additionally they reviewed the experiences of such equity in health observatories in cities such as London, Brussels, and Montreal, as international referents for the design. Based on the above, they created a design proposal for the observatory that includes the adopted theoretical focus, the objectives, the central processes, the methods and the basic structure of the operation. Speaking of this design, the operation of the observatory will come about through new institutional decisions, if the present proposal is considered to be important and viable for the future of the city.

Switching strategies to improve lipid profile and morphologic changes.

Metabolic alterations and body fat changes are well-recognized limitations of protease inhibitor-based regimens. Strategies of replacing protease inhibitors with nonnucleoside reverse transcriptase inhibitors or abacavir have been shown to improve metabolic abnormalities, particularly by decreasing cholesterol and triglyceride levels, and reducing cardiovascular risk. The various therapeutic options show differences in efficacy, tolerability, and metabolic outcomes. Abacavir seems to be better tolerated, at least in the only randomized trial in which the three options were compared face-to-face, but it is associated with higher virologic failure in patients with prior suboptimal nucleoside therapy. Nonnucleoside reverse transcriptase inhibitors, particularly nevirapine, result in a better lipid profile with a greater increase in HDL cholesterol and in the HDUtotal cholesterol ratio, one of the most important parameters associated with a reduction in cardiovascular risk. Efavirenz has been associated with increased triglyceride levels in some studies. Although protease inhibitor compounds as a family have been linked to metabolic and body fat alterations, new drugs such as atazanavir seem to be associated with a more favorable lipid profile. Lipoatrophy is a stigmatizing complication in HIV-infected patients receiving HAART. There is strong evidence suggesting a prominent role of thymidine analogs, mainly stavudine, in its development. Substitution of stavudine or zidovudine for abacavir or tenofovir partially improves peripheral fat loss. In addition, the lipid profile significantly improves. Finally, although the extended use of non-thymidine nucleoside analogs and the development of new families of antiretroviral drugs will probably result in a lower impact in lipids and morphologic changes, many patients are currently under treatment with these compounds. In this setting, switching strategies may be useful to minimize clinical and psychological consequences, improving the quality of life of HIV-infected patients treated with HAART.

Condiciones laborales de un grupo de empresas afiliadas al ISS que reportaron alto indice de accidentalidad de mano de Cundinamarca y D.E. 1987 / Work conditions of a group of enterprises affiliated to ISS that report high index of hand accidents in Cundinamarca and D.E. 1987

El trabajo realizado fue motivo de revision y analisis sobre los aspectos relacionados con la salud ocupacional: higiene y seguridad industrial y medicina preventiva del trabajo estos componentes del estudio dieron pauta para la posterior organizacion de los elementos de la investigacion que ofrecieron las estructuras de los diferentes instrumentos que fueron utiles para la recoleccion de datos. En la ejecucion de esta investigacion se llevaron a cabo los siguientes pasos:- Seleccion de la muestra: se eligieron las 50 empresas con el mas alto indice de accidentalidad de mano y con estas se realizo un muestreo no probabilistico al azar del cual se obtuvieron las 10 empresas a las cuales se aplico la encuesta. - Recoleccion de la informacion: a traves de las encuestas realizadas a cada una de las empresas que conformaron la muestra, se pretendio demostrar la presencia o ausencia de un programa de salud ocupacional. Teniendo encuenta la cantidad de datos evaluados, se distribuyo en cada una de las areas que integran la salud ocupacional un porcentaje de acuerdo al mayor o menor grado de la variable que influye en el alto indice de accidentalidad de mano. - Analisis con la interpretacion de los resultados que fueron dados en porcentajes se procedio a la elaboracion de las conclusiones y recomendaciones..