Molecular signatures of a TLR4 agonist-adjuvanted HIV-1 vaccine candidate in humans

Systems biology approaches have recently provided new insights into the mechanisms of action of human vaccines and adjuvants. Here, we investigated early transcriptional signatures induced in whole blood of healthy subjects following vaccination with a recombinant HIV-1 envelope glycoprotein subunit CN54gp140 adjuvanted with the TLR4 agonist glucopyranosyl lipid adjuvant-aqueous formulation (GLA-AF) and correlated signatures to CN54gp140-specific serum antibody responses. Fourteen healthy volunteers aged 18-45 years were immunized intramuscularly three times at 1-month intervals and whole blood samples were collected at baseline, 6 h, and 1, 3, and 7 days post first immunization. Subtle changes in the transcriptomic profiles were observed following immunization, ranging from over 300 differentially expressed genes (DEGs) at day 1 to nearly 100 DEGs at day 7 following immunization. Functional pathway analysis revealed blood transcription modules (BTMs) related to general cell cycle activation, and innate immune cell activation at early time points, as well as BTMs related to T cells and B cell activation at the later time points post-immunization. Diverse CN54gp140-specific serum antibody responses of the subjects enabled their categorization into high or low responders, at early ( < 1 month) and late (up to 6 months) time points post vaccination. BTM analyses revealed repression of modules enriched in NK cells, and the mitochondrial electron chain, in individuals with high or sustained antigen-specific antibody responses. However, low responders showed an enhancement of BTMs associated with enrichment in myeloid cells and monocytes as well as integrin cell surface interactions. Flow cytometry analysis of peripheral blood mononuclear cells obtained from the subjects revealed an enhanced frequency of CD56 dim NK cells in the majority of vaccines 14 days after vaccination as compared with the baseline. These results emphasize the utility of a systems biology approach to enhance our understanding on the mechanisms of action of TLR4 adjuvanted human vaccines

The Flagellum of Pseudomonas aeruginosa Is Required for Resistance to Clearance by Surfactant Protein A

Surfactant protein A (SP-A) is an important lung innate immune protein that kills microbial pathogens by opsonization and membrane permeabilization. We investigated the basis of SP-A-mediated pulmonary clearance of Pseudomonas aeruginosa using genetically-engineered SP-A mice and a library of signature-tagged P. aeruginosa mutants. A mutant with an insertion into flgE, the gene that encodes flagellar hook protein, was preferentially cleared by the SP-A(+/+) mice, but survived in the SP-A(-/-) mice. Opsonization by SP-A did not play a role in flgE clearance. However, exposure to SP-A directly permeabilized and killed the flgE mutant, but not the wild-type parental strain. P. aeruginosa strains with mutation in other flagellar genes, as well as mucoid, nonmotile isolates from cystic fibrosis patients, were also permeabilized by SP-A. Provision of the wild-type fliC gene restored the resistance to SP-A-mediated membrane permeabilization in the fliC-deficient bacteria. In addition, non-mucoid, motile revertants of CF isolates reacquired resistance to SP-A-mediated membrane permeability. Resistance to SP-A was dependent on the presence of an intact flagellar structure, and independent of flagellar-dependent motility. We provide evidence that flagellar-deficient mutants harbor inadequate amounts of LPS required to resist membrane permeabilization by SP-A and cellular lysis by detergent targeting bacterial outer membranes. Thus, the flagellum of P. aeruginosa plays an indirect but important role resisting SP-A-mediated clearance and membrane permeabilization

Treating attention-deficit/hyperactivity disorder beyond symptom control alone in children and adolescents: a review of the potential benefits of long-acting stimulants

Attention-deficit/hyperactivity disorder (ADHD), one of the most common neuropsychiatric conditions of childhood, often has a chronic course and persists into adulthood in many individuals. ADHD may have a clinically important impact on health-related quality of life in children, a significant impact on parents’ emotional health and interfere with family activities/cohesion. To date, the main targets of ADHD treatment have focused on reducing the severity of symptoms during the school day and improving academic performance. However, the treatment of ADHD should reach beyond symptom control to address the issues of social competencies and improvement of health-related quality of life from the perspectives of individuals with ADHD and their families, to support them in reaching their full developmental potential. Methylphenidate (MPH) is recognised as the first-line choice of pharmacotherapy for ADHD in children and adolescents. This paper focuses on the importance and benefits to child development of ADHD symptom control beyond the school day only, i.e. extending into late afternoon and evening and uses the example of an extended-release MPH formulation (OROS® MPH) to demonstrate the potential benefits of active full day coverage (12 h) with a single daily dose. Concerns of long-term stimulant treatment are also discussed

Fluid challenges in intensive care: the FENICE study A global inception cohort study

Fluid challenges (FCs) are one of the most commonly used therapies in critically ill patients and represent the cornerstone of hemodynamic management in intensive care units. There are clear benefits and harms from fluid therapy. Limited data on the indication, type, amount and rate of an FC in critically ill patients exist in the literature. The primary aim was to evaluate how physicians conduct FCs in terms of type, volume, and rate of given fluid; the secondary aim was to evaluate variables used to trigger an FC and to compare the proportion of patients receiving further fluid administration based on the response to the FC.This was an observational study conducted in ICUs around the world. Each participating unit entered a maximum of 20 patients with one FC.2213 patients were enrolled and analyzed in the study. The median [interquartile range] amount of fluid given during an FC was 500 ml (500-1000). The median time was 24 min (40-60 min), and the median rate of FC was 1000 [500-1333] ml/h. The main indication for FC was hypotension in 1211 (59 %, CI 57-61 %). In 43 % (CI 41-45 %) of the cases no hemodynamic variable was used. Static markers of preload were used in 785 of 2213 cases (36 %, CI 34-37 %). Dynamic indices of preload responsiveness were used in 483 of 2213 cases (22 %, CI 20-24 %). No safety variable for the FC was used in 72 % (CI 70-74 %) of the cases. There was no statistically significant difference in the proportion of patients who received further fluids after the FC between those with a positive, with an uncertain or with a negatively judged response.The current practice and evaluation of FC in critically ill patients are highly variable. Prediction of fluid responsiveness is not used routinely, safety limits are rarely used, and information from previous failed FCs is not always taken into account

Analysis of the prevalence of different topographical characteristics of the residual ridge in mandibular free-end arches Análise da prevalência de diferentes características topográficas do rebordo residual em arcos mandibulares com extremidades livres

This study observed the prevalence of different types of residual ridge inclination in free-ends of mandibles and reported possible correlative factors that may affect resorption. For this purpose, periapical radiographs and individual data collected from a sample of 64 hemiarches were used. Two radiographs were taken of each free-end, and tracing was employed to determine the angles formed by the resorption configuration in the area of the 1st mandibular molar. The following conclusions were drawn: 1) the great majority of alveolar ridges were distally descending; 2) the average angle was wider for users of mandibular removable partial dentures; 3) the results obtained suggest that the type of opposing maxillary arch affects the inclination of mandibular ridges; 4) greater inclination was observed when the 2nd bicuspids of the mandible were the abutment teeth; 5) no significant correlation was established between age, sex and residual ridge resorption.<br>Esta pesquisa constatou a prevalência dos tipos de rebordos residuais no sentido ântero-posterior em extremidades livres inferiores, além de correlacionar alguns fatores que possam influenciar as suas reabsorções. Para isso, utilizamos radiografias periapicais e dados individuais colhidos na amostra de 64 hemiarcos; foram obtidas 2 radiografias de cada área de extremidade livre e, a partir de traçados, determinamos os ângulos formados pela reabsorção na altura do 1º molar inferior. Podemos constatar que: 1º) a grande maioria de inclinação encontrada foi de rebordos descendentes para distal; 2º) a média de angulação foi maior para usuários de prótese parcial removível inferior; 3º) os resultados sugeriram existir influência do tipo de arco antagônico superior na inclinação dos rebordos inferiores; 4º) observou-se aumento de inclinação quando os segundos pré-molares inferiores eram os dentes adjacentes ao espaço protético; e 5º) não foram encontradas correlações significantes entre idade, sexo e reabsorção do rebordo residual

Ionic liquid modified poly(2,6-dimethyl-1,4-phenylene oxide) for CO2 separation

Ionic liquid modified poly(2, 6-dimethyl-1, 4-phenylene oxide) (PPO) was synthesized by introducing imidazolium-based, pyridinium-based, and ammonium-basd ionic liquid groups to the methyl position of PPO. Membranes were prepared from the different types of ionic liquid modified PPO (IPPO), and the permeability of CO and N2 in these membranes was characterized. For having the CO -philic ionic liquid groups in the structure, the CO solubility of the IPPO is better than that of PPO, while the CO diffusivity in the IPPO is proportional to glass transition temperatures. The adsorption and desorption of CO in the IPPO were also investigated, and the results manifest that the adsorption and desorption of CO in IPPO are completely reversible, which makes the polymer promising as solid adsorbent materials for CO separation