Bacterial growth rate and host factors as determinants of intracellular bacterial distributions in systemic Salmonella enterica infections.

Bacteria of the species Salmonella enterica cause a range of life-threatening diseases in humans and animals worldwide. The within-host quantitative, spatial, and temporal dynamics of S. enterica interactions are key to understanding how immunity acts on these infections and how bacteria evade immune surveillance. In this study, we test hypotheses generated from mathematical models of in vivo dynamics of Salmonella infections with experimental observation of bacteria at the single-cell level in infected mouse organs to improve our understanding of the dynamic interactions between host and bacterial mechanisms that determine net growth rates of S. enterica within the host. We show that both bacterial and host factors determine the numerical distributions of bacteria within host cells and thus the level of dispersiveness of the infection.

Spread of Salmonella enterica in the body during systemic infection: unravelling host and pathogen determinants.

Salmonella enterica causes a range of life-threatening diseases in humans and animals worldwide. Current treatments for S. enterica infections are not sufficiently effective, and there is a need to develop new vaccines and therapeutics. An understanding of how S. enterica spreads in tissues has very important implications for targeting bacteria with vaccine-induced immune responses and antimicrobial drugs. Development of new control strategies would benefit from a more sophisticated evaluation of bacterial location, spatiotemporal patterns of spread and distribution in the tissues, and sites of microbial persistence. We review here recent studies of S. enterica serovar Typhimurium (S. Typhimurium) infections in mice, an established model of systemic typhoid fever in humans, which suggest that continuous bacterial spread to new infection foci and host phagocytes is an essential trait in the virulence of S. enterica during systemic infections. We further highlight how infections within host tissues are truly heterogeneous processes despite the fact that they are caused by the expansion of a genetically homogeneous microbial population. We conclude by discussing how understanding the within-host quantitative, spatial and temporal dynamics of S. enterica infections might aid the development of novel targeted preventative measures and drug regimens.

The Metabolic Core and Catalytic Switches Are Fundamental Elements in the Self-Regulation of the Systemic Metabolic Structure of Cells

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Randomised, crossover clinical trial, in healthy volunteers, to compare the systemic availability of two topical intranasal budesonide formulations

Background: Budesonide has a long history as intranasal drug, with many marketed products. Efforts should be made to demonstrate the therapeutic equivalence and safety comparability between them. Given that systemic availability significantly varies from formulations, the clinical comparability of diverse products comes to be of clinical interest and a regulatory requirement. The aim of the present study was to compare the systemic availability, pharmacodynamic effect, and safety of two intranasal budesonide formulations for the treatment of rhinitis. Methods: Eighteen healthy volunteers participated in this randomised, controlled, crossover, clinical trial. On two separated days, subjects received a single dose of 512 mu g budesonide (4 puffs per nostril) from each of the assayed devices (Budesonida nasal 64 (R), Aldo-Union, Spain and Rhinocort 64 (R), AstraZeneca, Spain). Budesonide availability was determined by the measurement of budesonide plasma concentration. The pharmacodynamic effect on the hypothalamic-adrenal axis was evaluated as both plasma and urine cortisol levels. Adverse events were tabulated and described. Budesonide availability between formulations was compared by the calculation of 90% CI intervals of the ratios of the main pharmacokinetic parameters describing budesonide bioavailability. Plasma cortisol concentration-time curves were compared by means of a GLM for Repeated Measures. Urine cortisol excretion between formulations was compared through the Wilcoxon's test. Results: All the enroled volunteers successfully completed the study. Pharmacokinetic parameters were comparable in terms of AUC(t) (2.6 +/- 1.5 vs 2.2 +/- 0.7), AUCi (2.9 +/- 1.5 vs 2.4 +/- 0.7), t(max) (0.4 +/- 0.1 vs 0.4 +/- 0.2), C(max)/AUC(i) (0.3 +/- 0.1 vs 0.3 +/- 0.0), and MRT (5.0 +/- 1.4 vs 4.5 +/- 0.6), but not in the case of C(max) (0.9 +/- 0.3 vs 0.7 +/- 0.2) and t(1/2) (3.7 +/- 1.8 vs 2.9 +/- 0.4). The pharmacodynamic effects, measured as the effect over plasma and urine cortisol, were also comparables between both formulations. No severe adverse events were reported and tolerance was comparable between formulations. Conclusion: The systemic availability of intranasal budesonide was comparable for both formulations in terms of most pharmacokinetic parameters. The pharmacodynamic effect on hypothalamic-pituitary-adrenal axis was also similar. Side effects were scarce and equivalent between the two products. This methodology to compare different budesonide-containing devices is reliable and easy to perform, and should be recommended for similar products intented to be marketed or already on the market.

A transitividade nos textos de autoajuda para mulheres

A motivação inicial deste trabalho foi o interesse pelo desenvolvimento de estratégias argumentativas mais eficazes de ensino de produção textual na escola básica, no âmbito dos gêneros organizados segundo modo argumentativo. Além disso, motivou-nos também a percepção de que um grande número de alunas leem, hoje, crônicas voltadas para o público feminino, tendo seu discurso altamente influenciado pelo conteúdo ideológico-comportamental por elas veiculado o que acaba se refletindo nos textos que escrevem nas aulas de redação. Esse fato chamou nossa atenção, o que nos levou a perceber, também, a vendagem em massa de livros de autoajuda para mulheres. Percebemos que, ao examinarmos as escolhas linguísticas de um discurso de autoajuda, poderíamos trazer à tona algumas crenças e alguns valores, subjacentes à mensagem relativa à experiência de ser mulher e invisíveis para quem aceita esse tipo de discurso como algo natural. Analisaremos então - tendo como suporte teórico a Linguística Sistêmico-Funcional proposta por Halliday, no escopo da transitividade cinco crônicas voltada para o público feminino, com características dos discursos de autoajuda, em cujos textos se vê um grande quantitativo de estratégias argumentativas (algumas clichês) para o convencimento do leitor, estratégias essas apoiadas nas escolhas linguísticas de seus autores, cujo objetivo claro é a produção de determinados sentidos

Serological and Genetic Evidence for Altered Complement System Functionality in Systemic Lupus Erythematosus: Findings of the GAPAID Consortium

Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, complement deposition on tested protein and lipid autoantigens showed positive correlation with C4 levels. Genetic analysis revealed that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) had lower levels of dsDNA specific IgM among SLE patients. Both the non-synonymous variant rs1143679 and the high ratio of nucleic acid specific IgG/IgM were associated with multiple organ involvement. In summary, secondary complement deficiency in SLE does not impair opsonization of nucleic-acid-containing autoantigens but does affect other antigens and potentially other complement dependent processes. Dysfunction of the receptor recognizing complement opsonized immune complexes promotes the development of class-switched autoantibodies targeting nucleic acids.

Tenets, Principles, and Criteria for Management: The Basis for Systemic Management

This paper presents nine tenets for management as formulated in the literature in recent decades. These tenets, and the principles behind them, form the foundation for systemic management. All tenets are interrelated and far from mutually exclusive or discrete. When we consider them seriously and simultaneously, these tenets expose serious flaws of conventional resource management and define systemic management. Systemic management requires that we manage inclusively and avoid restricting management to any particular interaction between humans and other elements of nature. The management tenets presented here are considered with particular attention to the interrelationships among both the tenets and principles upon which they are based. The case is made that the tenets are inseparable and should be applied collectively. Combined consideration of the tenets clarifies the role of science, contributes to progress in defining management, and leads to the development of ways we can avoid mistakes of past management. Systemic management emerges as at least one form of management that will consistently account for and apply to the complexities of nature.

The myogenic automatism of the systemic heart of Octopus vulgaris (Cephalopoda: Coleoidea): evidence for localized stretch sensitivity and pacing activity

The localization of the stretch sensitivity and myogenic automatism in the systemic heart of Octopus vulgaris has been studied on an isolated preparation in which the ventricle was zoned by ligatures. Each region has been submitted to two different levels of internal hydrostatic pressure (1 and 2 kPa). Only the two atrio-ventricular regions were able to contract regularly when submitted to internal pressure, with a frequency dependent from the pressure value, while the ventricle-aortic region was insensitive to the stretching by internal pressure. This result supports the hypothesis that the automatism in this heart is localized. Electrocardiogram recordings from different areas of an isolated and perfused preparation of the systemic heart ventricle are also reported, which suggest that the electrical activity of the ventricle originates in two narrow areas near the atrio-ventricular valves.