The interrelationship between phagocytosis, autophagy and formation of neutrophil extracellular traps following infection of human neutrophils by Streptococcus pneumoniae

Neutrophils play an important role in the innate immune response to infection with Streptococcus pneumoniae, the pneumococcus. Pneumococci are phagocytosed by neutrophils and undergo killing after ingestion. Other cellular processes may also be induced, including autophagy and the formation of neutrophil extracellular traps (NETs), which may play a role in bacterial eradication. We set out to determine how these different processes interacted following pneumococcal infection of neutrophils, and the role of the major pneumococcal toxin pneumolysin in these various pathways. We found that pneumococci induced autophagy in neutrophils in a type III phosphatidylinositol-3 kinase dependent fashion that also required the autophagy gene Atg5. Pneumolysin did not affect this process. Phagocytosis was inhibited by pneumolysin but enhanced by autophagy, while killing was accelerated by pneumolysin but inhibited by autophagy. Pneumococci induced extensive NET formation in neutrophils that was not influenced by pneumolysin but was critically dependent on autophagy. While pneumolysin did not affect NET formation, it had a potent inhibitory effect on bacterial trapping within NETs. These findings show a complex interaction between phagocytosis, killing, autophagy and NET formation in neutrophils following pneumococcal infection that contribute to host defence against this pathogen

The use of a formal sensitivity analysis on epidemic models with immune protection from maternally acquired antibodies

This paper considers the outcome of a formal sensitivity analysis on a series of epidemic model structures developed to study the population level effects of maternal antibodies. The analysis is used to compare the potential influence of maternally acquired immunity on various age and time domain observations of infection and serology, with and without seasonality. The results of the analysis indicate that time series observations are largely insensitive to variations in the average duration of this protection, and that age related empirical data are likely to be most appropriate for estimating these characteristics

Interleukin-17 is required for control of chronic lung infection caused by Pseudomonas aeruginosa

Chronic pulmonary infection with Pseudomonas aeruginosa is a feature of cystic fibrosis (CF) and other chronic lung diseases. Cytokines of the IL-17 family have been proposed as important in the host response to P. aeruginosa infection through augmenting antibacterial immune responses, although their pro-inflammatory effect may contribute to lung damage that occurs as a result of chronic infection. We set out to explore the role of IL-17 in the host response to chronic P. aeruginosa infection. We used a murine model of chronic pulmonary infection with CF-related strains of P. aeruginosa. We demonstrate that IL-17 cytokine signaling is essential for survival and prevention of chronic infection at 2 weeks post-inoculation using two different P. aeruginosa strains. Following infection, there was a marked expansion of cells within mediastinal lymph nodes, comprised mainly of innate lymphoid cells (ILCs); ∼90% of IL-17 producing cells had markers consistent with Group 3 ILCs. A smaller percentage of IL-17+ cells had markers consistent with a B1 phenotype. In lung homogenates 14 days following infection, there was a significant expansion of IL-17+ cells – about 50% of these were CD3+, split equally between CD4+ Th17 cells and γδ T cells, while the CD3- IL-17+ cells were almost exclusively Group 3 ILCs. Further experiments with B cell deficient mice showed that B cell production of IL-17 or natural antibodies did not provide any defence against chronic P. aeruginosa infection. Thus, IL-17 rather than antibody is a key element in host defence against chronic pulmonary infection with P. aeruginosa

IL-17 can be protective or deleterious in murine pneumococcal pneumonia

Streptococcus pneumoniae is the major bacterial cause of community-acquired pneumonia, and the leading agent of childhood pneumonia deaths worldwide. Nasal colonization is an essential step prior to infection. The cytokine IL-17 protects against such colonization and vaccines that enhance IL-17 responses to pneumococcal colonization are being developed. The role of IL-17 in host defence against pneumonia is not known. To address this issue, we have utilized a murine model of pneumococcal pneumonia in which the gene for the IL-17 cytokine family receptor, Il17ra, has been inactivated. Using this model, we show that IL-17 produced predominantly from γδ T cells protects mice against death from the invasive TIGR4 strain (serotype 4) which expresses a relatively thin capsule. However, in pneumonia produced by two heavily encapsulated strains with low invasive potential (serotypes 3 and 6B), IL-17 significantly enhanced mortality. Neutrophil uptake and killing of the serotype 3 strain was significantly impaired compared to the serotype 4 strain and depletion of neutrophils with antibody enhanced survival of mice infected with the highly encapsulated SRL1 strain. These data strongly suggest that IL-17 mediated neutrophil recruitment to the lungs clears infection from the invasive TIGR4 strain but that lung neutrophils exacerbate disease caused by the highly encapsulated pneumococcal strains. Thus, whilst augmenting IL-17 immune responses against pneumococci may decrease nasal colonization, this may worsen outcome during pneumonia caused by some strains

Factors Influencing the Adoption of Clinical Informatics Tools among Medical Doctors in South Africa

The adoption of clinical informatics tools is not encouraging in many developing countries and a better understanding of the factors that influence their integration is expected to promote their effective utilisation. To shed more light on this phenomenon, the study employed the use of Universal Theory of Acceptance and Use of Technology (UTAUT) to identify the factors that influence the use of clinical informatics tools. The study employed a positivism research paradigm anchored on survey research design. Simple random sampling technique was used to select one hundred and five medical doctors in a tertiary hospital in South Africa. Data were collected with the use of a structured questionnaire. Structural equation modelling was used to analyse the data collected. Findings from the study reveal that effort expectancy was related to behavioural intention to use clinical informatics (β = 0.41, p< 0.05). Also, performance expectancy was related to behavioural intention to use clinical informatics (β = 0.47, p< 0.01). The study therefore recommends that the hospital management should create conducive environment that will promote effective use of clinical informatics tools and organise training programmes for effective use of the tools. The study also sees the need for technology producers to make the tools more user-friendly. Keywords: Adoption, clinical informatics, medical doctors, UTAUT and South Afric

Nonlinear controllability via the initial state : with application to the spread of rabies

There are many problems in medicine and biology involving some kind of spatial spread. Often the aim in such problems is to control the spread. A large proportion of medical and biological systems distinguish themselves from the types of system found in engineering by the way the control acts. This is illustrated by considering the specific example of the spread of rabies among foxes. A brief description of a model for the spatial spread of rabies among foxes, developed by Murray et al. (1986), is given. This model is then extended to include the control mechanism. The problem is to prevent the spread of the rabies virus by vaccinating or culling foxes via the distribution of bait in a region around an observed outbreak. The extended model can be formulated as a nonlinear time-varying control system described by partial differential equations. In contrast to most engineering type control problems the control does not continuously affect the system but only acts through the initial distributions. A general theory is developed for dealing with such nonlinear systems by the use of a fixed point theorem. In a similar way to Pritchard and Salamon (1987) and Hinrichsen and Pritchard (1994) the dynamics are considered on a triple of Banach spaces Z C Z c Z to allow for the possible unboundedness of the nonlinearity. Thus the nonlinearity is considered as a map from Z into Z. A mild form of the time-varying system is introduced to allow for a wider class of nonlinearities. Assumptions are introduced so that the mild form of system equation is well-defined and has a fixed point that, at least partially, solves the control problem. An adaptive scheme is introduced that constructs the control that gives rise to the fixed-point but is easier to implement computationally. This scheme is less intuitive than that provided by the fixed point theorem. However the method exploits the existence of the fixed point while only requiring the final states (and not the states on the whole time interval) to be stored at each step. By assuming that the linear part of the system is a time-varying perturbation of a time-invariant operator it is shown how a mild form for the system equation can be derived from the original dynamics. Moreover suppose that the time-invariant operator is the generator of a strongly continuous semigroup. Then the conditions for the mild form of the system to be well-defined and have a fixed point can be reduced to conditions on the semi group and perturbation. Existence theorems are provided for solutions of semilinear systems with unbounded nonlinearities. The theory is applied to the rabies model. The problem and the theory are illustrated by some numerical simulations

Structural identifiability analyses of candidate models for in vitro Pitavastatin hepatic uptake

In this paper a review of the application of four different techniques (a version of the similarity transformation approach for autonomous uncontrolled systems, a non-differential input/output observable normal form approach, the characteristic set differential algebra and a recent algebraic input/output relationship approach) to determine the structural identifiability of certain in vitro nonlinear pharmacokinetic models is provided. The Organic Anion Transporting Polypeptide (OATP) substrate, Pitavastatin, is used as a probe on freshly isolated animal and human hepatocytes. Candidate pharmacokinetic non-linear compartmental models have been derived to characterise the uptake process of Pitavastatin. As a prerequisite to parameter estimation, structural identifiability analyses are performed to establish that all unknown parameters can be identified from the experimental observations available

Kinerja Pengawas SMA/SMK Ditinjau dari Lingkungan Kerja dan Motivasi Kerja di Wilayah Kaili

Tujuan penelitian ini adalah untuk mengetahui besar hubungan kinerja pengawas SMA/SMK di tinjau dari lingkungan kerja dan motivasi kerja pengawas sekolah di Wilayah Kaili. (1) Lingkungan kerja dengan kinerja pengawas SMA/SMK di Wilayah Kaili, (2) Motivasi kerja dengan kinerja pengawas SMA/SMK di Wilayah Kaili, (3) Lingkungan kerja dan motivasi kerja dengan Kinerja pengawas SMA/SMK di Wilayah Kaili, (4) Lingkungan kerja dengan kinerja pengawas SMA/SMK di Wilayah Kaili apabila motivasi kerja dikontrol, (5) Motivasi kerja dengan kinerja pengawas SMA/SMK di Wilayah Kaili apabila lingkungan kerja pengawas dikontrol. Penelitian ini adalah penelitian survey yang bersifat korelasional. Populasi dalam penelitian ini adalah seluruh pengawas SMA / SMK di Wilayah Kaili yaitu Kota Palu, Kabupaten Donggala, Kabupaten Parigi, dan Kabupaten Sigi dengan jumlah pengawas sekolah 48 orang. Pengambilan sampel dilakukan secara rambang sederhana. Ukuran sampel dalam penelitian ini sebanyak 43 pengawas sekolah sebagai responden. Mengidentifikasi data sebagai outlier dari sekumpulan data yang menyimpang, terdapat 7 data pencilan sehingga data yang diinferensi sebanyak 37 orang. Instrumen yang digunakan berupa kuesioner. Pengembangan instrumen dilakukan mulai dari menyusun indikator, kisi-kisi instrumen, kemudian butir-butir instrumen yang di validasi isi, analisis butir secara kualitatif sehingga instrumen siap digunakan. Data dianalisis dengan menggunakan analisis deskriptif dan analisis inferensial. Hasil analisis deskriptif menunjukkan bahwa lingkungan kerja, motivasi kerja dan kinerja pengawas sekolah berada pada kategori baik. Hasil analisis inferensial menunjukkan bahwa: (1) Lingkungan kerja tidak mempunyai hubungan yang positif dan signifikan dengan kinerja pengawas SMA/SMK, (2) Motivasi kerja mempunyai hubungan yang positif dan signifikan dengan kinerja pengawas SMA/SMK, (3) Lingkungan kerja dan motivasi kerja mempunyai hubungan yang positif dan signifikan dengan Kinerja pengawas SMA/SMK, (4) Lingkungan kerja tidak mempunyai hubungan yang positif dan signifikan dengan kinerja pengawas SMA/SMK apabila motivasi kerja dikontrol, (5) Motivasi kerja mempunyai hubungan yang positif dan signifikan dengan kinerja pengawas SMA/SMK apabila lingkungan kerja pengawas dikontrol

A coupled drug kinetics-cell cycle model to analyse the response of human cells to intervention by topotecan

A model describing the response of the growth of single human cells in the absence and presence of the anti-cancer agent topotecan (TPT) is presented. The model includes a novel coupling of both the kinetics of TPT and cell cycle responses to the agent. By linking the models in this way, rather than using separate (disjoint) approaches, it is possible to illustrate how the drug perturbs the cell cycle. The model is compared to experimental in vitro cell cycle response data (comprising single cell descriptors for molecular and behavioural events), showing good qualitative agreement for a range of TPT dose levels

Input-dependent structural identifiability of nonlinear systems

A dynamic model is structurally identifiable if it is possible to infer its unknown parameters by observing its output. Structural identifiability depends on the system dynamics, output, and input, as well as on the specific values of initial conditions and parameters. Here we present a symbolic method that characterizes the input that a model requires to be structurally identifiable. It determines which derivatives must be non-zero in order to have a sufficiently exciting input. Our approach considers structural identifiability as a generalization of nonlinear observability and incorporates extended Lie derivatives. The methodology assesses structural identifiability for time-varying inputs and, additionally, it can be used to determine the input profile that is required to make the parameters structurally locally identifiable. Furthermore, it is sometimes possible to replace an experiment with time-varying input with multiple experiments with constant inputs. We implement the resulting method as a MATLAB toolbox named STRIKE-GOLDD2. This tool can assist in the design of new experiments for the purpose of parameter estimation