212 resultados para antigen delivery
Resumo:
Chlamydia trachomatis infections of the male and female reproductive tracts are the world's leading sexually transmitted bacterial disease, and can lead to damaging pathology, scarring and infertility. The resolution of chlamydial infection requires the development of adaptive immune responses to infection, and includes cell-mediated and humoral immunity. Whilst cluster of differentiation (CD)4+ T cells are known to be essential in clearance of infection [1], they are also associated with immune cell infiltration, autoimmunity and infertility in the testes [2-3]. Conversely, antibodies are less associated with inflammation, are readily transported into the reproductive tracts, and can offer lumenal neutralization of chlamydiae prior to infection. Antibodies, or immunoglobulins (Ig), play a supportive role in the resolution of chlamydial infections, and this thesis sought to define the function of IgA and IgG, against a variety of chlamydial antigens expressed during the intracellular and extracellular stages of the chlamydial developmental cycle. Transport of IgA and IgG into the mucosal lumen is facilitated by receptor-mediated transcytosis yet the expression profile (under normal conditions and during urogenital chlamydial infection) of the polymeric immunoglobulin receptor (pIgR) and the neonatal Fc receptor (FcRn) remains unknown. The expression profile of pIgR and FcRn in the murine male reproductive tract was found to be polarized to the lower and upper reproductive tract tissues respectively. This demonstrates that the two receptors have a tissue tropism, which must be considered when targeting pathogens that colonize different sites. In contrast, the expression of pIgR and FcRn in the female mouse was found to be distributed in both the upper and lower reproductive tracts. When urogenitally infected with Chlamydia muridarum, both male and female reproductive tracts up-regulated expression of pIgR and down-regulated expression of FcRn. Unsurprisingly, the up-regulation of pIgR increased the concentration of IgA in the lumen. However, down-regulation of FcRn, prevented IgG uptake and led to an increase or pooling of IgG in lumenal secretions. As previous studies have identified the importance of pIgR-mediated delivery of IgA, as well as the potential of IgA to bind and neutralize intracellular pathogens, IgA against a variety of chlamydial antigens was investigated. The protection afforded by IgA against the extracellular antigen major outer membrane protein (MOMP), was found to be dependent on pIgR expression in vitro and in vivo. It was also found that in the absence of pIgR, no protection was afforded to mice previously immunized with MOMP. The protection afforded from polyclonal IgA against the intracellular chlamydial antigens; inclusion membrane protein A (IncA), inclusion membrane proteins (IncMem) and secreted chlamydial protease-like activity factor (CPAF) were produced and investigated in vitro. Antigen-specific intracellular IgA was found to bind to the respective antigen within the infected cell, but did not significantly reduce inclusion formation (p > 0.05). This suggests that whilst IgA specific for the selected antigens was transported by pIgR to the chlamydial inclusion, it was unable to prevent growth. Similarly, immunization of male mice with intracellular chlamydial antigens (IncA or IncMem), followed by depletion CD4+ T cells, and subsequent urogenital C. muridarum challenge, provided minimal pIgR-mediated protection. Wild type male mice immunized with IncA showed a 57 % reduction (p < 0.05), and mice deficient in pIgR showed a 35 % reduction (p < 0.05) in reproductive tract chlamydial burden compared to control antigen, and in the absence of CD4+ T cells. This suggests that pIgR and secretory IgA (SIgA) were playing a protective role (21 % pIgR-mediated) in unison with another antigen-specific immune mechanism (36 %). Interestingly, IgA generated during a primary respiratory C. muridarum infection did not provide a significant amount of protection to secondary urogenital C. muridarum challenge. Together, these data suggest that IgA specific for an extracellular antigen (MOMP) can play a strong protective role in chlamydial infections, and that IgA targeting intracellular antigens is also effective but dependent on pIgR expression in tissues. However, whilst not investigated here, IgA targeting and blocking other intracellular chlamydial antigens, that are more essential for replication or type III secretion, may be more efficacious in subunit vaccines. Recently, studies have demonstrated that IgG can neutralize influenza virus by trafficking IgG-bound virus to lysosomes [4]. We sought to determine if this process could also traffic chlamydial antigens for degradation by lysosomes, despite Chlamydia spp. actively inhibiting fusion with the host endocytic pathway. As observed in pIgR-mediated delivery of anti-IncA IgA, FcRn similarly transported IgG specific for IncA which bound the inclusion membrane. Interestingly, FcRn-mediated delivery of anti-IncA IgG significantly decreased inclusion formation by 36 % (p < 0.01), and induced aberrant inclusion morphology. This suggests that unlike IgA, IgG can facilitate additional host cellular responses which affect the intracellular niche of chlamydial growth. Fluorescence microscopy revealed that IgG also bound the inclusion, but unlike influenza studies, did not induce the recruitment of lysosomes. Notably, anti-IncA IgG recruited sequestosomes to the inclusion membrane, markers of the ubiquitin/proteasome pathway and major histocompatibility complex (MHC) class I loading. To determine if the protection against C. muridarum infection afforded by IncA IgG in vitro translated in vivo, wild type mice and mice deficient in functional FcRn and MHC-I, were immunized, depleted of CD4+, and urogenitally infected with C. muridarum. Unlike in pIgR-deficient mice, the protection afforded from IncA immunization was completely abrogated in mice lacking functional FcRn and MHC-I/CD8+. Thus, both anti-IncA IgA and IgG can bind the inclusion in a pIgR and FcRn-mediated manner, respectively. However, only IgG mediates a higher reduction in chlamydial infection in vitro and in vivo suggesting more than steric blocking of IncA had occurred. Unlike anti-MOMP IgA, which reduced chlamydial infection of epithelial cells and male mouse tissues, IgG was found to enhance infectivity in vitro, and in vivo. Opsonization of EBs with MOMP-IgG enhanced inclusion formation of epithelial cells in a MOMP-IgG dose-dependent and FcRn-dependent manner. When MOMP-IgG opsonized EBs were inoculated into the vagina of female mice, a small but non-significant (p > 0.05) enhancement of cervicovaginal C. muridarum shedding was observed three days post infection in mice with functional FcRn. Interestingly, infection with opsonized EBs reduced the intensity of the peak of infection (day six) but protracted the duration of infection by 60 % in wild type mice only. Infection with EBs opsonized in IgG also significantly increased (p < 0.05) hydrosalpinx formation in the oviducts and induced lymphocyte infiltration uterine horns. As MOMP is an immunodominant antigen, and is widely used in vaccines, the ability of IgG specific to extracellular chlamydial antigens to enhance infection and induce pathology needs to be considered. Together, these data suggest that immunoglobulins play a dichotomous role in chlamydial infections, and are dependent on antigen specificity, FcRn and pIgR expression. FcRn was found to be highly expressed in upper male reproductive tract, whilst pIgR was dominantly expressed in the lower reproductive tract. Conversely, female mice expressed FcRn and pIgR in both the lower and upper reproductive tracts. In response to a normal chlamydial infection, pIgR is up-regulated increasing secretory IgA release, but FcRn is down-regulated preventing IgG uptake. Similarly to other studies [5-6], we demonstrate that IgA and IgG generated during primary chlamydial infections plays a minor role in recall immunity, and that antigen-specific subunit vaccines can offer more protection. We also show that both IgA and IgG can be used to target intracellular chlamydial antigens, but that IgG is more effective. Finally, IgA against the extracellular antigen MOMP can afford protection, whist IgG plays a deleterious role by increasing infectivity and inducing damaging immunopathology. Further investigations with additional antigens or combination subunit vaccines will enhance our understanding the protection afforded by antibodies against intracellular and extracellular pathogenic antigens, and help improve the development of an efficacious chlamydial vaccine.
Resumo:
Research and practice has observed a shift toward service-oriented approaches that depend on input from users and community as co-producers of services. Yet, in delivering public infrastructure the focus is still on assets rather than services. The contribution of external stakeholders in the co-production of public services is still limited. Using the Policy Delphi with a panel of experts, we found that although practitioners understand the need for asset management to follow the service approach, guidelines and policies still lack that service-centric perspective. Findings revealed a range of obstacles to effective service delivery, related to the sub-optimal involvement of stakeholders’, asymmetric levels of power, the lack of accountability, transparency and availability of government, and the lack of genuine consultations between government and stakeholder groups. The paper concludes by offering directions and strategies for asset managers and policymakers to support and reconnect disengaged government-citizen relations for optimal service delivery outcomes in asset management.
Resumo:
Immunogenicity and reactogenicity of DTPa and reduced antigen dTpa booster vaccines were compared to a hepatitis A control vaccine in DTPa-primed toddlers aged 18-20 months. Post-booster, all DTPa and dTpa recipients were seroprotected against diphtheria and tetanus, and >= 93.3% had a booster response to pertussis. There were similar reactogenicity rates in the DTPa and dTpa vaccine recipients. Few Grade 3 symptoms were reported. Just over one in four children in the control group had diphtheria antibody at or potentially below the correlate of protection benchmark (0.016 IU/ml). Larger studies should evaluate potential benefits of reduced antigen vaccines and seroprotection in children who do not receive a booster dose of DTPa at this age, including protection against diphtheria until subsequent booster doses are given. (C) 2009 Elsevier Ltd. All rights reserved.
Resumo:
Executive Summary Emergency health is a critical component of Australia’s health system and emergency departments (EDs) are increasingly congested from growing demand and blocked access to inpatient beds. The Emergency Health Services Queensland (EHSQ) study aims to identify the factors driving increased demand for emergency health and to evaluate strategies which may safely reduce the future demand growth. This monograph addresses the perspectives of users of both ambulance services and EDs. The research reported here aimed to identify the perspectives of users of emergency health services, both ambulance services and public hospital Emergency Departments and to identify the factors that they took into consideration when exercising their choice of location for acute health care. A cross-sectional survey design was used involving a survey of patients or their carers presenting to the EDs of a stratified sample of eight hospitals. A specific purpose questionnaire was developed based on a novel theoretical model which had been derived from analysis of the literature (Monograph 1). Two survey versions were developed: one for adult patients (self-complete); and one for children (to be completed by parents/guardians). The questionnaires measured perceptions of social support, health status, illness severity, self-efficacy; beliefs and attitudes towards ED and ambulance services; reasons for using these services, and actions taken prior to the service request. The survey was conducted at a stratified sample of eight hospitals representing major cities (four), inner regional (two) and outer regional and remote (two). Due to practical limitations, data were collected for ambulance and ED users within hospital EDs, while patients were waiting for or under treatment. A sample size quota was determined for each ED based on their 2009/10 presentation volumes. The data collection was conducted by four members of the research team and a group of eight interviewers between March and May 2011 (corresponding to autumn season). Of the total of 1608 patients in all eight emergency departments the interviewers were able to approach 1361 (85%) patients and seek their consent to participate in the study. In total, 911 valid surveys were available for analysis (response rate= 67%). These studies demonstrate that patients elected to attend hospital EDs in a considered fashion after weighing up alternatives and there is no evidence of deliberate or ill-informed misuse. • Patients attending ED have high levels of social support and self-efficacy that speak to the considered and purposeful nature of the exercise of choice. • About one third of patients have new conditions while two thirds have chronic illnesses • More than half the attendees (53.1%) had consulted a healthcare professional prior to making the decision. • The decision to seek urgent care at an ED was mostly constructed around the patient’s perception of the urgency and severity of their illness, reinforced by a strong perception that the hospital ED was the correct location for them (better specialised staff, better care for my condition, other options not as suitable). • 33% of the respondent held private hospital insurance but nevertheless attended a public hospital ED. Similarly patients exercised considered and rational judgements in their choice to seek help from the ambulance service. • The decision to call for ambulance assistance was based on a strong perception about the severity of the illness (too severe to use other means of transport) and that other options were not considered appropriate. • The decision also appeared influenced by a perception that the ambulance provided appropriate access to the ED which was considered most appropriate for their particular condition (too severe to go elsewhere, all facilities in one spot, better specialised and better care). • In 43.8% of cases a health care professional advised use of the ambulance. • Only a small number of people perceived that ambulance should be freely available regardless of severity or appropriateness. These findings confirm a growing understanding that the choice of professional emergency health care services is not made lightly but rather made by reasonable people exercising a judgement which is influenced by public awareness of the risks of acute health and which is most often informed by health professionals. It is also made on the basis of a rational weighing up of alternatives and a deliberate and considered choice to seek assistance from a service which the patient perceived was most appropriate to their needs at that time. These findings add weight to dispensing with public perceptions that ED and ambulance congestion is a result of inappropriate choice by patients. The challenge for health services is to better understand the patient’s needs and to design and validate services that meet those needs. The failure of our health system to do so should not be grounds for blaming the patient, claiming inappropriate patient choices.
Resumo:
Indigenous Australians are the most socially and economically disadvantaged population group in Australia and have the poorest health status. The statistics describe and highlight the degree of sicknesses and disadvantage along with lower life expectancy, elevated mortality rate and increased risk of cardiovascular disease, cancer, diabetes, respiratory disease and kidney disease. While these statistics reflect poor health status and a high level of illness within Indigenous communities, it is known that individual, family and community behaviours play a key role in Indigenous health and wellbeing outcomes. These behavioural issues include use of tobacco, alcohol and other substances along with lack of physical activity and poor nutrition. The paper Nutrition and older Indigenous Australians: Service delivery implications in remote communities. A narrative view explores some of the issues specific to nutrition. Bronwyn Fredericks was invited to provide this commentary by the Editor of the Australasian Journal on Aging.
Resumo:
Oral immunization is attractive as a delivery route because it is needle-free and useful for rapid mass vaccination programs to target pandemics or bioterrorism. This potential has not been realized for human vaccination, due to the requirement of large antigen doses and toxic (to humans) adjuvants to overcome the induction of oral tolerance and potential degradation of antigens in the stomach. To date, only oral vaccines based on live attenuated organisms have been approved for human use. In this study we describe the use of a lipid-based delivery system/adjuvant, Lipid C, for oral immunization to protect mice against genital tract chlamydial infection. Lipid C is formulated from food-grade purified and fractionated triglycerides. Bacterial shedding following vaginal challenge with Chlamydia muridarum was reduced by 50% in female mice orally immunized with the chlamydial major outer membrane protein (MOMP) formulated in Lipid C, protection equivalent to that seen in animals immunized with MOMP admixed with both cholera toxin (CT) and CpG oligodeoxynucleotides (CpG-ODN). Protection was further enhanced when MOMP, CT and CpG were all combined in the Lipid C matrix. Protection correlated with production of gamma interferon (IFN) by splenic T cells, a serum MOMP-specific IgG response and low but detectable levels of MOMP-specific IgA in vaginal lavage.
Resumo:
Olfactory ensheathing cells (OECs) play an important role in the continuous regeneration of the primary olfactory nervous system throughout life and for regeneration of olfactory neurons after injury. While it is known that several individual OEC subpopulations with distinct properties exist in different anatomical locations, it remains unclear how these different subpopulations respond to a major injury. We have examined the proliferation of OECs from one distinct location, the peripheral accessory olfactory nervous system, following large-scale injury (bulbectomy) in mice. We used crosses of two transgenic reporter mouse lines, S100ß-DsRed and OMP-ZsGreen, to visualise OECs, and main/accessory olfactory neurons, respectively. We surgically removed one olfactory bulb including the accessory olfactory bulb to induce degeneration, and found that accessory OECs in the nerve bundles that terminate in the accessory olfactory bulb responded by increased proliferation with a peak occurring 2 days after the injury. To label proliferating cells we used the thymidine analogue ethynyl deoxyuridine (EdU) using intranasal delivery instead of intraperitoneal injection. We compared and quantified the number of proliferating cells at different regions at one and four days after EdU labelling by the two different methods and found that intranasal delivery method was as effective as intrapeitoneal injection. We demonstrated that accessory OECs actively respond to widespread degeneration of accessory olfactory axons by proliferating. These results have important implications for selecting the source of OECs for neural regeneration therapies and show that intranasal delivery of EdU is an efficient and reliable method for assessing proliferation of olfactory glia.
Resumo:
Primary school provides an appropriate opportunity for children to commence comprehensive relationships and sexuality education (RSE), yet many primary school teachers avoid teaching this subject area. In the absence of teacher confidence and competence, schools have often relied on health promotion professionals, external agencies and/or one-off issue related presentations rather than cohesive, systematic and meaningful health education. This study examines the implementation of a ten-lesson pilot RSE unit of work and accompanying assessment task in two primary schools in South-East Queensland, Australia. Drawing predominantly from qualitative data, this research explores the experiences of primary school teachers as they engage with RSE curriculum resources and content delivery. The results show that the provision of a high quality RSE curriculum resource grounded in contemporary educational principles and practices enables teachers to feel more confident to deliver RSE and minimises potential barriers such as parental objections and fear of mishandling sensitive content.
Resumo:
Changes in the construction sector are creating opportunities in research to maximise the benefits of those changes and to continue the exciting developments in improved people skills, new processes and developing technologies. Many research centres around the world are investigating aspects of the current changes to drive their particular expertise forward. However, the CIB Integrated Design and Delivery Solutions (IDDS) priority research theme takes a higher-level view of the changes and then focuses down on a prioritised set of research targets. These targets have been investigated, re-focussed and validated over a period of four years through many workshops, conferences and meetings by a wide ranging group of representatives from approximately 90 industry and research organisations. The outcomes of such research, once put into practice should be significantly shortened timespans from conception of need to occupation of new or revised structures. As time is money, the owners will get their investments into productive use sooner, which means a shorter payback time. In addition, there will inevitably be a reduction in construction costs as productivity increases. The improvements in reliable delivery and improved quality currently being seen in relatively simplistic use of Building information Modelling (BIM) (compared to full IDDS) will inevitably continue its on-going trajectory of improvement. We should also consider the wider economic contribution to society that will stem from such improvements and, finally, and by no means unimportantly, the reliable modelling and delivery of sustainability at both the building and estate/ area scale will significantly improve carbon footprints and other sustainable outcomes. Whilst there are huge opportunities for early adopters, the primary risk will be the expansion of the gap between those working in this way and those who are not so advanced or who even refuse to progress . The opportunities to address the significant and widely varying wastes within the structure of the construction sector and within and across projects are huge and timely and industry is encouraged to become involved.
Resumo:
Integrated design and delivery solutions (IDDS) is a priority theme of the International Council for Research and Innovation in Building and Construction (CIB), which will be used to drive the global research agenda forward. IDDS will use collaborative work processes and enhanced skills together with integrated data, information and knowledge management to minimize structural and process inefficiencies and to enhance the value delivered during design, build, operation, and across projects. IDDS build on building information modelling (BIM), incorporating advances in the training and employment of people, together with supporting new technologies. The successful use of IDDS involves changes in each of the project phases from conceptual planning and business case formulation to all stages of the supply chain: design, construction, commissioning, operation, retrofit and decommissioning. For each of these phases, key changes in the structure and culture of the project team across the different collaborating firms create a favourable context for IDDS. Special for IDDS thinking is the idea of adding project and whole-life value in all phases, for all stakeholders...
Resumo:
A new approach of integrated design and delivery solutions (IDDS) aims to radically improve the performance of the construction industries. IDDS builds upon recent trends in the construction industries that have seen the widespread adoption of technologies such as building information modelling (BIM) and innovative processes such as integrated project delivery. However, these innovations are seen to develop in isolation, with little consideration of the overarching interactions between people, process and technology. The IDDS approach is holistic in that it recognizes that it is only through a combination of initiatives such as skill development, process re-engineering, responsive information technology, enhanced interoperability and integrating knowledge management, among others, that radical change can be achieved. To implement IDDS requires step changes in many project aspects, and this gap between current performance and that required for IDDS is highlighted. The research required to bridge the gaps is identified in four major aspects of collaborative processes, workforce skills, integrated information and knowledge management.
Resumo:
CIB is developing a priority theme, now termed Improving Construction and Use through Integrated Design & Delivery Solutions (IDDS). The IDDS working group for this theme adopted the following definition: Integrated Design and Delivery Solutions use collaborative work processes and enhanced skills, with integrated data, information, and knowledge management to minimize structural and process inefficiencies and to enhance the value delivered during design, build, and operation, and across projects. The design, construction, and commissioning sectors have been repeatedly analysed as inefficient and may or may not be quite as bad as portrayed; however, there is unquestionably significant scope for IDDS to improve the delivery of value to clients, stakeholders (including occupants), and society in general, simultaneously driving down cost and time to deliver operational constructed facilities. Although various initiatives developed from computer‐aided design and manufacturing technologies, lean construction, modularization, prefabrication and integrated project delivery are currently being adopted by some sectors and specialisations in construction; IDDS provides the vision for a more holistic future transformation. Successful use of IDDS requires improvements in work processes, technology, and people’s capabilities to span the entire construction lifecycle from conception through design, construction, commissioning, operation, refurbishment/ retrofit and recycling, and considering the building’s interaction with its environment. This vision extends beyond new buildings to encompass modifications and upgrades, particularly those aimed at improved local and area sustainability goals. IDDS will facilitate greater flexibility of design options, work packaging strategies and collaboration with suppliers and trades, which will be essential to meet evolving sustainability targets. As knowledge capture and reuse become prevalent, IDDS best practice should become the norm, rather than the exception.
Resumo:
Changes in the construction sector are creating opportunities in research to maximise the benefits of those changes and to continue the exciting developments in improved people skills, new processes and developing technologies. There are many research centres around the world investigating aspects of the current changes to drive their particular expertise forward. However, the CIB Integrated Design and Delivery Solutions (IDDS) priority research theme takes a higher-level view of the changes and then focuses down on a prioritised set of research targets. These targets have been investigated, re-focussed and validated over a period of four years through many workshops, conferences and meetings by a wide ranging group of representatives from approximately 90 industry and research organisations. This roadmap prioritises and details the research to be performed, why and by whom. In particular, some 25 CIB Working Commissions and Task Groups are explained as having potential roles in the delivery of this research theme. We are extremely privileged to have been urged on by such distinguished construction professionals in their forewords and the case for research. The outcomes of such research, once put into practice should be significantly shortened timespans from conception of need to occupation of new or revised structures. As time is money, the owners will get their investments into productive use sooner, which means a shorter payback time. In addition, there will inevitably be a reduction in construction costs as productivity increases. The improvements in reliable delivery and improved quality currently being seen in relatively simplistic use of Building information Modelling (BIM) (compared to full IDDS) will inevitably continue its on-going trajectory of improvement. We should also consider the wider economic contribution to society that will stem from such improvements and, finally, and by no means unimportantly, the reliable modelling and delivery of sustainability at both the building and estate/ area scale will significantly improve carbon footprints and other sustainable outcomes. Whilst there are huge opportunities for early adopters, the primary risk will be the expansion of the gap between those working in this way and those who are not so advanced or who even refuse to progress1. However, a similar issue arises between industry, clients, educators and trainers; the latter have particular challenges, having existed for many years in a sector that has had relatively few technological changes. However, the opportunities to address the significant and widely varying wastes within the structure of the construction sector and within and across projects are huge and timely. Whilst this Roadmap is specifically targeted at the Standing Commissions and Task Groups of the CIB, it is hoped that there are elements for research and applied research across academia and industry.
Resumo:
This article presents an overview of two aspects of the role the internet now plays in the court system - first, the extent to which judges, administrators and court officials at the different levels in the court hierarchy are using the internet to deliver enhanced access to the Australian justice system for the community as a whole, and second, how they have embraced that same technology as an aid for accessing information for better judgment delivery and administration.
Resumo:
This thesis described the synthesis of an L-leucine conjugate of the biodegradable polymer, chitosan and its potential application for the development of controlled release nanoparticulate dry powder inhaler (DPI) formulations. The study demonstrated that the physicochemical properties of conjugated chitosan nanoparticles had favourable effects on the dispersibility and controlled release profile of a model drug. The toxicity profile of the nanoparticulate formulation revealed promising outcome for its use in pulmonary delivery. The chitosan conjugate produced in this project would be useful for the application of polymer nanoparticulate systems for efficient lung delivery of drugs.