The role of immunoglobulins and their transporters in urogenital Chlamydial infections

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.

Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990–2013: Quantifying the epidemiological transition

Background The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age–sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development. Methods We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time. Findings Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6–6·6), from 65·3 years (65·0–65·6) in 1990 to 71·5 years (71·0–71·9) in 2013, HALE at birth rose by 5·4 years (4·9–5·8), from 56·9 years (54·5–59·1) to 62·3 years (59·7–64·8), total DALYs fell by 3·6% (0·3–7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6–29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non–communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries. Interpretation Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition—in which increasing sociodemographic status brings structured change in disease burden—is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions.

Increasing the Information available to Coroners : the effect on autopsy decision making

This paper details research completed in 2007 which investigated autopsy decision making in a death investigation. The data was gathered during the first year of operation of a new Coroners Act in Queensland, Australia, which changed the process of death investigation in three ways which are important to this paper. First, it required a greater amount of information to be gathered at the scene by police, and this included a thorough investigation of the circumstances of the death, including statements from witnesses, friends and family, as well as evidence gathering at the scene. Second, it required Coroners, for the first time, to determine the level of invasiveness of the autopsy required to complete the death investigation. Third, it enabled the communication of a genuine family concern, to be communicated to the Coroner. The outcome of such information was threefold. First, a greater amount of information offered to the Coroner led to a decrease in the number of full internal autopsies ordered, but an increase in the number of partial internal autopsies ordered. Second, this shift in autopsy decision making by Coroners saw certain factors given greater importance than others in decisions to order full internal or external only autopsies. Third, a raised family concern had a significant impact on autopsy decision making and tended to decrease the invasiveness of the autopsy ordered by Coroners.

Charles and Camilla Chair

The seat is an externally fixed seat for the public located at the entrance to the Prince Charles Hospital. The form of the seat is designed specifically for two, to celebrate the marriage of Charles and Camilla. The design of bench structure represents the Southern Cross which is predominant in our night sky, distinguishing us in location from Charles and Camilla, the night of their wedding. The design also incorporates references to undulating forms of the Queensland Landscape.

Re-envisioning sovereignty : the end of Westphalia?

Fables of sovereignty / Wayne Hudson Sovereignty discourse and practice : past and future / Joseph Camilleri Guises of sovereignty / Gerry Simpson Westphalian and Islamic concepts of sovereignty in the Middle East / Amin Saikal Wither sovereignty in Southeast Asia today? / See Seng Tan Ambivalent sovereignty : China and re-imagining the Westphalian ideal / Yongjin Zhang Confronting terrorism : dilemmas of principle and practice regarding sovereignty / Brian L. Job Sovereignty in the 21st century : security, immigration, and refugees / Howard Adelman State sovereignty and international refugee protection / Robyn Lui Do no harm : towards a Hippocratic standard for international civilisation / Neil Arya Sovereignty and the global politics of the environment : beyond Westphalia? / Lorraine Elliott Westphalian sovereignty in the shadow of international justice? a fresh coat of paint for a tainted concept / Jackson Nyamuya Maogoto Development assistance and the hollow sovereignty of the weak / Roland Rich Corruption and transparency in governance and development : reinventing sovereignty for promoting good governance / C. Raj Kumar Re-envisioning economic sovereignty : developing countries and the International Monetary Fund / Ross P. Buckley Trust, legitimacy, and the sharing of sovereignty / William Maley Sovereignty as indirect rule / Barry Hindess Indigenous sovereignty / Paul Keal Civil society in a post-statist circumstance / Jan Aart Scholte.

From Civil Strife to Civil Society: civil and military responsibilities in disrupted states

"The 1990s saw the United Nations, the militaries of key member states, and NGOs increasingly entangled in the complex affairs of disrupted states. Whether as deliverers of humanitarian assistance or as agents of political, social, and civic reconstruction, whether in Somalia, Bosnia, Kosovo, or East Timor, these actors have had to learn ways of interacting with each other in order to optimize the benefits for the populations they seek to assist. Yet the challenges have proved daunting. Civil and military actors have different organizational cultures and standard operating procedures and are confronted with the need to work together to perform tasks to which different actors may attach quite different priorities."--BOOK JACKET.

Introduction

The 1990s saw the United Nations, the militaries of key member states, and NGOs increasingly entangled in the complex affairs of disrupted states. Whether as deliverers of humanitarian assistance or as agents of political, social, and civic reconstruction, whether in Somalia, Bosnia, Kosovo, or East Timor, these actors have had to learn ways of interacting with each other in order to optimize the benefits for the populations they seek to assist. Yet the challenges have proved daunting. Civil and military actors have different organizational cultures and standard operating procedures and are confronted with the need to work together to perform tasks to which different actors may attach quite different priorities. From Civil Strife to Civil Society explores the nature of these challenges, blending the experience of scholars and practitioners. It is underpinned by an understanding that recovery from disruption is a laborious process that can easily be de-railed. The first part of the book offers a rigorous examination of the dimensions of state disruption and the roles of the international community in responding to it; the second part looks at military doctrine for dealing with disorder and humanitarian emergencies; the third part examines mechanisms for ending violence and delivering justice in post-conflict times; the fourth part investigates the problems of rebuilding trust and promoting democracy; the fifth part deals with the reconstitution of the rule of law; while the sixth and seventh parts address the reestablishment of social and civil order.

Ethics and Socially Responsible Investment : A Philosophical Approach

This volume breaks new ground by approaching Socially Responsible Investment (SRI) as an explicitly ethical practice in financial markets. The work explains the philosophical and practical shortcomings of ‘long term shareholder value’ and the origins and conceptual structure of SRI, and links its pursuit to both its deeper philosophical foundations and the broader, multi-dimensional global movement towards greater social responsibility in global markets. Interviews with fund managers in the Australian SRI sector generate recommendations for better integrating ethics into SRI practice via ethically informed engagement with invested companies, and an in-depth discussion of the central practical SRI issue of fiduciary responsibility strengthens the case in favour of SRI. The practical and ethical theoretical perspectives are then brought together to sketch out an achievable ideal for SRI worldwide, in which those who are involved in investment and business decisions become part of an ‘ethical chain’ of decision makers linking the ultimate owners of capital with the business executives who frame, advocate and implement business strategies. In between there are investment advisors, fund managers, business analysts and boards. The problem lies in the fact that the ultimate owners are discouraged from considering their own values, or even their own long term interests, whilst the others often look only to short term interests. The solution lies in the latter recognising themselves as links in the ethical chain.

Queensland requirements (old and new) for the appointment of a real estate agent

In Moneywood Pty Ltd v Salamon Nominees Pty Ltd 1 the High Court of Australia considered an appeal from the Queensland Court of Appeal in relation to the correct interpretation of s76 (1)(c) Auctioneers and Agents Act 1971 (Qld). In paraphrase, s76(1)(c) provides that a real estate agent shall not be entitled to sue for or recover any commission unless “the engagement or appointment to act as …..real estate agent ….. in respect of such transaction is in writing signed by the person to be charged with such…..commission…..or the person’s agent or representative” (“the statutory requirement”).

The role of coronial autopsies in a context of decreasing hospital autopsies: An investigation of the issues

This article scrutinises the argument that decreasing hospital autopsy rates are outside the control of medical personnel, based as they are on families’ unwillingness to consent to autopsy procedures, and that, as a consequence, the coronial autopsy is the appropriate alternative to the important medical and educational role of the autopsy. It makes three points which are well supported by the research. First, that while hospital autopsy rates are decreasing, they have been doing so for more than 60 years, and issues beyond the simple notion of consent, like funding formulae in hospitals, increased technology and fear of litigation by doctors are all playing their part in this decline. Secondly, the issue of consent has as much to do with families not being approached as with families declining to give consent. This is well supported by recent changes in hospital policy and procedures which include senior medical personnel and detailed consent forms, both of which have been linked to rising consent rates in recent years. Finally, the perception that coronial autopsies are beyond familial consent has been challenged recently by legislative changes in both Australia and the United States of America which allow objections based on religion and culture to be heard by coroners. For these reasons, it is argued that medical personnel need to focus on increasing hospital autopsy rates, while also addressing the complex ethical issues associated with conducting medical research within the context of the coronial autopsy.

Intention, foresight and ending life : a response to "The Double Effect effect" by Charles Foster, Jonathan Herring, Karen Melham and Tony Hope, (CQ 20(1))

In this paper I examine the recent arguments by Charles Foster, Jonathan Herring, Karen Melham and Tony Hope against the utility of the doctrine of double effect. One basis on which they reject the utility of the doctrine is their claim that it is notoriously difficult to apply what they identify as its 'core' component, namely, the distinction between intention and foresight. It is this contention that is the primarily focus of my article. I argue against this claim that the intention/foresight distinction remains a fundamental part of the law in those jurisdictions where intention remains an element of the offence of murder and that, accordingly, it is essential ro resolve the putative difficulties of applying the intention/foresight distinction so as to ensure the integrity of the law of murder. I argue that the main reasons advanced for the claim that the intention/foresight distinction is difficult to apply are ultimately unsustainable, and that the distinction is not as difficult to apply as the authors suggest.