1^st C2D2 Conference, 25-26 September 2013

Chronic infections

Session 1 – chaired by Professor Rod Hubbard

Mark Coles (HYMS), Jon Timmis (Electronics): Systems Modelling:  A new approach to developing therapies for human autoimmune disease

Immune responses are highly complex, involving interactions between multiple different cell types in complex cellular environments and a plethora of intracellular and extracellular signalling molecules.  In the last 30 years advances in human genetics, animal models, imaging technologies and functional assays have permitted a deeper understanding of human immune function and the process driving the formation of autoimmune disease pathologies. However although these reductionist approaches have provided windows into mechanisms of disease pathology, they have struggled to explain the complexity underlying human disease and thus its treatment.  Here we present a new methodology using agent-based modelling to simulate human autoimmune disease and develop potential intervention strategies in silico.  Simulations created using this technique have explicit representation of spatial and temporal immune cells, capturing the heterogeneous and stochastic cellular behaviours that lead to emergence of disease pathology, closely resembling behaviour found in vivo.  Using a calibrated model of autoimmune pathology we will show how this can be used to predicting drug efficacy and optimal delivery strategies.  This technology is a powerful new method to understand cellular behaviours leading to pathology, permitting rational design of drug interventional strategies and can provided new insights into mechanisms of autoimmune disease progression.  Simulation modelling has the potential to greatly accelerate the development of novel therapeutic interventions for human autoimmune disease and inflammatory disorders.

Carbon monoxide (CO) is a well-known toxic gas. However, at low concentrations it has signalling capabilities that give it potential as a therapeutic agent. Additionally, CO may have potential as a novel antimicrobial. Here we have developed several new series of CO releasing molecules (CORMs) that liberate CO in a controlled manner, either through thermal activation or photolysis. These CORMs can be specifically toxic to bacterial pathogens, whilst not impacting on viability in eukaryotic cells. The targets of CO action in bacterial cells are currently unclear, and CORMs offer the potential to study this interaction in detail.

Leishmania parasites are causative agents of the human leishmaniases, a spectrum of neglected tropical diseases that affect millions worldwide, with often fatal consequences.  Parasites are vector-transmitted as extracellular flagellated cells (metacyclic promastigotes) by female sand flies during blood feeding. Once in the host, the metacyclic promastigotes are phagocytosed by host cells (including neutrophils and macrophages) and differentiate intracellularly into replicative amastigotes, the agents of disease in man. Relatively little is known about the molecular mechanisms of parasite differentiation within the vector or interactions between the parasite and the sand fly however, processes that could influence parasite transmission and disease progression. Recent data investigating the genetics and development of Leishmania in the sand fly will be presented and discussed.

There is increasing agreement within circles such as the World Health Organization that history- and social science-based analyses are of use to policy development, implementation and analysis. However, there is no unanimity in policy - and, increasingly, funding circles - about what role the discipline of history is supposed to play. For some, its uses are seen to lie in the production of propaganda: a historical narrative that cynically creates a very specific description of the past for the purpose of justifying contemporary funding and policy choices. For others, this interaction between global public health, science and history needs to be informed by completely different motives. It is expected to be a complex, no-holds-barred assessment of the recent past, in the hope that this provides effective insights to institutions and individuals about the challenges that they are likely to face. Intertwined with this process is the self-conscious search for methods that provide a rounded assessment of shape health-seeking behaviours and health delivery mechanisms in a variety of locales. One size has never fitted all in global health policy implementation. Using a range of vignettes, drawn from detailed historical and social science research funded by the Wellcome Trust, this presentation will seek to engage with these themes. It will end with a short presentation about how complex histories can result in the production of effective public engagement activities. Ideas presented simply and clearly do not need to be simplistic; independent research that asks and answers difficult questions is often able to hold the attention of many audiences, public or otherwise, especially when the power of multilingualism is recognised.

Bacteria often exist in communities called biofilms. When these biofilms form on the surface of in-dwelling medical devices, it becomes a serious clinical problem because the infections seem recalcitrant to antimicrobial treatment and therapies.  Thus therapeutic approaches targeting these communities and their formation might improve the efficacy of currently available antibiotics.  The Potts and van der Woude labs have expertise in studying the molecular aspects of bacterial interactions and antimicrobial therapies using biochemical and microbiology/imaging approaches.  The combined expertise is applied to studying the molecular basis of staphylococcal biofilm formation by Staphylococcus epidermidis and potential techniques for the disruption of these bacterial communities.

Chronic periodontal disease is caused by the overgrowth of pathogenic oral bacteria, leading to bone destruction and tooth loss. Beyond its effects on oral health, individuals with chronic periodontitis are also at higher risk for cardiovascular disease, stroke, diabetes, and respiratory illnesses. Based on observations of archaeological skeletons, we know that humans have been suffering from periodontal disease for millennia, although the frequency and severity of periodontal disease varies between geographic areas and historical periods. In order to effectively treat periodontal disease in modern society, we need to have a clear understanding of both the species of bacterial pathogens that cause the disease in the past and today, and how these bacteria have evolved through time. Our study is investigating the genetic diversity and evolution of periodontal pathogens over a 4000 year period through the biomolecular analysis of dental calculus (mineralized plaque) preserved on archaeological skeletons from Yorkshire. Our study is examining the relationship between skeletal markers for periodontal disease, proteins associated with human immune response to periodontitis, and DNA and proteins of bacteria associated with periodontal disease. Using bacterial DNA and proteins from dental calculus, we can observe evolutionary changes relating to periodontal pathogen virulence from the Iron Age through to the modern era.

Neurological & mental health disorders

Macular degeneration is the leading cause of blindness in the developed world.  This retinal disease renders sufferers blind in the centre of the visual field.  As a result, patients can no longer achieve high spatial resolution, which is only found in central visual field locations, and therefore struggle to read and perform other everyday visual tasks.  The centre of the visual field has a disproportionately large representation in the human brain – about half the area of the primary visual cortical map is concerned with processing only the central 10 degrees of the visual field. Therefore, a large part of the visual brain receives no retinal input as a result of macular degeneration.  We have shown previously that the primary visual cortical map (V1) does not remap the visual information that remains spared in patients with macular degeneration (Baseler et al 2011 Nature Neuroscience).  This is reassuring as a large reconfiguration on the visual cortex could limit the success of treatments that aim to restore retinal function in patients with macular degeneration.  However, the success of restorative treatments also depends on the way in which different visual maps in the occipital lobe communicate with each other.  In the C2D2 funded work we investigated whether the second cortical visual area, V2, continues to sample information from V1 normally in the parts of these visual maps that no longer receive an input from the retina.  This work relies on a newly established method - connective field modelling - that can assess the connectivity of brain areas even when those areas are not directly stimulated.  We found that connectivity between areas V1 and V2 is maintains topographic connectivity in patients with macular degeneration, although less strictly than in controls with simulated retinal lesions. However, the extent to which connectivity was disordered in the patients correlated negatively with their ability to keep their eyes stable while fixating. This suggests that the difference between the pattern of connectivity in patients and controls is related to poor fixation and that the spatial patterns of connectivity between visual maps remains largely intact, despite the prolonged loss of visual input. These results suggest that the restoration of sight in MD can probably assume largely unchanged cortical visual fields maps.

We analysed in depth the personal possessions and student rooms of 45 neuro-typical students at University and 5 individuals with diagnosed Autism Spectrum Disorder (ASD). Within the neuro-typically developing group we analysed Autism Quotient (AQ) scores and created 3 subgroups based on these scores in order to explore the influence of autism symptomatology on use of personal possessions in student accommodation.  Our initial hypothesis expected a difference in approach to objects and various properties of objects as a function of AQ score: The higher the result on the AQ, the less interest one would have in an objects capacity to act as a reminder of others or for abstract emotional purposes.

Counter to our initial hypothesis, we found that AQ score had very little predictive capacity when considering self-assessment value attributions on a range of everyday objects and a range of measures, including monetary worth, functionality, capacity of the object to act as a reminder of others and capacity of the object to act as a source of comfort. Emotional processing of the comfort or value of objects is not absent in those with autism but nonetheless appears to differ from that of neuro-typically developing people in subtle ways.

For example rather than a small number of particularly moving photographs, those high on the AQ score often had many photographs. This suggestion would fit with anthropological perspectives on autistic sociality as ‘social but different’.  This research has established a new research network exploring links between the departments of archaeology and psychology/psychiatry. This is already yielding several new research ideas aimed at helping us to better understand the role of anthropology, archaeology and evolution in gaining insights into psychological development in for example individuals with autism spectrum disorders.

Developments in medical technologies and procedures are associated with a rapid rise in the number of people who survive catastrophic brain injuries with chronic disorders of consciousness e.g. the ‘permanent vegetative’ or ‘minimally conscious’ states.  There has been very little research addressing the social implications of this or exploring how those most closely involved with these patients (family members and clinicians) understand and explain their experience.  We have recorded more than 50 in-depth interviews with family members of people with chronic disorders of consciousness (and are currently building a data base of interviews with neurologists, rehabilitation teams, and other who work with such patients).  This talk will begin with an introduction to the work of research group overall (by the group’s Director, Celia Kitzinger) and we will then present brief snapshots of four of our current projects:

• Alice Hall will describe how Isabel Allende's Paula brings together fiction and memoir forms to explore important debates about voicelessness in relation to chronic disorders of consciousness.
• Stephen Holland will report on the ways in which our interview data support the view that permanently vegetative patients are in a strange state, being neither straightforwardly alive nor simply dead
• Celia Kitzinger will discuss the implications of what our interviewees say for end-of-life planning, especially in relation to Advance Decisions to refuse treatment
• Simon Halliday will show that, in the perceptions of families of patients with chronic disorders of consciousness, law is something of a double-edged sword - both empowering and disempowering in their attempts to negotiate the best interests of their relative.

We will end by indicating our future plans for developing our research and maximizing its applications in developing biomedical ethical practice

Parkinson’s disease (PD) affects approximately 120,000 people in the UK alone and is likely to increase dramatically over the next decade as people live longer. The most effective form of treatment for PD symptoms is a drug called levodopa, but approximately 90% patients who take it for ten years or more develop involuntary troublesome movements called dyskinesia. Currently, physicians rely on patients’ own descriptions to monitor symptoms and adjust their medication accordingly, and in severe cases, patients are admitted to hospital for several days or more.

This presentation will describe novel technology to measure dyskinesia that is simple, reliable and safe to use. The system simply requires the patient to wear six small wireless sensors (on the limbs, head and trunk) that continually monitor the patient’s movements over a period of 24 hours.  Specially designed computer programs are able to determine how frequently, and how strongly, the involuntary movements (dyskinesia) occur. This technology is currently being prepared for commercialization to monitor not only Parkinson’s disease, but also a range of neurodegenerative conditions including Alzheimer’s disease and Lewy Body dementia.

Very little is known about Human T lymphotropic virus type (HTLV) prevalence and co-infection with other viruses in Malawi. We tested the HTLV prevalence and co-infection rates in the most vulnerable population group, women of reproductive age and their children, living in Malawi and performed a systematic review and meta-analysis of HTLV prevalence in healthy women in Africa. We took a study population of 418 paired mother using child blood samples. Our systematic review was based on a PubMed search for reports on HTLV prevalence in healthy women (antenatal care, blood donors, healthy volunteers and sex workers) where confirmatory test on ELISA positive samples had been performed. Meta-analysis was performed.

We found that 2.6% of healthy women were HTLV carriers and remarkably 1.7% were HTLV-2 carriers. Two children were HTLV carriers: one child was dually infected with HTLV 1 + 2 and was the child of a HTLV-1 positive mother. The second child was infected with HTLV-2, although the mother was HTLV-1 carrier. HCV antibody prevalence was very low among healthy women (0.48%) but the child of one of the two infected women was a HCV antibody positive. HTLV/HCV co-infection was not observed. Our analysis revealed an overall 3% prevalence of HTLV in healthy African women. This varied considerably depending on geographical area and reporting frequency per country and grouping of women. HTLV was more prevalent in older women and sex workers (data not shown).  HTLV-2 was reported very rarely (10 reports), and at a much lower rate (estimated 0.89%, range 0.1-3.8) than our observation in Malawi. Prevalence data from North Africa was scarce. Three groups reported on mother to child transmission which was very high in Gabon (18%).

Our data detected a high prevalence of HTLV-2 in healthy women living in Malawi. This was unexpected and has not been reported before. Horizontal transmission of HTLV is possibly the cause of sero-positivity of the children. The low prevalence of HCV in Malawi is reassuring although sampling bias cannot be excluded.  Our systematic review highlights large gaps in HTLV surveillance reporting and confirms previous reports of high prevalence of HTLV in women.

Exhibitions

Over the last 20 years, the biocultural and political ecological concept of syndemics — which draws attention to the role of unjust social conditions in the deleterious clustering and adverse interaction of diseases — has developed into a multidisciplinary disease model. Syndemics emerge through the interaction of diseases of all types (e.g., infections, chronic infections, chronic noncommunicable diseases, mental health problems, behavioural conditions, toxic exposures, and malnutrition) that produce an increased burden of disease in a population. Syndemics of chronic and persistent infection, involving the interface of diseases that evade or overwhelm the immune system, are among the leading global causes of years of productive life lost, a measure of disability and premature death due to disease. Based on an examination of the contexts of disease clustering and pathways of disease interaction in chronic infections, the goal of this presentation is to contribute to recognition of the practical utility for health improvement of the syndemics perspective.

Merrill Singer, PhD, a medical and cultural anthropologist, is a Professor in the departments of Anthropology and Community Medicine, and a Senior Research Scientist at Center for Health, Intervention and Prevention at the University of Connecticut.  Additionally, he is affiliated with the Center for Interdisciplinary Research on AIDS at Yale University. Over his career, his research and writing have addressed HIV/AIDS in highly vulnerable and disadvantaged populations, illicit drug use and drinking behaviour in light of political economy, community and structural violence, health disparities, and the political ecology of health. His research focuses especially on the nature and impact of both syndemics (interacting epidemics) and pluralea (intersecting ecocrises) on health.  Dr. Singer has published over 260 articles and book chapters and has authored or edited 25 books. He is a recipient of the Rudolph Virchow Prize, the George Foster Memorial Award for Practicing Anthropology, the AIDS and Anthropology Paper Prize, the Prize for Distinguished Achievement in the Critical Study of North America, and the Solon T. Kimball Award for Public and Applied Anthropology from the American Anthropological Association.

Adolescence is a time for growth, development, increasing independence and also a time for forming new relationships. Thus life both at home and at school can be seriously affected by chronic ill-health. There are huge variations in the prevalence of chronic disease between countries and these differential risks are rarely explored. Data summarising the chronic health of adolescents worldwide is most often presented in large data sets, dull reports or duller academic journals and rarely disseminated in any other way, remaining largely hidden from the public view. In this innovative, multidisciplinary and exciting project, epidemiological data on the global chronic health of adolescents will be developed into an installation that will include data sonification, composed music and a visual representation of the challenges facing young people and their strength and resilience to overcome them. The collaboration led by Amanda Mason-Jones, Senior Lecturer in Global Public Health, involving colleagues from the departments of Health Sciences (Amanda Mason-Jones, Antonina Mikocka-Walus); Theatre, Film and Television (TFTV) (Sandra Pauletto, Patrick Titley); Music (Jez Wells); Sociology (Darren Read); English (Alice Hall); the Centre for Applied Human Rights (CAHR) (Juliana Mensah), composer Bartek Walus and film director Nik Morris and actress Katie-Marie Armstrong aims to create an experiential learning opportunity that will raise the issues of chronic health faced by young people worldwide. This will then be used as a platform to engage with young people to develop the project further and to secure further funding.

Tuberculosis (TB) has long been regarded as a major danger to public health, and in the twenty first century it is widely seen as a disease that is not only endemic across the world, but also one that has developed new strains that threaten to explode in epidemic proportions. This exhibition, produced by the Centre for Global Health Histories, presents a worldwide history of TB’s impact and the efforts to control it from the nineteenth century up until the present day.  It showcases a selection of extraordinary images reproduced from the Wellcome Library image collection and the World Health Organization's photographic archives. Each one highlights important episodes in the story of this most dangerous of diseases. Copies of an accompanying publication (right), featuring images from the exhibition and introductions to different episodes in the history of tuberculosis, will be available and it is also possible to download the publication from the Centre for Global Health Histories’ website: www.york.ac.uk/history/global-health-histories/publications/outreach-materials/

Posters of a wide range of C2D2-funded projects, many of which are not included in the programme of talks, are on display in the Atrium area. There are also a number of special displays of C2D2-linked and C2D2-funded projects including:

• An exhibition of postcards articulating the experiences and thoughts of relatives of those who have suffered severe brain injuries by CDoC
• A display of projects from the first (2011) cohort of students on the Combating Infectious Disease: Computational Approaches in Translational Science (CIDCATS) Wellcome Trust PhD Programme
• A display on research into antibiotic resistance and new antimicrobial therapies at the University of York
• A display by the University spin-out company Immune Modelling Solutions
• An interactive display on engineering improved care in Parkinson’s Disease

Registration

Registration closed on Saturday 31st August

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