Over the course of this thesis we will build and develop a model for the dynamics of an environmentally transmitted disease such as cholera. We will also develop methods to analyse and understand that model. The dynamics of a disease in a heterogeneous developing world city have not yet been fully explored, particularly when those dynamics are affected by a natural disaster. Yet, natural disasters such as floods alter infrastructure and population characteristics in a manner that affects disease transmission. Therefore, we shall address this omission from the literature. We will also develop a novel model analysis framework for 'systems epidemiology' where we combine systems biology techniques with epidemiological modelling.

This thesis examines the politics of Zimbabwe's catastrophic cholera outbreak in 2008/09, which caused an unprecedented 98,000 cases and over 4,000 deaths. Epidemiologically, the outbreak can be explained by the breakdown of the country's water and sanitation systems. Such a reading, however, belies the byzantine political, economic and historical processes that precipitated the dysfunction of the water systems, that delineate the socio-spatial pattern of the outbreak and that account for the fragmented and inadequate response of the national health system. The complex causal factors and the far-reaching consequences of the outbreak indicate that cholera is a unique prism through which to view different political phenomena including the dilemmas and contradictions of political change, bureaucratic order, humanitarianism, crisis and citizenship in Zimbabwe. Drawing on extensive field research, I make three inter-locking arguments in this thesis. First, I argue that Zimbabwe's cholera outbreak was a 'man-made' disaster. It was the final stage of both path-dependent and contingent processes rooted in questions of political economy such as the collapse of public health infrastructure, failing livelihood strategies and violent repression. Second, I argue that cholera reproduced and exacerbated a multiplicity of socio-political crises pertaining to the legitimacy of the Zimbabwean state, the nature of structural inequalities in Zimbabwean society and fundamental flaws in the global humanitarian response to epidemics. Third, I look at the myriad meanings, memories and narratives the epidemic has left in its wake across public institutions and in civic life. I argue that cholera has been committed to historical memory as a health crisis, a political-economic crisis, and a social crisis as well as a crisis of expectations, history and social identity.

Shiga toxin and cholera toxin are members of the AB5 family of protein exotoxins. The A subunit is the enzymatic subunit, whereas the pentameric B subunit binds cell surface receptors and carries the A subunit to the endoplasmic reticulum (ER) where it can be released into the cytosol. The B-subunits (STxB or CTxB) mediate toxin traffic along the retrograde pathway from the plasma membrane to the ER via early/recycling endosomes and the Golgi apparatus. It is unknown if STxB requires transport through the Golgi, or if it is just kinetically favorable. It is also unknown if the recycling endosome (RE) plays a role in the retrograde transport of STxB and CTxB. The first goal of this dissertation research was to demonstrate that transport through the Golgi is required for STxB to reach the ER. Using aluminum fluoride treatment, a simple temperature block, and cytoplast studies, I show that Golgi transport is necessary for STxB to reach the ER. The second goal of this dissertation research was to tease apart how STxB and CTxB move through early and recycling endosomes as well as elucidate a mechanism of how STxB exits endosomes en route to the Golgi. The role of the RE in STxB and CTxB transport is unclear. I used transferrin colocalization and temperature block studies to show that STxB and CTxB traffic through the RE. I then used HRP ablation of the RE to show that STxB requires the RE to reach the Golgi. I also examined the role of an RE-specific protein, EHD1, in exit of STxB from the RE. EHD1 has been previously shown to regulate recycling Tfn exit from the RE but its role in STxB transport is unknown. Expression of a dominant negative form of EHD1 arrested STxB at the RE and prevented it from reaching the Golgi. Together, these results suggest that STxB and CTxB transit the RE, STxB requires a functional RE for normal retrograde trafficking, and that STxB exit from the RE is regulated by EHD1.

Abstract not available

The bacterial pathogen Vibrio cholerae is responsible for ongoing cholera outbreaks in Haiti and elsewhere. Association of V. cholerae with the human host is responsible for fatal disease, but the bacteria also reside as natural inhabitants of aquatic environments, commonly attaching as biofilms to chitinous surfaces of copepods and crabs. Prior studies in V. cholerae demonstrated that competence for genetic transformation, a mechanism of horizontal gene transfer (HGT), requires the TfoX regulator protein that is triggered by chitin, and the HapR transcription factor that is made in response to quorum sensing (QS) signals produced by V. cholerae and Vibrios. To define regulatory components connecting extracellular signals to natural competence, I first demonstrated that QS molecules produced by Vibrios within multi-species chitinous biofilms are required for DNA uptake by V. cholerae, confirming the critical role of QS signals in HGT. Second, I identified by transposon-mutagenesis a new positive regulator of competence, CytR (cytidine repressor), only studied prior in E. coli as a regulator of nucleoside scavenging. Specific mutations in V. cholerae CytR impaired expression of competence genes and halted DNA uptake; and the addition of exogenous cytidine had similar affects as predicted in E. coli. V. cholerae and other competent Vibrios encode TfoX, HapR, and CytR, although none of these regulators directly controls genes coding for the DNA uptake apparatus. Thus, these results have uncovered a regulatory network, likely used by many Vibrios, that contains additional factors linking several extracellular chemical molecules (cytidine, chitin, and QS signals) to DNA uptake. My study has begun to define a molecular mechanism by which both environment and genetics contribute to genome evolution for this important marine pathogen.

Cholera remains a threat to public health in many developing countries, including Mozambique. Although the disease is easily preventable by practices of hygiene and sanitation, cases are reported in the country every year, as for example in the Lago district in 2015. This qualitative research project set out to explore in what ways the promotion of hygiene and sanitation practices on district level in Mozambique is carried out. Therefore, actors, messages and channels involved in these communication processes were explored via a field study in Lago and a review of relevant literature. Subsequently, the results of the field study and literature review were analysed by applying the concepts of one-way and two-way communication which are part of public relations theory. This analytical framework allowed the researchers to fill a gap identified in the existing literature about hygiene and sanitation promotion, which did not seem to include communication theories linked to public relation practices when it came to hygiene and sanitation promotion in developing countries as a method to prevent cholera. It has been found that the one-way communication approach towards the public was successful in handling the recent cholera outbreak of 2015, however, the approach is not substantial and should be improved into a two-way communication approach, which would allow the local population to express their needs in hygiene and sanitation, as well as their capabilities to implement change in these matters. Simultaneously, a lack of resources within the district authorities involved in hygiene and sanitation promotion seems to encourage one-way communication towards the public from their side, as two-way communication would demand further resources for research into the above mentioned needs and capabilities of communities.

This study examines the cholera epidemic in Montreal during the summer of 1832, focusing on the Montreal Board of Health, the public health regulations, medical involvement on the Board, and the voluntary movement. Using newspapers, judicial documents, and correspondence, it seeks to re-examine the epidemic to further the understanding of the modernization of the Canadian state in the area of public health. / Many of the histories concerning the modernization of the Lower Canadian state have focussed on the 1837 rebellions as a breaking point between the 'old' state and the 'modern' state. If modernization can be equated with the process of increased state influence on society, then the 1832 epidemic provided an opportunity for the government to become more involved in the social regulation of individual lives. And the process was not solely influenced by the 'state,' as citizen committees played a role during the epidemic. Nor must Lower Canada be seen in a vacuum, as the shifts that occurred in Montreal during the epidemic coincided with those taking place in London, Paris and New York. / An analysis of the state during the epidemic suggests its growing significance in individual lives, particularly those of the poor. The appearance of cholera hospitals, the use and enforcement of public health regulations by a board of health, and the social assistance to the immigrants, orphans, and widows illustrate this modernizing state.

Focusing on the 1851 International Sanitary Conference, this dissertation analyses an important episode in the international regulation of health, trade, passengers, and cargo in a period of epidemic crisis. It argues that a group of diplomats and physicians appointed to represent 12 European nations instituted a new international forum that extended – and occasionally rivalled – national and local agencies for epidemic governance. Together, delegates endeavoured to establish a common sanitary policy in Europe and in the Orient. By creating shared surveillance and judicial mechanisms – while standardising definitions and practices – delegates aimed to engineer the flow of people, vessels, cargo, and diseases in the Mediterranean region. As a transnational forum, the Conference was a platform where doctors and diplomats reinterpreted models of public health and sanitary administration while creating institutions that challenged conventional concepts of borders, national policy, and state sovereignty. As a multinational event, the Conference marked the unprecedented transition from local, national and, bilateral public health policies into a coherent transnational project for the governance of epidemics. The dissertation is based on extensive research conducted in hitherto largely unexplored medical, diplomatic, and national collections in Britain, France, Italy, Portugal, Spain, and the United States of America. Sources ranging from diplomatic correspondence to medical publications and personal diaries, tie together multiple national and professional perspectives while untangling a diversity of personal and state agendas that fundamentally shaped the foundation of international public health mechanisms and contributed towards the crystallisation of medical concepts. Chapter one demonstrates how economic and political concerns about the impact of quarantine on international trade led to calls for international regulation and the standardization of quarantine practices in the Mediterranean region. Drawing on medical reports, pamphlets and diplomatic correspondence, the chapter exposes the multitude of quarantine practices in the Mediterranean region and a growing international demand for prophylactic reform. These exchanges, it is shown, culminated with the organization of the 1851 International Sanitary Conference in Paris. Chapter two argues that the Conference challenged previous diplomatic and medical protocols by including two professional groups in the process of regulating international public health. The lack of precedent allowed diplomatic and medical delegates to establish new rules for the conduct of the conference, which gave them a relatively high level of autonomy from the states they represented. Chapter three focuses on the problems of constructing a shared aetiological classification and regulating quarantine practices. It shows that, although doctors gained progressive control over the Conference, ultimately diplomatic agendas shaped the final outcome. In addition, it demonstrates that, rather than defending the elimination of quarantines, liberal states supported the continuation of quarantine practice in the Mediterranean; albeit that they managed to severely limit its operation in practice. Finally, chapter four examines how European and Oriental sanitary institutions were uniformly redesigned and new international judicial mechanisms created. These measures variously affected the sovereignty of the participating states by limiting their independent capacity to set national epidemic policies. However, the chapter argues that these negotiations took the shape of sovereignty bargains: by loosening control over specific elements of their sovereignty, states managed to advance their political, economic and sanitary agendas. By looking at the International Sanitary Conference of 1851, this dissertation shows how the foundations of international public health had consequences not only for the control of epidemic diseases and the circulation of goods and people in the Mediterranean region, but also for the authority and status of the nation states. By doing so, it reveals that international public health governance resulted from the amalgamation of a particular configuration of expert and diplomatic struggles and compromises. Moreover, the dissertation shifts the traditional local and national focus in the history of medicine to a wider and international context where local and national traditions struggled to produce coherent discourses and practices.

Classical Swine Fever in the Lao Peoples’ Democratic Republic: Virological, Epidemiological and Clinical studies. Classical swine fever (CSF) is a highly contagious virus infection of swine caused by classical swine fever virus (CSFV). The CSF virus is a member of the genus Pestivirus of the family Flaviviridae. Classical swine fever is believed to be endemic in Lao Peoples’ Democratic Republic (Lao PDR). Infectious diseases, including CSF, are a major constraint to pig production in developing countries such as Lao PDR. The aim of this thesis was to investigate aspects and present data regarding the nature of CSF pertinent to Lao PDR. An introduction to Lao PDR, local pig production and a review of pertinent CSF literature is presented in Chapter 1. Low levels of veterinary infrastructure have exacerbated infectious disease problems in developing countries. Chapter 2 of this thesis described the construction and refurbishment of a project laboratory in Lao PDR for the diagnosis of viral diseases, in particular CSF virus Furthermore, a diagnostic specimen submission system was adapted to the local domestic and economic conditions. Poor diagnostic facilities and lack of disease reporting systems in Lao PDR have allowed diseases to spread largely unchecked due to low levels of recognition. The process of development and assessment of appropriate diagnostic assays to the local conditions is presented and discussed in Chapter 3. ELISA and RT-PCR technologies for CSF virus detection in clinical specimens were implemented. Variations to RT-PCR methodologies were also investigated to determine the most suitable technique for the local situation. Results indicated that the RT-PCR methodology was more sensitive than ELISA for the detection of CSF virus in fresh clinical specimens. Notably, the situation was reversed when decomposed samples were tested. Methodologies for the preservation and detection of CSF virus in samples subjected to local tropical condition were also investigated. The proprietary reagent RNAlater ™ was found to be suitable for the preservation of CSF virus RNA under local conditions. Methodologies for CSF virus serology using the ELISA technique are also described. The majority of the pigs in Lao PDR are raised within village small-holder systems, with indigenous breeds being the most popular. Very little is known about the response of indigenous breed pigs to CSF virus infection. Chapter 4 described the pathogenicity of a Lao strain of CSF virus (Lao/Kham225) in both indigenous (Moo Laat) and imported pig breeds (Large white/Landrace cross-breed). Statistically significant (p = 0.05) differences in the breed-related susceptibility to CSF infection were demonstrated in clinical and haematological responses, and post-mortem pathology. The results demonstrated the course of CSF infection in the Large white/Landrace cross-breed was generally more acute than in the indigenous breed. Investigations into the epidemiology of CSF in Lao PDR are presented in Chapter 5. The distribution of CSF outbreaks during the period of mid-1997 to the end of 1999 was investigated and crude incidence results were calculated. Serological surveillance to determine the serological prevalence of CSF virus antibodies in selected regions of Lao PDR was performed during 1997 to 1999. Structured serological surveillance was performed in Vientiane Municipality, Bhorikhamxai, Khammouane and Savannakhet provinces during the survey period. Passive serological surveillance using samples from eight abattoirs in Lao PDR was also performed. Statistically significant (p = 0.05) intra- and inter-provincial differences were noted in a number of the surveys. The success of CSF vaccination via post-vaccination serology was also assessed. The results of the investigations determined that vaccination to prevent CSF infection was insufficient and post-vaccination responses were variable. Phylogenetic and phylogeographic studies to determine the genetic characteristics of Lao PDR and other regional CSF virus isolates are presented in Chapter 6. The 5’-non-coding region and the E2 gene of CSF viruses were investigated to determine genetic relationships between Lao PDR and regional isolates. Genetic typing of all field virus isolates using phylogenetic analysis techniques indicated that all viruses belonged to genogroup 2. Phylogeographic analysis of field viruses revealed a delineation of sub-genogroup allocation on a geographic basis. Members of the sub-genogroup 2.1 originated in Northern and Central regions of Lao PDR. Conversely, members of the sub-genogroup 2.2 originated in Southern and Central regions of Lao PDR. All Vietnamese viruses examined belonged to sub-genogroup 2.2. Phylogenetic analysis indicated that the Vietnamese viruses were largely distinct from Lao and Thai CSF viruses. With the exception of one virus isolate, all Thai viruses also belonged to sub-genogroup 2.2. With the exception of one Vietnamese vaccine virus, all vaccines examined belonged to genogroup 1. A general discussion of the results presented in all chapters, as well as implications for future research into this field, are presented in Chapter 7.

Thesis--Universidad de Sevilla. / "Apéndice demografico": p. 134-180. Includes bibliographical references (p. 132-134).