Proceedings of a Joint Meeting held between The Norwegian Society of Infectious Diseases and the Royal Society of Tropical Medicine and Hygiene, Oslo, 20th June 2008

The Royal Society of Tropical Medicine and Hygiene (RSTMH) has a tradition of holding joint meetings with fellow European Societies, providing opportunities to facilitate discussion, exchange information, foster mutual interests and develop collaboration between the societies’ members and fellows. This paper presents the proceedings from a scientific meeting that was held between The RSTMH and the Norwegian Infectious Diseases Society at Ulleval University Hospital, Oslo on 20th June 2008. Three speakers from each society gave state-of-the-art lectures in their areas of expertise and the meeting ended with a series of case presentations

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thesisHow and why has a group of conservative housewives become the most powerful lobbying group in one of the most populous states in the Mountain West? Since its founding in 1972, the Eagle Forum has risen to prominence as a dominant force in Utah state politics. This formidable conservative grassroots social movement shaped legislation, influenced elections, and advocated an agenda that is unwavering in its support of families, Christianity and small government. The Utah Eagle Forum's power is unparalleled by other state chapters of the organization. This thesis explores the efforts of housewife-activists to advance conservative agendas at local and state levels of government in Utah. In a complex milieu of Mormonism, Western libertarianism, changing gender roles and shifting national politics, the Utah Eagle Forum has assumed the role of moral "watchdog" over state politics. From its beginnings as a single issue organization opposed to the ERA, to its efforts to form coalitions empowering housewives with a voice in politics, its cultivation of a phone tree an efficient statewide mobilization tool and a notorious reputation for vigilant legislative lobbying, the Utah Eagle Forum is an example of the possibilities for right wing women's activism in a conservative political environment. This paper dramatically expands historians' understanding of the Eagle Forum at the local level as it explores the roles and activities of conservative women in twentieth-century American social movements

DNA entropy reveals a significant difference in complexity between housekeeping and tissue specific gene promoters

BACKGROUND The complexity of DNA can be quantified using estimates of entropy. Variation in DNA complexity is expected between the promoters of genes with different transcriptional mechanisms; namely housekeeping (HK) and tissue specific (TS). The former are transcribed constitutively to maintain general cellular functions, and the latter are transcribed in restricted tissue and cells types for specific molecular events. It is known that promoter features in the human genome are related to tissue specificity, but this has been difficult to quantify on a genomic scale. If entropy effectively quantifies DNA complexity, calculating the entropies of HK and TS gene promoters as profiles may reveal significant differences. RESULTS Entropy profiles were calculated for a total dataset of 12,003 human gene promoters and for 501 housekeeping (HK) and 587 tissue specific (TS) human gene promoters. The mean profiles show the TS promoters have a significantly lower entropy (p<2.2e-16) than HK gene promoters. The entropy distributions for the 3 datasets show that promoter entropies could be used to identify novel HK genes. CONCLUSION Functional features comprise DNA sequence patterns that are non-random and hence they have lower entropies. The lower entropy of TS gene promoters can be explained by a higher density of positive and negative regulatory elements, required for genes with complex spatial and temporary expression

Baseline cytokine profiles of tuberculin-specific CD4 T-cells in non-muscle invasive bladder cancer may predict outcomes of BCG immunotherapy within reach?

Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy preserves the bladder after resection of high-risk non-muscle invasive bladder cancer (NMIBC). About 30% of patients experience treatment failure, which cannot be predicted a priori and carries a high risk of disease progression. We examined the in vitro tuberculin-responsiveness of CD4+ T cells before BCG immunotherapy in 42 patients with high-risk NMIBC. The frequencies and functionalities of cytokine-expressing CD4+ T cells immediately before and after BCG immunotherapy induction were assessed by flow cytometry after overnight tuberculin stimulation. Tuberculin-induced secreted mediators were measured by electrochemiluminescence. We correlated the results with recurrence-free patient survival 6 months after induction. A tuberculin-induced, secreted, IL2 concentration > 250 pg/ml was the best predictor of recurrence-free survival, providing 79% sensitivity, 86% specificity (AUC = 0.852, P = 0.000), and overall correct classification in 78.6% of cases. In 50% of patients later experiencing recurrence, but not in any of the recurrence-free survivors, IL2 secretion was < 120 pg/ml. Other parameters predicting recurrence-free survival included secreted IFNγ (AUC = 0.796, P = 0.002) and the frequencies of TNF-producing (TNF+) CD4+ T cells (AUC = 0.745, P = 0.010). 'Polyfunctional' CD4+ T cells (IFNγ+/IL2+/ TNF+) were significantly associated with recurrence-free survival (AUC = 0.801, P = 0.002). Thus, the amount of IL2 secretion from CD4+ T cells after overnight in vitro incubation with tuberculin predicted the outcome of BCG immunotherapy. As many as half of potential BCG failures could be identified before induction therapy is begun, enabling better choices regarding treatment

Impact of social stigma on the process of obtaining informed consent for genetic research on podoconiosis: a qualitative study

Background The consent process for a genetic study is challenging when the research is conducted in a group stigmatized because of beliefs that the disease is familial. Podoconiosis, also known as 'mossy foot', is an example of such a disease. It is a condition resulting in swelling of the lower legs among people exposed to red clay soil. It is a very stigmatizing problem in endemic areas of Ethiopia because of the widely held opinion that the disease runs in families and is untreatable. The aim of this study was to explore the impact of social stigma on the process of obtaining consent for a study on the genetics of podoconiosis in Southern Ethiopia. Methods We adapted a rapid assessment tool validated in The Gambia. The methodology was qualitative involving focus-group discussions (n = 4) and in-depth interviews (n = 25) with community members, fieldworkers, researchers and staff of the Mossy Foot Treatment and Prevention Association (MFTPA) working on prevention and treatment of podoconiosis. Results We found that patients were afraid of participation in a genetic study for fear the study might aggravate stigmatization by publicizing the familial nature of the disease. The MFTPA was also concerned that discussion about the familial nature of podoconiosis would disappoint patients and would threaten the trust they have in the organization. In addition, participants of the rapid assessment stressed that the genetic study should be approved at family level before prospective participants are approached for consent. Based on this feedback, we developed and implemented a consent process involving community consensus and education of fieldworkers, community members and health workers. In addition, we utilized the experience and established trust of the MFTPA to diminish the perceived risk. Conclusion The study showed that the consent process developed based on issues highlighted in the rapid assessment facilitated recruitment of participants and increased their confidence that the genetic research would not fuel stigma. Therefore, investigators must seek to assess and address risks of research from prospective participants' perspectives. This involves understanding the issues in the society, the culture, community dialogues and developing a consent process that takes all these into consideration

Podoconiosis

Podoconiosis is a non-infectious geochemical disease that results in swelling of the lower legs. It is caused by long term exposure of bare feet to red clay soil derived from volcanic rock. In southern Ethiopia, where much of our research has been conducted, and north-western Cameroon, it affects 5-8% of the population and is more common than HIV, TB or malaria. Podoconiosis imposes immense economic burdens (the estimated cost to Ethiopia's economy is $208 million per year) and severe social stigma. Very little research on disease aetiology or pathogenesis has been done, yet such research is needed for rational deployment of limited resources towards prevention, treatment and ultimately eradication of the disease. There is convincing evidence that an area of the genome commonly involved in human responses to infectious and environmental challenges plays a major role in susceptibility to podoconiosis. In this talk I will discuss the work we have undertaken to identify the genetic variation that predisposes to podoconiosis and how this work could have impact on the lives of people affected by the condition. For example, establishing the importance of genetic susceptibility has justified the use of a family history tool in determining which children should be offered shoes for prevention of disease, when shoes are a scarce resource

Tailoring consent to context: designing an appropriate consent process for a biomedical study in a low income setting

Background Currently there is increasing recognition of the need for research in developing countries where disease burden is high. Understanding the role of local factors is important for undertaking ethical research in developing countries. We explored factors relating to information and communication during the process of informed consent, and the approach that should be followed for gaining consent. The study was conducted prior to a family-based genetic study among people with podoconiosis (non-filarial elephantiasis) in southern Ethiopia. Methodology/Principal Findings We adapted a method of rapid assessment validated in The Gambia. The methodology was entirely qualitative, involving focus-group discussions and in-depth interviews. Discussions were conducted with podoconiosis patients and non-patients in the community, fieldworkers, researchers, staff of the local non-governmental organisation (NGO) working on prevention and treatment of podoconiosis, and community leaders. We found that the extent of use of everyday language, the degree to which expectations of potential participants were addressed, and the techniques of presentation of information had considerable impact on comprehension of information provided about research. Approaching podoconiosis patients via locally trusted individuals and preceding individual consent with community sensitization were considered the optimal means of communication. Prevailing poverty among podoconiosis patients, the absence of alternative treatment facilities, and participants' trust in the local NGO were identified as potential barriers for obtaining genuine informed consent. Conclusions Researchers should evaluate the effectiveness of consent processes in providing appropriate information in a comprehensible manner and in supporting voluntary decision-making on a study-by-study basis

The role of the A C395 IFNGR1 mutation in determining susceptibility to intracellular infection in Malta

Background: The first human mycobacterial susceptibility gene was identified amongst four children on the island of Malta in 1995. All affected children were homozygous for a nonsense mutation at position 395 of the interferon gamma receptor 1 (IFNGR1) gene, and all but one died of overwhelming mycobacterial infection. The population of Malta has high rates of infection with intracellular pathogens; leishmania, brucellosis and tuberculosis are all endemic, while leprosy, which was previously endemic, has only recently been eradicated. We hypothesised that heterozygous carriers of the IFNGR1 gene mutation, while resistant to infection with poorly pathogenic organisms, may have increased susceptibility to infection with more virulent pathogens. Methodology and Result: Screening patients with a past history of intracellular infection and healthy newborns for the presence of the IFNGR1 A->C395 mutation, using sequence specific primer PCR, did not identify any carriers of the mutation. Conclusion: These results suggest that the IFNGR1 mutation is unlikely to be of public health significance on Malta.peer-reviewe

Prediction of HLA class II alleles using SNPs in an African population

BACKGROUND: Despite the importance of the human leukocyte antigen (HLA) gene locus in research and clinical practice, direct HLA typing is laborious and expensive. Furthermore, the analysis requires specialized software and expertise which are unavailable in most developing country settings. Recently, in silico methods have been developed for predicting HLA alleles using single nucleotide polymorphisms (SNPs). However, the utility of these methods in African populations has not been systematically evaluated. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we investigate prediction of HLA class II (HLA-DRB1 and HLA-DQB1) alleles using SNPs in the Wolaita population, southern Ethiopia. The subjects comprised 297 Ethiopians with genome-wide SNP data, of whom 188 had also been HLA typed and were used for training and testing the model. The 109 subjects with SNP data alone were used for empirical prediction using the multi-allelic gene prediction method. We evaluated accuracy of the prediction, agreement between predicted and HLA typed alleles, and discriminative ability of the prediction probability supplied by the model. We found that the model predicted intermediate (two-digit) resolution for HLA-DRB1 and HLA-DQB1 alleles at accuracy levels of 96% and 87%, respectively. All measures of performance showed high accuracy and reliability for prediction. The distribution of the majority of HLA alleles in the study was similar to that previously reported for the Oromo and Amhara ethnic groups from Ethiopia. CONCLUSIONS/SIGNIFICANCE: We demonstrate that HLA class II alleles can be predicted from SNP genotype data with a high level of accuracy at intermediate (two-digit) resolution in an African population. This finding offers new opportunities for HLA studies of disease epidemiology and population genetics in developing countrie

Modelling environmental factors correlated with podoconiosis: a geospatial study of non-filarial elephantiasis

Introduction The precise trigger of podoconiosis — endemic non-filarial elephantiasis of the lower legs — is unknown. Epidemiological and ecological studies have linked the disease with barefoot exposure to red clay soils of volcanic origin. Histopathology investigations have demonstrated that silicon, aluminium, magnesium and iron are present in the lower limb lymph node macrophages of both patients and non-patients living barefoot on these clays. We studied the spatial variation (variations across an area) in podoconiosis prevalence and the associated environmental factors with a goal to better understanding the pathogenesis of podoconiosis. Methods Fieldwork was conducted from June 2011 to February 2013 in 12 kebeles (administrative units) in northern Ethiopia. Geo-located prevalence data and soil samples were collected and analysed along with secondary geological, topographic, meteorological and elevation data. Soil data were analysed for chemical composition, mineralogy and particle size, and were interpolated to provide spatially continuous information. Exploratory, spatial, univariate and multivariate regression analyses of podoconiosis prevalence were conducted in relation to primary (soil) and secondary (elevation, precipitation, and geology) covariates. Results Podoconiosis distribution showed spatial correlation with variation in elevation and precipitation. Exploratory analysis identified that phyllosilicate minerals, particularly clay (smectite and kaolinite) and mica groups, quartz (crystalline silica), iron oxide, and zirconium were associated with podoconiosis prevalence. The final multivariate model showed that the quantities of smectite (RR = 2.76, 95% CI: 1.35, 5.73; p = 0.007), quartz (RR = 1.16, 95% CI: 1.06, 1.26; p = 0.001) and mica (RR = 1.09, 95% CI: 1.05, 1.13; p < 0.001) in the soil had positive associations with podoconiosis prevalence. Conclusions More quantities of smectite, mica and quartz within the soil were associated with podoconiosis prevalence. Together with previous work indicating that these minerals may influence water absorption, potentiate infection and be toxic to human cells, the present findings suggest that these particles may play a role in the pathogenesis of podoconiosis and acute adenolymphangitis, a common cause of morbidity in podoconiosis patients