Investigation of filarial associated immune modulation and effects on HIV susceptibility

Despite coordinated global activities supported by the WHO, lymphatic filariasis remains a large public health problem in many parts of the world. One important reason for this is the lack of treatment options available for the ~40 million peo-ple who suffer from chronic pathology (lymphedema or hydrocele), most of whom live in already poor communities in sub-Saharan Africa. Lymphatic filaria-sis is typically found in rural, hard to reach areas which can make it difficult for researchers to preserve samples from infected individuals. Because of this, we developed a novel whole blood flow cytometry method to minimize the amount of blood required (over the standard method), which maintains the integrity of ex-tracellular markers, and eliminates the need for a -80°C freezer. This method was thoroughly tested and implemented in ongoing clinical trials in rural Ghana-ian and Tanzanian field laboratories; our aim was to investigate immunological alterations in patients with lymphatic filariasis pathology as compared to those asymptomatically infected and control individuals, particularly regarding CD4+ T cell activation and CD8+ T cell exhaustion. We saw an increase of immune acti-vation – defined by HLADR/CD38 expression on CD4+ T cells – in lymphedema individuals as compared to filarial infected individuals without pathology as well as uninfected individuals from the same area. In addition, for the first time, we observed an increase of activation corresponding to lymphedema stage in sam-ples from both Tanzania and Ghana. We next investigated the role of exhausted CD8+ T cells in W. bancrofti infections by looking at a number of markers asso-ciated with exhaustion on both whole blood and PBMC samples since cells would be expected to proceed through activation to exhaustion with constant antigen exposure. Interestingly, we found that the cells from lymphedema pa-tients displayed altered expression on exhausted CD8+ T cell subsets when compared to uninfected controls and asymptomatic W. bancrofti infections. Also notable is that the asymptomatic W. bancrofti-infected individuals showed com-parable results to the control samples in all of the markers examined. This thesis enhances the knowledge on the immune response of individuals to both asymp-tomatic W. bancrofti infections as well as the chronic pathology disease state through the development of a novel field method and flow cytometric analysis. This knowledge might help to prevent debilitating manifestations in filarial infect-ed individuals in the future

Distinct Immune Profiles of Exhausted Effector and Memory CD8+ T Cells in Individuals With Filarial Lymphedema

CD8+ T cells are crucial for the clearance of viral infections, and current research begins to highlight their importance in parasitic diseases too. In-depth research about characteristics of CD8+ T-cell subsets and exhaustion remains uncertain, especially during filariasis, a chronic helminth infection. Lymphatic filariasis, elicited by Wuchereria bancrofti, remains a serious health problem in endemic areas in Ghana, especially in those suffering from morbidity due to lymphedema (LE). In this observational study, the characteristics and profiles of CD8+ T cells were compared between asymptomatic Wuchereria bancrofti-infected individuals, uninfected endemic normals, and those with LE (grades 2–6). Focusing on exhausted memory (CD8+exmem: CD8+ T-betdimEomeshi) and effector (CD8+exeff: CD8+T-bethiEomesdim) CD8+ T-cell subsets, advanced flow cytometry revealed that LE individuals presented reduced frequencies of IFN-γ+CD8+exmem T cells expressing Tim-3 or LAG-3 which negatively correlated to the presence of LE. Moreover, the LE cohort further showed significantly higher frequencies of IL-10+CD8+exeff T cells expressing either Tim-3, LAG-3, CD39, KLRG-1, or PD-1, all associated markers of exhaustion, and that these frequencies positively correlated with the presence of LE. In summary, this study shows that distinct exhausted CD8+ T-cell subsets are prominent in individuals suffering from LE, suggesting that enhanced inflammation and constant immune activation might drive exhaustion of CD8+ T cells. Since T-cell exhaustion is known to be associated with insufficient control of persisting antigen, the data presented here reveals that these CD8+ T-cell exhaustion patterns in filarial LE should be taken into consideration for prevention and control management of LE

Foundations of character: methodological aspects of a study of character development in three- to six-year-old children with a focus on sharing behaviours

This article focuses on methodological issues arising in a study of character development, using illustrations of ‘sharing behaviours.’ Based primarily in six early years settings in southeast England the research records naturalistic observations of peer interactions for 55 children aged three to six years. Applying grounded theory to the processes of observing, analysing and interpreting evidence required a cautious and collectively reflective approach. The methodology sought to moderate the influence of the researchers' prior knowledge of ‘grand theories’ of moral development and assumptions about relevance to the observation records. The study's originality lay in the exploration of moral development without reference to any particular grand theory as an explanatory framework; and in the reluctance to be drawn to potentially simplistic rationalisations of the children's intentions on the basis of their observed behaviours. Exploring young children's subjective experiences, this research provides insights into the intricacy of this process, steering away from ‘neat’ findings and attempting to reflect the sophistication of the children's skilful and sometimes surprising negotiations of moral dilemmas. Implications for practice relate to the complexities involved in attempts to unravel the developing moral characters of young children and the practice through which this may be nurtured

Risk of second primary cancer in men with breast cancer

INTRODUCTION: A retrospective registry-based cohort study was conducted to examine the risk of second primary cancer following the occurrence of breast cancer in males. METHODS: Data obtained from the California Cancer Registry in the period 1988 to 2003 included 1,926 men aged 85 years and younger diagnosed with a first primary breast cancer. Person-year analysis was applied to determine the risk of second primary cancers after the occurrence of a first primary breast cancer. The effects of age, race, and time since the first breast cancer diagnosis were assessed. RESULTS: Of the 1,926 male breast cancer cases, 221 (11.5%) developed a second primary cancer. Men with first incidence of breast cancer have a significantly higher risk of second cancer (standardized incidence ratio (SIR) = 1.16, 95% confidence interval (CI) = 1.01–1.32). The risk of a second site-specific cancer is elevated for breast cancer (SIR = 52.12, 95% CI = 31.83–80.49), cutaneous melanoma (SIR = 2.98, 95% CI = 1.63–5.00) and stomach cancer (SIR = 2.11, 95% CI = 1.01–3.88). There is a general tendency towards higher risks of second malignancies among younger men compared to older men and the risk increased with the passage of time. CONCLUSION: Male breast cancer patients should be monitored carefully for the occurrence of second primary cancers, especially a second primary breast cancer

DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures

Background: The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances.Results: We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value -10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations.Conclusion: Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.</p

Mild phenotype in an adult male with X-linked adrenoleukodystrophy – case report

Key Clinical Message X-linked adrenoleukodystrophy may present with a deceptively mild phenotype, even in adult males. Tight collaboration between clinicians, geneticists, biochemists, and other specialists is increasingly required for clarification of diagnosis in cases with atypical presentation

Milde phenotype in an adult male With X-linked adrenoleukodystrophy

Key Clinical Message:X-linked adrenoleukodystrophy may present with a deceptively mild phenotype, even in adult males. Tight collaboration between clinicians, geneticists, biochemists, and other specialists is increasingly required for clarification of diagnosis in cases with atypical presentation

Implementing The Comandos Architecture

This paper describes the three different implementations of the COMANDOS kernel being undertaken within the current project. The differing goals of each implementation as well as the particular hardware environment targeted are summarised. The different approaches being followed in each implementation are overviewed, followed by a preliminary presentation of the results of each implementation to date. 1 1 INTRODUCTION The fundamental goal of the three year ESPRIT project 834, COMANDOS, is to identify and construct an integrated platform for programming distributed applications which may manipulate persistent - i.e. long-lived - data. The intention is to eventually provide such a platform running on a range of machines from different vendors. Although the main intended application domain is office systems, we expect that the COMANDOS platform may be valuable as a basis for integrated information systems in such application domains as CAD, software factories and manufacturing administration. COMANDOS itself does not provide end-user applications, but rather a basis for the development of these. The essential features of the COMANDOS platform - the &quot;virtual machine&quot; interface - are:- - support for distributed and concurrent processing in a loosely coupled LAN and WAN environment; - an extensible and distributed data management system, which can be tailored to specific application areas; - tools to monitor and administer the distributed environment. Further aspects of the project include tools to aid in office systems design and maintenance, particularly in the light of operational experience [Horn88], and interworking with existing data management systems constructed independently of the COMANDOS model [COMANDOS88c]. The programming environment provided by COMANDOS is in..

Antiplatelet therapy does not influence outcome or host response biomarkers during sepsis: a propensity-matched analysis

Introduction Sepsis is a life-threatening condition, during which triggering of inflammatory and coagulation cascades, together with endothelial damage, invariably leads to activation of platelets. Although platelets are essential components of primary hemostasis, uncontrolled platelet activation during sepsis may contribute to organ failure. The aim of this study was to investigate whether chronic antiplatelet therapy impacts on the presentation and outcome of, and the host response to, sepsis. Methods We performed a prospective observational study in patients admitted with sepsis to the mixed ICUs of two hospitals in the Netherlands between January 2011 and July 2013. Cox proportional hazards regression was used to estimate the effect of antiplatelet therapy on mortality. To account for indication bias, a propensity score was constructed, and used to match antiplatelet therapy users to nonusers. Plasma biomarker levels, providing insight into hallmark host responses to sepsis, including activation of endothelial cells and the cytokine network, were determined during the first 4 days after ICU admission. Results Of 1,070 sepsis patients, 297 (27.8%) were on antiplatelet therapy, including acetylsalicylic acid, clopidogrel and dipyridamole, prior to ICU admission. Antiplatelet users and nonusers differed significantly with regard to several baseline characteristics, such as age, gender and cardiovascular disease. Antiplatelet therapy was not related to sepsis severity at presentation, the primary source of infection, causative pathogens, the development of organ failure or shock during ICU stay, or mortality up to 90 days after admission, in either the unmatched or propensity-matched analyses. Antiplatelet therapy did also not modify plasma concentrations of biomarkers. Conclusion Pre-existing antiplatelet therapy does not influence clinical disease severity at presentation, nor the host response or outcome following sepsis