Immune regulation during chronic visceral leishmaniasis

Visceral leishmaniasis is a chronic parasitic disease associated with severe immune dysfunction. Treatment options are limited to relatively toxic drugs and there is no vaccine for humans available. Hence, there is an urgent need to better understand immune responses following infection with Leishmania species by studying animal models of disease and clinical samples from patients. Here, we review recent discoveries in these areas and highlight shortcomings in our knowledge that need to be addressed if better treatment options are to be developed and effective vaccines designed.

Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P combined = 2.76 × 10 -17 and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species. © 2013 Nature America, Inc. All rights reserved.

Development of immunotherapies and vaccines against visceral leishmaiasis

Visceral leishmaniasis (VL) is a chronic parasitic disease prevalent in tropical and sub- tropical countries. This study focused on the development of immune-based therapy with immune checkpoint inhibitors and/or activators, as well as cytokines as a way to treat VL either alone or in combination with conventional drugs. Since many chronic infectious diseases share mechanisms of immune suppression, these findings have broader implications for other infectious diseases, such as HIV, tuberculosis and malaria.

Tissue requirements for establishing long-term CD4+ T cell-mediated immunity following Leishmania donovani infection

Organ-specific immunity is a feature of many infectious diseases, including visceral leishmaniasis caused by Leishmania donovani. Experimental visceral leishmaniasis in genetically susceptible mice is characterized by an acute, resolving infection in the liver and chronic infection in the spleen. CD4+ T cell responses are critical for the establishment and maintenance of hepatic immunity in this disease model, but their role in chronically infected spleens remains unclear. In this study, we show that dendritic cells are critical for CD4+ T cell activation and expansion in all tissue sites examined. We found that FTY720-mediated blockade of T cell trafficking early in infection prevented Ag-specific CD4+ T cells from appearing in lymph nodes, but not the spleen and liver, suggesting that early CD4+ T cell priming does not occur in liver-draining lymph nodes. Extended treatment with FTY720 over the first month of infection increased parasite burdens, although this associated with blockade of lymphocyte egress from secondary lymphoid tissue, as well as with more generalized splenic lymphopenia. Importantly, we demonstrate that CD4+ T cells are required for the establishment and maintenance of antiparasitic immunity in the liver, as well as for immune surveillance and suppression of parasite outgrowth in chronically infected spleens. Finally, although early CD4+ T cell priming appeared to occur most effectively in the spleen, we unexpectedly revealed that protective CD4+ T cell-mediated hepatic immunity could be generated in the complete absence of all secondary lymphoid tissues.

A methodological approach to visceral hedonic rhetoric

One of the most important tasks as an industrial designer is to evoke specific affective responses via the creation of their designed products. This paper describes an investigation of visceral hedonic rhetoric through the study of interactive products. This research lays the foundation for this work by discussing the scope, significance and limitations of currently available research in the areas of visceral design, consumer hedonics and product rhetoric. Understanding why consumers respond to certain visceral hedonic rhetoric stimulus and what those stimuli are will provide further understanding into the field of emotional design. The study examines visceral hedonic responses given by consumers to three interactive products including mobile telephones, USB memory sticks and MP3 players. The methods used in this study will be discussed in further detail in this paper.

Visceral hedonic rhetoric : exploring the design of interactive products

Blurb: This empirical study analysed consumer emotional responses towards interactive products, specifically looking at properties that persuasively induce the pursuit of pleasure at an instinctual level of cognition, now known as ‘visceral hedonic rhetoric'. By analysing three different types of interactive products results found hierarchical and inter-relatable attributes with the potential to provide a positive consumer-product relationship that is more meaningful, less disposable and more sustainable in the future.

Visceral hedonic rhetoric

Emotional responses can incite and entice consumers to select a particular product from a row of similar items and thus have a considerable impact on purchase decisions. Consequently, more and more companies are challenging designers to address the emotional impact of their work and to design for emotion and consumerproduct relationships. Furthermore, the creation of emotional attachment to one’s possessions is one way of approaching a sustainable consumer-product relationship. The aim of this research is to gain a deeper understanding of the instantaneous emotional attachment that consumers form with products and its subsequent implications for product development. The foci of the study are visceral design, consumer hedonics and product rhetoric. Studied in a conglomerate they become an area of new investigation: visceral hedonic rhetoric. In this context, the term “visceral hedonic rhetoric” is defined as the properties of a product that persuasively elicit the pursuit of pleasure at an instinctual level of cognition. This study explores visceral hedonic rhetoric evident in the design of interactive products and resides within the context of emotional design research. It employs an empirical approach to understand how consumers respond hedonically on a visceral level to rhetoric in products. Specifically, it examines visceral hedonic responses given by thirty participants to the stimuli of six mobile telephones, six Mp3 players and six USB memory flash drives. The study findings demonstrate a hierarchy of visceral hedonic rhetoric evident in interactive products. This hierarchy of visceral hedonic attributes include: colour, size, shape, intrigue, material, perceived usability, portability, perceived function, novelty, analogy, brand, quality, texture and gender. However, it is the interrelationships between these visceral hedonic attributes that are the most significant findings of this research. Certain associations were revealed between product attribute combinations and consumer perception. The most predominant of these were: gender bias associated with colour selection; the creation of intrigue through a vibrant attention-grabbing colour; perceived ease of use and function; product confidence as a result of brand familiarity and perceived usability; analogous association through familiarity with similar objects and shapes; and the association of longevity with quality, novelty or recent technology. A significant outcome of the research is the distillation of visceral hedonic rhetoric design principles, and a tool to assist designers in harnessing the full potential of visceral hedonic rhetoric. This study contributes to the identification of the emerging research field of visceral hedonic rhetoric. Application of this study’s findings has the potential to provide a hedonic consumer-product relationship that is more meaningful, less disposable and more sustainable. This theory of visceral hedonic rhetoric is not only a significant contribution to design knowledge but is also generally transferable to other research domains, as later suggested in future research avenues.

Hunger

Poet's statement: My father died of pancreatic cancer a few years ago, and since then other family members and friends have developed cancer. Some have recovered, perhaps temporarily, while for others the prospect is one of inevitable decline, raising questions about when the point is reached where death is preferable to life. This poem expresses the ambiguity of visceral urges which could be towards either continued life or a relieving death.

Inactivation of the Huntington's disease gene (Hdh) impairs anterior streak formation and early patterning of the mouse embryo

Background Huntingtin, the HD gene encoded protein mutated by polyglutamine expansion in Huntington's disease, is required in extraembryonic tissues for proper gastrulation, implicating its activities in nutrition or patterning of the developing embryo. To test these possibilities, we have used whole mount in situ hybridization to examine embryonic patterning and morphogenesis in homozygous Hdhex4/5 huntingtin deficient embryos. Results In the absence of huntingtin, expression of nutritive genes appears normal but E7.0–7.5 embryos exhibit a unique combination of patterning defects. Notable are a shortened primitive streak, absence of a proper node and diminished production of anterior streak derivatives. Reduced Wnt3a, Tbx6 and Dll1 expression signify decreased paraxial mesoderm and reduced Otx2 expression and lack of headfolds denote a failure of head development. In addition, genes initially broadly expressed are not properly restricted to the posterior, as evidenced by the ectopic expression of Nodal, Fgf8 and Gsc in the epiblast and T (Brachyury) and Evx1 in proximal mesoderm derivatives. Despite impaired posterior restriction and anterior streak deficits, overall anterior/posterior polarity is established. A single primitive streak forms and marker expression shows that the anterior epiblast and anterior visceral endoderm (AVE) are specified. Conclusion Huntingtin is essential in the early patterning of the embryo for formation of the anterior region of the primitive streak, and for down-regulation of a subset of dynamic growth and transcription factor genes. These findings provide fundamental starting points for identifying the novel cellular and molecular activities of huntingtin in the extraembryonic tissues that govern normal anterior streak development. This knowledge may prove to be important for understanding the mechanism by which the dominant polyglutamine expansion in huntingtin determines the loss of neurons in Huntington's disease.

The iatrogenic reflex and belief that repression can coercively suppress asymmetric coercive violence : does very robust action by the government decrease functional support for insurgents?

Non-state insurgent actors are too weak to compel powerful adversaries to their will, so they use violence to coerce. A principal objective is to grow and sustain violent resistance to the point that it either militarily challenges the state, or more commonly, generates unacceptable political costs. To survive, insurgents must shift popular support away from the state and to grow they must secure it. State actor policies and actions perceived as illegitimate and oppressive by the insurgent constituency can generate these shifts. A promising insurgent strategy is to attack states in ways that lead angry publics and leaders to discount the historically established risks and take flawed but popular decisions to use repressive measures. Such decisions may be enabled by a visceral belief in the power of coercion and selective use of examples of where robust measures have indeed suppressed resistance. To avoid such counterproductive behaviours the cases of apparent 'successful repression' must be understood. This thesis tests whether robust state action is correlated with reduced support for insurgents, analyses the causal mechanisms of such shifts and examines whether such reduction is because of compulsion or coercion? The approach is founded on prior research by the RAND Corporation which analysed the 30 insurgencies most recently resolved worldwide to determine factors of counterinsurgent success. This new study first re-analyses their data at a finer resolution with new queries that investigate the relationship between repression and insurgent active support. Having determined that, in general, repression does not correlate with decreased insurgent support, this study then analyses two cases in which the data suggests repression seems likely to be reducing insurgent support: the PKK in Turkey and the insurgency against the Vietnamese-sponsored regime after their ousting of the Khmer Rouge. It applies 'structured-focused' case analysis with questions partly built from the insurgency model of Leites and Wolf, who are associated with the advocacy of US robust means in Vietnam. This is thus a test of 'most difficult' cases using a 'least likely' test model. Nevertheless, the findings refute the deterrence argument of 'iron fist' advocates. Robust approaches may physically prevent effective support of insurgents but they do not coercively deter people from being willing to actively support the insurgency.

Grandiflora : Recent Paintings by Daniel Mafe

Grandiflora: Recent Paintings by Daniel Mafe The paintings of Grandiflora are improvised around a range of different flower motifs culled from medieval textiles and botanical illustrations. Each of the paintings is constructed upon a ground of flat, palely luminous yellow occasionally supplemented by additional areas of high-keyed pastel. Pink, blue, green and mauve together with the yellow, generate a shimmering and even incandescent glow. The graphic images of the flowers with the flat colour areas are then contrasted and worked over with richly sensual, abstract gestures of paint. Within the work there is a pronounced almost rococo-esque opticality as it operates between these different visual codes of flat colour, recognizable floral forms, and gesture. These codes combine to produce a definite visceral impact on the viewer, a pronounced and tactile sense of the experience and ambiguity inherent in perceiving. This ambiguity is interestingly at odds with the apparently clean and crisp quality each painting demonstrates as an integrated whole. Indeed each piece goes on to reveal, despite the use of overt figurative quotations, a sense of the purely abstract which in its turn concretely establishes the ornamental.

Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease

Objectives In non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is intricately linked with a number of metabolic alterations. We studied substrate utilisation in NAFLD during basal, insulin-stimulated and exercise conditions, and correlated these outcomes with disease severity. Methods 20 patients with NAFLD (mean±SD body mass index (BMI) 34.1±6.7 kg/m2) and 15 healthy controls (BMI 23.4±2.7 kg/m2) were assessed. Respiratory quotient (RQ), whole-body fat (Fatox) and carbohydrate (CHOox) oxidation rates were determined by indirect calorimetry in three conditions: basal (resting and fasted), insulin-stimulated (hyperinsulinaemic–euglycaemic clamp) and exercise (cycling at an intensity to elicit maximal Fatox). Severity of disease and steatosis were determined by liver histology, hepatic Fatox from plasma β-hydroxybutyrate concentrations, aerobic fitness expressed as , and visceral adipose tissue (VAT) measured by computed tomography. Results Within the overweight/obese NAFLD cohort, basal RQ correlated positively with steatosis (r=0.57, p=0.01) and was higher (indicating smaller contribution of Fatox to energy expenditure) in patients with NAFLD activity score (NAS) ≥5 vs <5 (p=0.008). Both results were independent of VAT, % body fat and BMI. Compared with the lean control group, patients with NAFLD had lower basal whole-body Fatox (1.2±0.3 vs 1.5±0.4 mg/kgFFM/min, p=0.024) and lower basal hepatic Fatox (ie, β-hydroxybutyrate, p=0.004). During exercise, they achieved lower maximal Fatox (2.5±1.4 vs. 5.8±3.7 mg/kgFFM/min, p=0.002) and lower (p<0.001) than controls. Fatox during exercise was not associated with disease severity (p=0.79). Conclusions Overweight/obese patients with NAFLD had reduced hepatic Fatox and reduced whole-body Fatox under basal and exercise conditions. There was an inverse relationship between ability to oxidise fat in basal conditions and histological features of NAFLD including severity of steatosis and NAS

Irritable bowel syndrome : the role of gut neuroendocrine peptides

Irritable bowel syndrome (IBS) is a common chronic disorder with a prevalence ranging from 5 to 10 % of the world's population. This condition is characterised by abdominal discomfort or pain, altered bowel habits, and often bloating and abdominal distension. IBS reduces quality of life in the same degree of impairment as major chronic diseases such as congestive heart failure and diabetes and the economic burden on the health care system and society is high. Abnormalities have been reported in the neuroendocrine peptides/amines of the stomach, small- and large intestine in patients with IBS. These abnormalities would cause disturbances in digestion, gastrointestinal motility and visceral hypersensitivity, which have been reported in patients with IBS. These abnormalities seem to contribute to the symptom development and appear to play a central role in the pathogenesis of IBS. Neuroendocrine peptides/amines are potential tools in the treatment and diagnosis of IBS. In particular, the cell density of duodenal chromogranin A expressing cells appears to be a good histopathological marker for the diagnosis of IBS with high sensitivity and specificity.