Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an <i>in vitro</i> model of CNS tuberculosis

Central nervous system tuberculosis (CNS TB) has a high mortality and morbidity associated with severe inflammation. The blood-brain barrier (BBB) protects the brain from inflammation but the mechanisms causing BBB damage in CNS TB are uncharacterized. We demonstrate that Mycobacterium tuberculosis (Mtb) causes breakdown of type IV collagen and decreases tight junction protein (TJP) expression in a co-culture model of the BBB. This increases permeability, surface expression of endothelial adhesion molecules and leukocyte transmigration. TJP breakdown was driven by Mtb-dependent secretion of matrix metalloproteinase (MMP)-9. TJP expression is regulated by Sonic hedgehog (Shh) through transcription factor Gli-1. In our model, the hedgehog pathway was downregulated by Mtb-stimulation, but Shh levels in astrocytes were unchanged. However, Scube2, a glycoprotein regulating astrocyte Shh release was decreased, inhibiting Shh delivery to brain endothelial cells. Activation of the hedgehog pathway by addition of a Smoothened agonist or by addition of exogenous Shh, or neutralizing MMP-9 activity, decreased permeability and increased TJP expression in the Mtb-stimulated BBB co-cultures. In summary, the BBB is disrupted by downregulation of the Shh pathway and breakdown of TJPs, secondary to increased MMP-9 activity which suggests that these pathways are potential novel targets for host directed therapy in CNS TB

Mortality following Campylobacter infection: a registry-based linkage study

BACKGROUND: Campylobacteriosis is one of the most commonly identified causes of bacterial diarrheal disease and a common cause of gastroenteritis in travellers from developed nations. Despite the widespread occurrence, there is little information on Campylobacter mortality. METHODS: Mortality among a cohort of Campylobacter cases were compared with the general population 0–1, 1–3, 3–12 and more than 12 month after the onset of the illness. The cases were sub-grouped according to if they had been infected domestically or abroad. RESULTS: The standardized mortality ratio for cases infected domestically was 2.9 (95% CI: 1.9–4.0) within the first month following the illness. The risk then gradually diminished and approached 1.0 after one year or more have passed since the illness. This initial excess risk was not attributable to any particular age group (such as the oldest). In contrast, for those infected abroad, a lower standardized mortality ratio 0.3 (95% CI: 0.04–0.8) was shown for the first month after diagnosis compared to what would be expected in the general population. CONCLUSION: Infection with Campylobacter is associated with an increased short-term risk of death among those who were infected domestically. On the contrary, for those infected abroad a lower than expected risk of death was evident. We suggest that the explanation behind this is a "healthy traveler effect" among imported cases, and effects of a more frail than average population among domestic cases

Political leadership and the politics of performance:France, Syria and the chemical weapons crisis of 2013

This article draws upon developments in UK research on political rhetoric and political performance in order to examine the incident in 2013 when French President François Hollande committed French forces to a US-led punitive strike against Syria, after the use of chemical weapons in a Damascus suburb on 21 August. The US-led retaliation did not take place. This article analyses Hollande's declaration on 27 July and his TV appearance on 15 September. His rhetoric and style are best understood as generic to the nature of the presidential office of the Fifth Republic. The article concludes by appraising how analysis of the French case contributes to the developing literature on rhetoric, celebrity and performance

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

High-quality habitat and facilitation ameliorate competitive effects of prior residents on new settlers

Many species disperse during their lifetime. Two factors that can affect the performance of individuals following dispersal are the presence of conspecifics and intrinsic habitat quality at the settlement site. Detecting the influence of these factors can be difficult for at least two reasons: (1) the outcomes of interactions with conspecifics are often variable including both competition and facilitation, and (2) selection of high quality habitats often leads to positive covariance between habitat quality and density. In this study, I investigate positive and negative effects of resident blue streak cleaner wrasse (Labroides dimidiatus) on the growth and survival of recently settled conspecifics while accounting for habitat quality. Juvenile L. dimidiatus settle near adult conspecifics, but likely have to compete with resident adults for access to food. However, field experiments indicate that settlers have access to more resources at occupied sites, and as a result, grow faster despite evidence for competition with residents. This result is a direct consequence of two factors: (1) resident conspecifics facilitate settlers by attracting client fish, and (2) resident conspecifics are strongly associated with high quality habitat. These results highlight the need to simultaneously consider habitat quality and competitive and facilitative interactions between conspecifics when making inferences about ecological processes from spatial patterns of individual performance

The role of dendritic cells in the immunopathogenesis of psoriasis

Psoriasis vulgaris is a chronic inflammatory skin disease that is marked by a complex interplay of dendritic cells (DCs), T-cells, cytokines, and downstream transcription factors as part of a self-sustaining type 1 cytokine network. As integral players of the immune system, DCs represent antigen-presenting cells that are crucial for efficient activation of T-cells and B-cells. DCs have also been linked to distinct chronic inflammatory conditions, including psoriasis. In the setting of psoriasis therapy, DC/T cell interactions serve as a potential target for biologic response modifiers. Here we describe the major DC subsets as well as the immunologic involvement of DCs within the context of psoriatic lesions

Dietary advice for muscularity, leanness and weight control in Men's Health magazine: a content analysis

Background: The dietary content of advice in men’s lifestyle magazines has not been closely scrutinised. Methods: We carried out an analysis of such content in all 2009 issues (n = 11) of Men’s Health (MH) focusing on muscularity, leanness and weight control. Results: Promotion of a mesomorphic body image underpinned advice to affect muscle building and control weight. Diet advice was underpinned by a strong pseudo-scientific discourse, with citation of expert sources widely used to legitimise the information. Frequently multiple dietary components were advocated within one article e.g. fat, omega-3 fatty acids, thiamine, zinc and high-glycaemic index foods. Furthermore advice would cover numerous nutritional effects, e.g. strengthening bones, reducing stress and boosting testosterone, with little contextualisation. The emphasis on attainment of a mesomorphic body image permitted promotion of slimming diets. Advice to increase calorie and protein intake to augment muscle mass was frequent (183 and 262 references, respectively). Such an anabolic diet was advised in various ways, including consumption of traditional protein foods (217 references) and sports foods (107 references), thereby replicating muscle magazines’ support for nutritional supplements. Although advice to increase consumption of red meat was common (52 references), fish and non-flesh sources of protein (eggs, nuts & pulses, and soy products) together exceeded red meat in number of recommendations (206 references). Advice widely asserted micronutrients and phytochemicals from plant food (161 references) as being important in muscle building. This emphasis diverges from stereotypical gender-based food consumption patterns. Dietary advice for control of body weight largely replicated that of muscularity, with strong endorsement to consume fruits and vegetables (59 references), diets rich in nuts and pulses and fish (66 references), as well as specific micronutrients and phytochemicals (62 references). Notably there was emphasis on fat-burning, good fats and consumption of single foods, with relatively little mention of dietary restriction. Conclusions: Despite the widespread use of scientific information to endorse dietary advice, the content, format and scientific basis of dietary content of MH leaves much to be desired. The dietary advice as provided may not be conducive to public health

Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption

To prevent dehydration, terrestrial animals and humans have developed a sensitive and versatile system to maintain their water homeostasis. In states of hypernatremia or hypovolemia, the antidiuretic hormone vasopressin (AVP) is released from the pituitary and binds its type-2 receptor in renal principal cells. This triggers an intracellular cAMP signaling cascade, which phosphorylates aquaporin-2 (AQP2) and targets the channel to the apical plasma membrane. Driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels. When water homeostasis is restored, AVP levels decline, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again. The action of AVP is counterbalanced by several hormones like prostaglandin E2, bradykinin, dopamine, endothelin-1, acetylcholine, epidermal growth factor, and purines. Moreover, AQP2 is strongly involved in the pathophysiology of disorders characterized by renal concentrating defects, as well as conditions associated with severe water retention. This review focuses on our recent increase in understanding of the molecular mechanisms underlying AVP-regulated renal water transport in both health and disease