The role of platelets in the pathogenesis of and immunity to helminth infections

Background: Platelets are small, anucleate cells which circulate in blood and are often the first to respond to tissue damage and vascular inflammation caused by pathogens. Here they not only maintain tissue integrity and prevent bleeding, but also initiate and regulate a vast variety of immunologic responses. Little is known on the role of platelets in helminth infections, despite our understanding that many helminth species cause significant vascular pathology as they transfer from the circulatory system to diverse tissues as part of their life cycles. Based on previous studies showing tight association between platelets and innate immune responses during infection with other pathogens, we hypothesized that platelets significantly contribute toward acute (vascular) immunity to helminth infection. Objectives: This project aimed to investigate the role of platelets in regulating acute innate immune responses following infection with the murine gastro-intestinal nematode N. brasiliensis (Nb), commonly used to model human helminthiases. Specifically, it aimed to characterized plateletregulated responses involved in acute innate immunity during the pulmonary stage of infection, in which larvae exit the pulmonary vasculature and invade host lung tissue. Methods: C57BL/6mice were infected with 500 L3 Nb larvae, and the association of platelets with acute innate immune responses in the circulation and the lung were established by flow cytometry and immunohistochemistry. In further experiments, mice were depleted of their platelets using antibodies prior to infection with Nb and the effect of this on pulmonary pathology and innate immune responses was inferred from flow cytometric and histologic analyses of pulmonary tissues. Lastly, antibodies were used to interfere with platelet receptors during Nb infection to gain mechanistic insight into platelet regulation of neutrophil responses. Results: Infection with N. brasiliensis was associated with significant changes in the activation of platelets, their localisation into lung tissue and their interaction with innate immune cells. Additionally, platelet -immune cell interaction was associated with changes in the expression of factors known to play a role in driving the early immune response to Nb, including IFN-γ and RELMα. Furthermore, mice depleted of their platelets prior to infection had significantly enhanced pulmonary pathology and rapidly succumbed to infection. This was associated with significant changes in neutrophil responses, and depletion of neutrophils together with platelets significantly protected against enhanced pathology. Finally, direct and indirect targeting of the platelet receptors CD62P and CLEC-2 did not result in significantly enhanced pulmonary pathology but was associated with altered platelet and neutrophil responses. Conclusion: Herein, we have provided evidence that platelets tightly associate with protective host responses during acute N. brasiliensis infection and that their absence correlates with a dysregulated neutrophil response and enhanced helminth – associated pulmonary pathology. These data therefore collectively show that platelets play notable roles in the acute innate immune response to N. brasiliensis and that future investigations into the immunological functioning of platelets during helminth infection are warranted

Targeting the menin-MLL-LEDGF Interaction with Small Molecule Inhibitors.

Mixed Lineage Leukemia 1 (MLL) is a large multi-domain protein (430 kDa) encoded by the MLL gene that catalyzes the methylation of histone H3 lysine 4 (H3K4). Chromosomal translocations of the Mixed Lineage Leukemia (MLL) gene result in acute myeloid and lymphoblastic leukemias. MLL mediated leukemia is present in about 10% of adult acute leukemia and up to 70% of infant leukemias. Patients with MLL leukemia do not respond well to conventional treatment methods; therefore, have very poor prognosis with only about a 35% overall 5-year survival rate and high risk of relapse. This demonstrates the urgent need for novel targeted therapeutics to treat these leukemias. Chromosomal translocation of the MLL gene with one of over 60 partner genes generates an oncogenic chimeric fusion protein. MLL fusion proteins lead to enhanced cell proliferation, up-regulation of Hoxa9 and Meis1 genes and block hematopoietic differentiation, ultimately leading to acute leukemia. The oncogenic function of MLL fusion proteins is reliant on the interaction with menin and with Lens Epithelium Derived Growth Factor (LEDGF). Menin functions as a scaffolding protein and interacts with wild type (WT) MLL or MLL fusion proteins which are localized to target genes through association with LEDGF. Formation of the menin-MLL-LEDGF ternary complex is critical for MLL associated gene regulation and leukemogenic transformation. Therefore, inhibition of the menin-MLL interaction should abrogate the development and progression of MLL leukemia. Our laboratory was the first to report small molecule inhibitors of the menin-MLL interaction. We have identified two classes of reversible menin-MLL inhibitors and rationally designed a new class of covalent menin-MLL inhibitors. Using high resolution crystal structures of menin in complex with inhibitors we applied structure-based design to further optimize inhibitors of the menin-MLL interaction. We performed extensive characterization and optimization of potency, solubility and pharmacokinetic properties of these compounds. These efforts led to the development of compounds suitable for in vivo analysis and demonstrated significant survival benefit in murine models of MLL leukemias. Overall, we have demonstrated that menin-MLL inhibitors may offer a novel therapeutic strategy for MLL leukemia patients and have developed a promising lead scaffold for clinical optimization.PHDMolecular & Cellular PathologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/135906/1/pollojon_1.pd

Differential effects of NGF, FGF, EGF, cAMP, and dexamethasone on neurite outgrowth and sodium channel expression in PC12 cells

PC12 cells are a pheochromocytoma cell line that can be made to differentiate into sympatheticlike neurons by nerve growth factor (NGF). An essential component of the NGF-induced differentiation is the development of action potentials and sodium channels. Using whole-cell clamp we have confirmed that NGF produces a 5- to 6-fold increase in sodium channel density. The sodium channels induced by NGF are not different from those in cells not treated with NGF and are similar to those in other cell types. Basic fibroblast growth factor (FGF), another growth factor that causes PC12 cells to differentiate into sympathetic-like neurons, also produces a 5- to 6-fold increase in sodium current density with channels indistinguishable from those in PC12 cells treated and not treated with NGF. Basic FGF produces the same or somewhat larger increase in sodium channel density but much less neurite outgrowth. In contrast, epidermal growth factor does not produce neurite outgrowth but induces a small, reproducible increase in sodium channel density. Cyclic AMP produces spike-like processes but not neurites and results in a decrease in sodium current and sodium current density. Dexamethasone, a synthetic glucocorticoid, inhibits the increase in sodium current and sodium current density but does not antagonize the neurite outgrowth induced by NGF. Thus, although the increase in sodium channel expression induced by NGF and basic FGF parallels the changes in morphology that lead to neurite outgrowth, it clearly does not depend on them. The results show that different aspects of neuronal differentiation might be independently regulated by the microenvironment

Shakespeare et le Théâtre de la Cruauté d’Antonin Artaud

Synthèse inédite de la fête populaire, du drame religieux médiéval et de la tragédie sénéquienne, le théâtre élisabéthain se présente comme l’ancêtre direct du Théâtre de la Cruauté. Antonin Artaud s’y réfère plus souvent qu’à aucune autre période de l’histoire dramatique. Or, sur les vingt pièces élisabéthaines qu’il évoque au cours de son oeuvre, treize sont de Shakespeare. Macbeth prend un relief particulier du fait que cette tragédie est la seule dans le corpus shakespearien dont Artaud projette la mise en scène. En outre, Artaud fait une « lecture-jouée » de Richard II en vue de trouver des commanditaires au même moment où il termine une monographie sur la vie de l’empereur romain Héliogabale. Il s’agit donc de déterminer en quoi ces deux drames participent d’un mythique théâtre de la cruauté qu’Artaud s’applique à ressusciter sous de nouvelles formes.Stemming from popular carnaval, Medieval religious drama and Senecan tragedy, the Elizabethan theatrical tradition appears as a direct ancestor of the Théâtre de la Cruauté. Antonin Artaud refers to Shakespeare more often than any other playwright, mentioning in all thirteen of his plays. He intended to stage Macbeth after Les Cenci, and he gave a one-man performance of Richard II in an attempt to raise funds whilst finishing his monography on Heliogabalus, the anarchic Roman emperor. Why did Artaud choose these two plays in particular? In what way do they meet the requirements of his Theatre of Cruelty

Goal adjustment by people living with long-term conditions: a scoping review of literature published from January 2007 to June 2018

Long-term health conditions can limit achievement of personal goals. We aimed to map and synthesize definitions of goal adjustment, theoretical underpinnings, associations with recovery and supportive interventions for adults with long-term conditions. We searched multiple databases (January 2007–June 2018) and identified peer-reviewed research relating to goal adjustment. Data were charted, mapped and synthesized using content analysis and descriptive summaries. Two stakeholder consultations informed the review. Ninety-one articles were included. A range of long-term conditions were represented including cancer (22%), stroke (12%) and mixed neurological conditions (8%). Goal adjustment was one available option when faced with unattainable goals; other options were goal disengagement and goal re-engagement. Most studies were quantitative (58%), reporting mainly positive associations between goal adjustment, disengagement, reengagement and recovery. The Dual Process Model, Goal Adjustment Model and Self-Regulation Theory were most cited underpinning models/theory. Five interventions were identified; only one (self-system therapy) was evaluated in a randomized controlled trial. Our review provides original and significant insights into goal adjustment definitions, theoretical underpinnings and association with recovery. Effective interventions to support goal adjustment, disengagement and reengagement are lacking. This research-practice gap warrants attention to ensure people with long-term conditions are optimally supported when facing unattainable goals

Why do some CEOs become celebrities while others don’t?

Celebrity benefits chief executives personally: increased pay, more opportunities to join boards, and protection from dismissal. But their firms do not enjoy similarly positive outcomes. These CEOs often demonstrate higher levels of complacency, risk-taking, and hubris. But what leads them to attain celebrity in the first place? Jeffrey B. Lovelace, Jonathan N. Bundy, Tim Pollock, and Donald Hambrick write that a CEO’s personal attributes, a firm’s non-conforming actions, and a CEO’s use of self-promotion tactics play important roles in attracting high levels of positive media attention — with implications for individuals, firms, and society

Lower Extremity Salvage in the Setting of Bullous Pemphigoid Exacerbation: A Case Report

Bullous pemphigoid is an autoimmune blistering disease where patients suffer from painful bullae, often covering large portions of the skin and requiring management with immune-suppression. Our case report of recurring bullous pemphigoid illustrates the importance of considering immunosuppressive perioperative management in patients with a history of autoimmune blistering even when the disease has been quiescent for some time. With multidisciplinary care and immune suppressive therapies in the perioperative period, a free flap complicated by recurrent bullous pemphigoid can be salvaged

"Liberalizing" the English National Health Service: background and risks to healthcare entitlement

Resumo: A recente reforma do Serviço Nacional de Saúde (NHS) inglês por meio do Health and Social Care Act de 2012 introduziu mudanças importantes na organização, gestão e prestação de serviços públicos de saúde na Inglaterra. O objetivo deste estudo é analisar as reformas do NHS no contexto histórico de predomínio de teorias neoliberais desde 1980 e discutir o processo de "liberalização" do NHS. São identificados e analisados três momentos: (i) gradativa substituição ideológica e teórica (1979-1990) - transição da lógica profissional e sanitária para uma lógica gerencial/comercial; (ii) burocracia e mercado incipiente (1991-2004) - estruturação de burocracia voltada à administração do mercado interno e expansão de medidas pró-mercado; e (iii) abertura ao mercado, fragmentação e descontinuidade de serviços (2005-2012) - fragilização do modelo de saúde territorial e consolidação da saúde como um mercado aberto a prestadores públicos e privados. Esse processo gradual e constante de liberalização vem levando ao fechamento de serviços e à restrição do acesso, comprometendo a integralidade, a equidade e o direito universal à saúde no NHS