Inflammatory mechanisms in focal cerebral ischaemia

Stroke is a complex pathophysiological process and the role of inflammation in its initiation and resolution has been much debated. Inflammation is now emerging as a contributor in the development of ischaemic brain damage. The use of anti -inflammatory strategies to reduce damage and improve functional outcome of stroke patients may be valuable in the treatment for a condition that currently has no effective treatment. The exact contribution of the inflammatory response and the involvement of the various components of the immune system are still under investigationIn this thesis, focal cerebral ischaemia was induced in three animal models in an attempt to investigate the contribution of the inflammatory response. The rat monofilament model of middle cerebral artery (MCA) occlusion, considered by some to be a pro- inflammatory model, was set up for the first time in Edinburgh and validated as suitable model for further investigation. Permanent and transient models were established to allow the evaluation of possible reperfusion injury. Both monofilament models were compared with the Endothelin -1 model already established and routinely in use in the laboratory. Analysis of the volume of damage and distribution of the lesion revealed no differences between the three models. However, this observation did not in itself rule out the possibility of different pathophysiological mechanisms in the three models that ultimately resulted in apparently similar sized lesions.FK506, a potent neuroprotectant widely used experimentally, exhibited different neuroprotective efficacies. In all models, FK506 significantly reduced the overall volume of both damage and oedema. The majority of the neuroprotection was observed in the cortex although striatal protection was seen in the transient rat monofilament model. The neuroprotection observed in the transient monofilament model was approximately twice that seen in the permanent model and similar to that in the Endothelin -1 model suggesting distinct pathways that lead to cell death. Data for FK506 administration in the mouse monofilament model demonstrated neuroprotection for the first time in this species was included as an interesting comparison with the rat data.In keeping with the investigation of inflammation in cerebral ischaemia, it was proposed that FK506 neuroprotection was in part mediated through modulation of the inflammatory response. The response of the microglia, the resident immune cells of the central nervous system was examined following FK506 administration. Although the drug appeared to have a noticeable effect the activation state of the microglia, the response was not consistent and difficult to quantify by histological methods. Microglial cultures were established to investigate the effect of FK506 in a less complex system. Ramified microglial cultures were established but the analysis of microglia in vitro by morphology also proved difficult and another method of assessing activation of the cells was pursued. The microglia are known to secrete noxious stimuli when activated amongst which are the pro- inflammatory cytokines. IL-1P, IL -6 and TNFa gene expression was investigated to assess microglial activation. Lipopolysaccharide treated animals and treated microglial preparations were used initially to refine the use of multiplex polymerase chain reaction (MPCR) analysis of gene products. This was extended to tissue from both monofilament models. IL -1(3, IL -6 and TNFa were detected in the cortex and striatum when measured at 3 and 24 hrs post occlusion and showed an earlier cytokine response where reperfusion occurred. It is suggested that the early cytokine response is associated with the endogenous inflammatory cells. Western analysis experiments were performed to verify the presence of the corresponding cytokine proteins with little success. The recent availability of improved cytokine antibodies enabled the examination of cytokines (IL -1f3 and TNFa) in ischaemic by enzyme linked immunosorbant assay (ELISA). No TNFa response was detected despite the presence of mRNA. IL -lß was detected at 3 and 24 hrs post -insult with greater expression at 24 hrs. It may be speculated that this increased expression at the later time is related to the peripheral inflammatory cell infiltration. There was no difference in expression levels between models and FK506 had no affect on the cytokine expression.In summary, the re- introduction of blood to ischaemic tissue appears to alter the response of the individual cells although this does not change their ultimate fate. In instances where reperfusion is established, the tissue appears to be more amenable to neuroprotection by FK506. It is suggested that this is associated with the blockade of the endogenous inflammatory mechanisms that respond acutely to an ischaemic insult

The Effects of Prolonged Job Insecurity on the Psychological Well-Being of Workers

Job insecurity has been increasing since the 1980s. While researchers have found job insecurity to be negatively associated with multiple indicators of well-being for workers and their families in cross sectional studies, less is known about the long term effects of prolonged job insecurity. Specifically, there is a need to collect measures of both insecurity and its consequences at multiple time periods. The current study followed workers for 3 1/2 years to assess the effects of chronic job insecurity on psychological distress. Results indicate that while workers reported increased feelings of security over time, there were longer term negative effects on workers\u27 depression levels. The importance of government regulations to decrease insecurity is discussed

Bringing Racial Justice to the Courtroom and Community: Race Matters for Juvenile Justice and the Charlotte Model

This article describes regional institutional organizing efforts to bring racial justice to the Charlotte courts and community through a collaborative called Race Matters for Juvenile Justice (RMJJ). The authors explain community and institutional organizing in-depth using the example of minority overrepresentation in the juvenile justice system, but recognize the pervasiveness of racial and ethnic disparities. Moreover, as the Race Matters for Juvenile Justice-Charlotte Model has gained national prominence, many jurisdictions seek to replicate the collaborative and the authors, therefore, provide RMJJ’s history as well as strategies for changing the narrative through communication and education, workforce development, data and research, community collaboration, practice change, and legislation reform

Diverse Intestinal Bacteria Contain Putative Zwitterionic Capsular Polysaccharides with Anti-inflammatory Properties

Zwitterionic capsular polysaccharides (ZPSs) are bacterial products that modulate T cells, including inducing anti-inflammatory IL-10-secreting T regulatory cells (Tregs). However, only a few diverse bacteria are known to modulate the host immune system via ZPS. We present a genomic screen for bacteria encoding ZPS molecules. We identify diverse host-associated bacteria, including commensals and pathogens with known anti-inflammatory properties, with the capacity to produce ZPSs. Human mononuclear cells stimulated with lysates from putative ZPS-producing bacteria induce significantly greater IL-10 production and higher proportions of Tregs than lysates from non-ZPS-encoding relatives or a commensal strain of Bacteroides cellulosilyticus in which a putative ZPS biosynthetic operon was genetically disrupted. Similarly, wild-type B. cellulosilyticus DSM 14838, but not a close relative lacking a putative ZPS, attenuated experimental colitis in mice. Collectively, this screen identifies bacterial strains that may use ZPSs to interact with the host as well as those with potential probiotic properties

Diverse Intestinal Bacteria Contain Putative Zwitterionic Capsular Polysaccharides with Anti-inflammatory Properties

Zwitterionic capsular polysaccharides (ZPSs) are bacterial products that modulate T cells, including inducing anti-inflammatory IL-10-secreting T regulatory cells (Tregs). However, only a few diverse bacteria are known to modulate the host immune system via ZPS. We present a genomic screen for bacteria encoding ZPS molecules. We identify diverse host-associated bacteria, including commensals and pathogens with known anti-inflammatory properties, with the capacity to produce ZPSs. Human mononuclear cells stimulated with lysates from putative ZPS-producing bacteria induce significantly greater IL-10 production and higher proportions of Tregs than lysates from non-ZPS-encoding relatives or a commensal strain of Bacteroides cellulosilyticus in which a putative ZPS biosynthetic operon was genetically disrupted. Similarly, wild-type B. cellulosilyticus DSM 14838, but not a close relative lacking a putative ZPS, attenuated experimental colitis in mice. Collectively, this screen identifies bacterial strains that may use ZPSs to interact with the host as well as those with potential probiotic properties

Selected abstracts from the Breastfeeding and Feminism International Conference 2016

Table of contents A1. Infant feeding and poverty: a public health perspective in a global context Lisa H. Amir A2. Mothers’ experiences with galactagogues for lactation: an exploratory cross sectional study Alessandra Bazzano, Shelley Thibeau, Katherine P. Theall A3. The motherhood journey and breastfeeding: from self-efficacy to resilience and social stigma Anna Blair, Karin Cadwell A4. Breastfeeding as an evolutionary adaptive behavior Emily A. Bronson A5. Conflict-of-interest in public health policy: as real as that logo on your website Elizabeth C. Brooks A6. Co-opting sisterhood and motherhood: behind the scenes of Similac’s aggressive social media campaigns Jodine Chase A7. The exclusion of women from the definition of exclusive breastfeeding Ellen Chetwynd, Rebecca Costello, Kathryn Wouk A8. Healthy maternity policies in the workplace: a state health department’s experience with the “Bring Your Infant to Work” program Lindsey Dermid-Gray A9. Implications for a paradigm shift: factors related to breastfeeding among African American women Stephanie Devane-Johnson, Cheryl Woods Giscombe, Miriam Labbok A10. Social experiences of breastfeeding: building bridges between research and policy: an ESRC-funded seminar series in the UK Sally Dowling A11. Manager’s perspectives of lactation breaks Melanie Fraser A12. The challenging second night: a dialogue from two perspectives Jane Grassley, Deborah McCarter-Spaulding, Becky Spencer A13. The role of lactation consultants in two council breastfeeding services in Melbourne, Australia – some preliminary impressions Jennifer Hocking, Pranee Liamputtong A14. Integrating social marketing and community engagement concepts in community breastfeeding programs Sheree H. Keitt, Harumi Reis-Reilly A15. What happens before and after the maternity stay? Creating a community-wide Ten Steps approach Miriam Labbok A16. #RVABREASTFEEDS: cultivating a breastfeeding-friendly community Leslie Lytle A17. Public health vs. free trade: a longitudinal analysis of a global policy to protect breastfeeding Mary Ann Merz A18. Legislative advocacy and grassroots organizing for improved breastfeeding laws in Virginia Kate Noon A19. Breastfeeding and the rights of incarcerated women Krista M Olson A20. Barriers and support for Puerto Rican breastfeeding working mothers Ana M. Parrilla-Rodríguez, José J. Gorrín-Peralta Melissa Pellicier, Zeleida M. Vázquez-Rivera A21. Pumping at work: a daily struggle for Puerto Rican breastfeeding mothers in spite of the law Melissa Pellicier A22. “I saw a wrong and I wanted to stand up for what I thought was right:” a narrative study on becoming a breastfeeding activist Jennifer L. Pemberton A23. Peer breastfeeding support: advocacy and action Catherine McEvilly Pestl A24. Good intentions: a study of breastfeeding intention and postpartum realities among first-time Central Brooklyn mothers Jennifer Pierre, Philip Noyes, Khushbu Srivastava, Sharon Marshall-Taylor A25. Women describing the infant feeding choice: the impact of the WIC breastfeeding classes on infant feeding practices in Ionia, Michigan Jennifer Proto, Sarah Hyland Laurie Brinks A26. Local and state programs and national partnership to reduce disparities through community breastfeeding support Harumi Reis-Reilly, Martelle Esposito, Megan Phillippi A27. Beyond black breastfeeding week: instagram image content analysis for #blackwomendobreastfeed/#bwdbf Cynthia L. Sears, Delores James, Cedric Harville, Kristina Carswell A28. Stakeholder views of breastfeeding education in the K-12 environment: a review of the literature Nicola Singletary, L. Suzanne Goodell, April Fogleman A29. “The Breastfeeding Transition”: a framework for explaining changes in global breastfeeding rates as related to large-scale forces shaping the status of women Paige Hall Smith A30. Breastfeeding, contraception, and ethics, oh my! Advocacy and informed decision-making in the post-partum period Alison M. Stuebe, Amy G. Bryant, Anne Drapkin Lyerly A31. A hard day’s night: juggling nighttime breastfeeding, sleep, and work Cecilia Tomori A32. Empowering change in Indian country through breastfeeding education Amanda L. Watkins, Joan E. Dodgson A33. Servants and “Little Mothers” take charge: work, class, and breastfeeding rates in the early 20th-century U.S. Jacqueline H. Wol

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A Potential Role of Chronic Exposure to Extremely Low-Frequency Electromagnetic Fields in Triggering Persistent Pain Post Breast Cancer Surgery: A Review

Persistent Pain after Breast Cancer Surgery (PPBCS) ranks second to amputation of extremities for neuropathic chronic pain. PPBCS is associated with the formation of intercostobrachial neuroma bulbs along the lateral chest. These neuroma bulbs are either un-/thinly myelinated and express hypersensitivity to environmental stimuli. Hypersensitivity is manifested as spontaneous pain in response to innocuous stimuli and exaggerating pain in response to noxious stimuli. Excision of neuromas, a common intervention to alleviate pain, has been reported as ineffective. Experience of individuals with amputation of extremities and experimental models of human nerve injuries confirm anthropogenic EMF evoke excruciating pain. Findings from invitro and animal studies clearly support that EMF exposure depolarizes cell membranes, interrupts voltage gated calcium channels which then activates peripheral sensory neurons and initiates propagation of a train of action potentials along the axons of primary afferent nerve fibers. The World Health Organization guidelines, established based on approximation of the human anatomy are limited and assumes no potential compounding effects of nerve injuries or alterations of physiological milieu of tissues. The objective of this review is to direct the attention of the medical community to the potential role of anthropogenic EMF as a risk factor for persistent pain after breast surgery. Patients rely heavily on the recommendations of their providers to manage their pain. The current epidemic of opioid abuse in the US has been partially attributed to the high prescription rate of opioid-based pain killers. Understanding the potential triggers of chronic pain can reduce dependency on pharmaceutical agents