Pro-inflammatory TNFα and IL-1ß differentially regulate the inflammatory phenotype of brain microvascular endothelial cells.

BACKGROUND: The vasculature of the brain is composed of endothelial cells, pericytes and astrocytic processes. The endothelial cells are the critical interface between the blood and the CNS parenchyma and are a critical component of the blood-brain barrier (BBB). These cells are innately programmed to respond to a myriad of inflammatory cytokines or other danger signals. IL-1ß and TNFα are well recognised pro-inflammatory mediators, and here, we provide compelling evidence that they regulate the function and immune response profile of human cerebral microvascular endothelial cells (hCMVECs) differentially. METHODS: We used xCELLigence biosensor technology, which revealed global differences in the endothelial response between IL-1ß and TNFα. xCELLigence is a label-free impedance-based biosensor, which is ideal for acute or long-term comparison of drug effects on cell behaviour. In addition, flow cytometry and multiplex cytokine arrays were used to show differences in the inflammatory responses from the endothelial cells. RESULTS: Extensive cytokine-secretion profiling and cell-surface immune phenotyping confirmed that the immune response of the hCMVEC to IL-1ß was different to that of TNFα. Interestingly, of the 38 cytokines, chemokines and growth factors measured by cytometric bead array, the endothelial cells secreted only 13. Of importance was the observation that the majority of these cytokines were differentially regulated by either IL-1ß or TNFα. Cell-surface expression of ICAM-1 and VCAM-1 were also differentially regulated by IL-1ß or TNFα, where TNFα induced a substantially higher level of expression of both key leukocyte-adhesion molecules. A range of other cell-surface cellular and junctional adhesion molecules were basally expressed by the hCMVEC but were unaffected by IL-1ß or TNFα. CONCLUSIONS: To our knowledge, this is the most comprehensive analysis of the immunological profile of brain endothelial cells and the first direct evidence that human brain endothelial cells are differentially regulated by these two key pro-inflammatory mediators.

Health-related quality of life measures used with Indigenous children/youth in the Pacific Rim: a scoping review.

OBJECTIVE: To identify and describe (1) which health-related quality of life (HRQoL) measures have been used with Indigenous children/youth (aged 8-17 years) within the Pacific Rim; and (2) studies that refer to Indigenous health concepts in the use of child/youth HRQoL measures. DESIGN: A scoping review. DATA SOURCES: Ovid (Medline), PubMed, Scopus, Web of Science and CINAHL were searched up until 25 June 2020. ELIGIBILITY CRITERIA: Eligible papers were identified by two independent reviewers. Eligible papers were written in English, published between January 1990 and June 2020 and included an HRQoL measure used in research with Indigenous child/youth populations (aged between 8 and 17 years) in the Pacific Rim region. DATA EXTRACTION AND SYNTHESIS: Data extracted included study characteristics (year, country, Indigenous population, Indigenous sample size, age group), HRQoL measure characteristics (generic or condition-specific measure, child or adult measure, who completed the measure(s), dimensions, items and response scale of measure) and consideration of Indigenous concepts (created for Indigenous population, modified for Indigenous population, validated for Indigenous population, reliability in Indigenous populations, Indigenous involvement, reference to Indigenous theories/models/frameworks). RESULTS: After removing duplicates, 1393 paper titles and abstracts were screened, and 543 had full-text review for eligibility. Of these, 40 full-text papers were eligible, reporting on 32 unique studies. Twenty-nine HRQoL measures were used across eight countries. Thirty-three papers did not acknowledge Indigenous concepts of health, and only two measures were specifically created for use with Indigenous populations. CONCLUSIONS: There is a paucity of research investigating HRQoL measures used with Indigenous children/youth and a lack of involvement of Indigenous peoples in the development and use of HRQoL measures. We strongly recommend explicit consideration of Indigenous concepts when developing, validating, assessing and using HRQoL measures with Indigenous populations.

Examining the barriers and facilitators for Maori accessing injury and rehabilitation services: a scoping review protocol.

INTRODUCTION: Injury accounts for 10% of the global burden of disease. While the literature is scarce, research investigating injury among Indigenous populations has found incidence and prevalence rates are higher, compared with non-Indigenous populations. New Zealand is no exception; Maori have higher rates of injury and disability compared with non-Maori. Given the burden of injury for Maori, this scoping review aims to identify, understand and map available literature related to the barriers and facilitators to accessing injury-related healthcare for Maori in New Zealand. METHODS AND ANALYSIS: A scoping review will be conducted to identify the relevant literature and provide an opportunity to highlight key concepts and research gaps in the literature. This work will be guided by the scoping review framework developed by Arksey and O'Malley and will be underpinned by Kaupapa Maori research principles. The overall project is also be guided by a Maori advisory group. Database searches, for example, MEDLINE (Ovid), Scopus and Embase, will be used to identify empirical literature, and Google, New Zealand government websites and relevant non-government organisations will be used to identify relevant grey literature. ETHICS AND DISSEMINATION: To the best of our knowledge, this scoping review is the first to systematically examine the currently available literature relating to the barriers and facilitators of accessing injury-related healthcare for Maori in New Zealand. Ethical approval was not required for this scoping review. Dissemination will include publication of the scoping review findings in a peer-reviewed journal, as well as presentations at conferences, to the project's advisory group, and staff working in the field of Maori disability and rehabilitation.

Indigenous perspectives on concepts and determinants of flourishing in a health and well-being context: a scoping review protocol.

INTRODUCTION: Indigenous people, including Maori in New Zealand, face many inequities in health and the determinants of health. Historically, the analysis and reporting of Indigenous health in the literature has usually taken a western medical view, often with a descriptive and deficit-oriented approach-ignoring the holistic nature of Indigenous health. This project takes a nondeficit approach and is interested in the factors that support the health and well-being of Indigenous people, including Maori. Flourishing is a recent and increasingly used term within the well-being literature; however, concepts, theories and determinants related to Indigenous flourishing are largely unknown. This scoping review aims to identify, describe and synthesise the nature and extent of the current empirical literature related to concepts, theories and determinants of Indigenous flourishing, in health and well-being contexts. METHODS AND ANALYSIS: Scoping review methods and guidelines included in the framework developed by Arksey and O'Malley, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews, will be followed for best practice and reporting of this scoping review. The literature for this review will be identified by searching the following databases: Medline (OVID), EMBASE (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, MAI journal, the Cochrane Library and Google Scholar. The research team has formulated a systematic search strategy, which will be restricted to articles published between January 1970 and May 2020 and published in the English language. Two reviewers will independently screen eligible studies for final study selection. A third reviewer will resolve any discrepancies that arise. Data from included studies will be extracted and included in thematic analysis, using a tool developed iteratively by the research team. ETHICS AND DISSEMINATION: Ethical approval was not required for this review. Dissemination of results will include publication in peer-reviewed journal articles, presentation of results at conferences and interactive discussions with a project expert advisory group. This scoping review also informs a larger project, examining the long-term health and flourishing of Maori, the Indigenous people of New Zealand and their whanau (families).

POIS-10 Maori: Outcomes and Experiences in the Decade Following Injury.

Injury-related disability burden extends well beyond two years post-injury, especially for Maori (Indigenous) New Zealanders. Maori also experience greater difficulty accessing health services. This prospective cohort study extension uses mixed-methods and aims to understand and identify factors contributing to long-term experiences and outcomes (positive and negative) at 12 years post-injury for injured Maori and their whanau (families), and explore the barriers and facilitators to whanau flourishing, and access to health and rehabilitation services. Five hundred and sixty-six Maori, who were injured between 2007-2009, participated in the Prospective Outcomes of Injury Study (POIS). Of these, 544 consented to long-term follow up, and will be invited to participate in a POIS-10 Maori interview at 12 years post-injury. We anticipate a 65% follow-up rate (~n = 350). Aligned with the Meihana Model, interviews will collect information about multiple inter-related dimensions. Administrative injury and hospitalisation data up to 12 years post-injury will also be collected. Regression models will be developed to examine predictors of long-term health and disability outcomes, after adjusting for a range of confounders. POIS-10 Maori will identify key points in the injury and rehabilitation pathway to inform future interventions to improve post-injury outcomes for Maori and whanau, and will highlight the support required for Maori flourishing post-injury.

Experiences of New Zealand Haemodialysis Patients in Relation to Food and Nutrition Management: A Qualitative Study.

People receiving haemodialysis have considerable and complex dietary and healthcare needs, including co-morbidities. A recent New Zealand study has shown that few patients on haemodialysis are able to meet nutritional requirements for haemodialysis. This study aims to describe the perspectives and experiences of dietary management among patients on haemodialysis in New Zealand. This exploratory qualitative study used in-depth semi-structured interviews. Purposive sampling was used to recruit participants from different ethnic groups. Forty interviews were conducted, audio-recorded and transcribed verbatim. An inductive approach was taken using thematic analysis. Forty participants were interviewed. Participants spoke of major disruption to their lives as a result of their chronic kidney disease and being on haemodialysis, including loss of employment, financial challenges, loss of independence, social isolation and increased reliance on extended family. Most had received adequate dietary information, although some felt that more culturally appropriate support would have enabled a healthier diet. These findings show that further support to make the recommended dietary changes while on haemodialysis should focus on socio-cultural factors, in addition to the information already provided.

A chitosan/dextran-based hydrogel as a delivery vehicle of human bone-marrow derived mesenchymal stem cells.

A chitosan/dextran-based (CD) injectable, surgical hydrogel has been developed and shown to be an effective post-operative aid in prevention of scar tissue formation in vivo. The CD hydrogel's effectiveness in a surgical setting prompted an investigation into its capacity as a potential delivery vehicle for bone marrow derived mesenchymal stem cells (BM-MSCs) for regenerative wound healing applications. By housing BM-MSCs within a biocompatible, injectable, hydrogel matrix, viability and protection in cultivation, as well as direct delivery to the damaged site in the host tissue may be achieved. In vitro BM-MSC cell viability in the presence of CD hydrogel was determined by LIVE/DEAD® fluoresence staining. Flow cytometry studies revealed expression of a conventional BM-MSC surface marker profile. A colony forming cell assay showed a slight statistically significant decrease in the number of colonies grown in CD hydrogel as compared to control cells. In addition, BM-MSCs in the CD hydrogel were able to successfully differentiate into adipocytes and osteocytes. In summary, the CD hydrogel supports MSC growth and differentiation; and therefore, may be used as a potential stem cell delivery vehicle for regenerative medicine and tissue engineering applications.

Regulation of human cerebro-microvascular endothelial baso-lateral adhesion and barrier function by S1P through dual involvement of S1P1 and S1P2 receptors.

Herein we show that S1P rapidly and acutely reduces the focal adhesion strength and barrier tightness of brain endothelial cells. xCELLigence biosensor technology was used to measure focal adhesion, which was reduced by S1P acutely and this response was mediated through both S1P1 and S1P2 receptors. S1P increased secretion of several pro-inflammatory mediators from brain endothelial cells. However, the magnitude of this response was small in comparison to that mediated by TNFα or IL-1ß. Furthermore, S1P did not significantly increase cell-surface expression of any key cell adhesion molecules involved in leukocyte recruitment, included ICAM-1 and VCAM-1. Finally, we reveal that S1P acutely and dynamically regulates microvascular endothelial barrier tightness in a manner consistent with regulated rapid opening followed by closing and strengthening of the barrier. We hypothesise that the role of the S1P receptors in this process is not to cause barrier dysfunction, but is related to controlled opening of the endothelial junctions. This was revealed using real-time measurement of barrier integrity using ECIS ZΘ TEER technology and endothelial viability using xCELLigence technology. Finally, we show that these responses do not occur simply though the pharmacology of a single S1P receptor but involves coordinated action of S1P1 and S1P2 receptors.

Octanoate in Human Albumin Preparations Is Detrimental to Mesenchymal Stromal Cell Culture.

Cell therapies hold great promise as the next major advance in medical treatment. To enable safe, effective ex vivo culture whilst maintaining cell phenotype, growth media constituents must be carefully controlled. We have used a chemically defined mesenchymal stromal cell culture medium to investigate the influence of different preparations of human serum albumin. We examined two aspects of cell culture, growth rate as measured by population doubling time and colony forming ability which is a representative measure of the stemness of the cell population. Albumin preparations showed comparative differences in both of these criteria. Analysis of the albumin bound fatty acids also showed differences depending on the manufacturing procedure used. We demonstrated that octanoate, an additive used to stabilize albumin during pasteurization, slows growth and lowers colony forming ability during ex vivo culture. Further to this we also found the level of Na(+)/K(+) ATPase, a membrane bound cation pump inhibited by octanoate, is increased in cells exposed to this compound. We conclude that the inclusion of human serum albumin in ex vivo growth media requires careful consideration of not only the source of albumin, but also the associated molecular cargo, for optimal cell growth and behavior.