Community and cultural engagement for people with lived experience of mental health conditions: what are the barriers and enablers?

BACKGROUND: Community and cultural engagement can support recovery, help symptom management and increase social connections for people with lived experience of mental health conditions. However, research suggests that people with mental health conditions experience significant barriers to participation. The aim of this study was to explore barriers and enablers of participation in community and cultural activities among people with mental health conditions. METHODS: A qualitative interview study with 23 people with mild-to-moderate mental health conditions was undertaken. Data were analysed thematically, and themes were mapped to domains of the Capability, Opportunity and Motivation Model of Behaviour (COM-B). RESULTS: Eleven themes were identified from the analysis. Three themes involved participant Capability: physical skills, psychological traits and physical health limitations and three themes related to Opportunity: affordability and accessibility, structure and nature of the group, and support from others to attend. Five themes mapped to Motivation: creative identity, recovery and coping, enjoyment and fun, connecting with others, and information and planning. Participants were motivated to engage with community and cultural activities through "a creative identity", belief that engagement would help recovery from mental illness, and a desire to connect with others and make friends. Motivation to participate was sustained by the enjoyable nature of activities. However, participants' ability to engage was hampered by the expense, inaccessibility and sometimes unstructured nature of activities, and social anxiety associated with attending. Some participants had physical limitations such as fatigue or physical health problems to overcome. Interventions that could address these barriers include peer support, training for social prescribers to account for identity and previous experiences of participation, training for community organisations in providing a welcoming and structured environment, and provision of long-term sustainable funding to community organisations to subsidise attendance, transport or equipment costs. CONCLUSION: People with mental health conditions may be at risk of experiencing barriers to community and cultural engagement due to existing social inequalities and social anxiety, however believing that involvement will support mental health was an enabler to participation. Future studies are needed to test the effectiveness of potential interventions to address the barriers and harness the facilitators identified here, to enable a more socially inclusive community and voluntary sector, and a potentially more responsive and effective social prescribing service in the UK for people experiencing mental health problems.

Social prescribing for individuals with mental health problems: a qualitative study of barriers and enablers experienced by general practitioners.

BACKGROUND: There is growing evidence for the use of social prescribing as a means to improve the mental health of patients. However, there are gaps in understanding the barriers and enablers faced by General Practitioners (GPs) when engaging in social prescribing for patients with mental health problems. METHODS: This study uses a qualitative approach involving one-to-one interviews with GPs from across the UK. The COM-B model was used to elucidate barriers and enablers, and the Theoretical Domains Framework (TDF) and a Behaviour Change Theory and Techniques tool was used to identify interventions that could address these. RESULTS: GPs recognised the utility of social prescribing in addressing the high levels of psychosocial need they saw in their patient population, and expressed the need to de-medicalise certain patient problems. GPs were driven by a desire to help patients, and so they benefited from regular positive feedback to reinforce the value of their social prescribing referrals. They also discussed the importance of developing more robust evidence on social prescribing, but acknowledged the challenges of conducting rigorous research in community settings. GPs lacked the capacity, and formal training, to effectively engage with community groups for patients with mental health problems. Link workers, when available to GPs, were of fundamental importance in bridging the gap between the GP and community. The formation of trusting relationships was crucial at different points of the social prescribing pathway, with patients needing to trust GPs in order for them to agree to see a link worker or attend a community activity, and GPs requiring a range of strong inter-personal skills in order to gain patients' trust and motivate them. CONCLUSION: This study elucidates the barriers and enablers to social prescribing for patients with mental health problems, from the perspectives of GPs. Recommended interventions include a more systematic feedback structure for GPs and more formal training around social prescribing and developing the relevant inter-personal skills. This study provides insight for GPs and other practice staff, commissioners, managers, providers and community groups, to help design and deliver future social prescribing services.

How Participatory Music Engagement Supports Mental Well-being: A Meta-Ethnography.

Participatory music engagement has the capacity to support well-being. Yet, there is little research that has scrutinized the processes through which music has an effect. In this meta-ethnography [PROSPERO CRD42019130164], we conducted a systematic search of 19 electronic databases and a critical appraisal to identify 46 qualitative studies reporting on participants' subjective views of how participatory music engagement supports their mental well-being. Synthesis of first-order and second-order interpretations using thematic coding resulted in four third-order pathways that account for how participatory music engagement supports mental well-being: managing and expressing emotions, facilitating self-development, providing respite, and facilitating connections. Our interpretation suggests that people benefit from participatory music engagement by engaging with specific and multiple processes that meet their individual needs and circumstances. These findings inform research directions within the field of music and well-being, as well as guiding the development and delivery of future music interventions.

Differential participation in community cultural activities amongst those with poor mental health: Analyses of the UK Taking Part Survey.

RATIONALE: There is a growing literature on the benefits of arts and cultural engagement for mental health. However, whether poor mental health is a barrier to engaging in cultural activities remains unclear. OBJECTIVE: To identify whether there are differential participation rates in community cultural activities amongst those with differing levels of mental health (specifically, feelings of anxiety and happiness) and identify potential explanatory factors. METHOD: We analysed data from 7241 participants in the Taking Part survey; a random face-to-face household survey conducted in England (2016-2017). Cultural engagement was measured using a four-factor variable of cultural participation derived from assessing annual attendance at 21 receptive cultural activities. Mental health was measured using two of the Office for National Statistics measures of subjective wellbeing: happiness and anxious feelings. Analyses were adjusted for demographic, socio-economic, geographic and behavioural factors. RESULTS: There was no difference in participation amongst individuals experiencing high levels of anxious feelings, but individuals experiencing low levels of happiness were less likely to engage in 'popular' cultural activities (e.g., live music events/cinema), 'high art' cultural activities (e.g., opera/ballet), and crafts and literary cultural events (e.g., exhibitions/book fairs). Education and socio-economic status largely explained differences, but for 'high art' and 'popular' activities, differences persisted independent of all explanatory factors tested. There was no difference in participation in global cultural activities (e.g., festivals). CONCLUSIONS: Using behaviour change theory, our findings suggest that lower levels of physical and social opportunity and psychological capability may reduce levels of cultural participation amongst individuals with low levels of happiness, but other physical and perceived barriers still remain to be explored.

What are the barriers to, and enablers of, working with people with lived experience of mental illness amongst community and voluntary sector organisations? A qualitative study.

There is increasing emphasis on psychological and social approaches to managing and treating mental illness, including a growing evidence base on the effectiveness of community-based social interventions including arts and heritage activities, library programmes, volunteering schemes, nature-based activities and community groups. However, there is a gap in understanding of what the barriers to, and enablers of, working with individuals with mental illness might be for the community and voluntary sector. A qualitative approach was used involving focus groups with non-profit organisations delivering social activities within communities across the United Kingdom. Behaviour Change Theory, the COM-B model and the Theoretical Domains Framework, were employed as the theoretical framework, to develop interventions to address the barriers raised. Representatives of the organisations reported being motivated by the mental health needs of others, and by seeing the benefits of participation. Further motivations included expanding inclusion, and economic motivation to ensure sustainability. Strengths identified included offering innovative, responsive services that were distinct from conventional mental health services. Running these services demanded new and potentially challenging skills, such as understanding statutory responsibilities, and being able to train and support staff. Further challenges included maintaining boundaries between their roles as community organisations and clients' mental health needs and avoiding burn-out. Ability to deliver this work was enhanced by support of peer organisations and opportunities to share practice. However, funding was often short term, and complex to obtain, which could destabilise organisations' sustainability. Lack of transparency around the process, differences in language between the community and health sectors, and confusion around commissioning pathways undermined the potential opportunity offered by social prescribing policy. Interventions to address these barriers were identified, including long term funding to support core costs, training on engaging with the commissioning process, around mental health support and safeguarding, and developing mentoring schemes and local co-operatives of organisations for developing partnerships with the health sector.

Barriers and enablers to engagement in participatory arts activities amongst individuals with depression and anxiety: quantitative analyses using a behaviour change framework.

BACKGROUND: There is a large literature on the health benefits of engagement with the arts. However, there are also well-recognised challenges in ensuring equity of engagement with these activities. Specifically, it remains unclear whether individuals with poor mental health experience more barriers to participation. This study used a behaviour change framework to explore barriers to engagement in participatory arts activities amongst people with either depression or anxiety. METHODS: Data were drawn from a large citizen science experiment focused on participation in creative activities. Participants who reported engaging infrequently in performing arts, visual arts, design and crafts, literature-related activities, and online, digital and electronic arts were included and categorised into no mental health problems (n = 1851), depression but not anxiety (n = 873) and anxiety but not depression (n = 808). Barriers and enablers to engagement were measured using an 18-item scale based on the COM-B Self-Evaluation Questionnaire, with subscales assessing psychological and physical capabilities, social and physical opportunities, and automatic and reflective motivations. Logistic regression analyses were used to identify whether individuals with either depression or anxiety reported greater barriers across any of the six domains than individuals without any mental health problems. Where differences were found, we calculated the percentage of protective association explained by various demographic, socio-economic, social, physical or geographical factors. RESULTS: Individuals with depression and anxiety felt they would be more likely to engage in arts activities if they had greater psychological and physical capabilities, more social opportunities, and stronger automatic and reflective motivations to engage. However, they did not feel that more physical opportunities would affect their engagement. Covariates explained only 8-37% of the difference in response amongst those with and without anxiety and depression. CONCLUSIONS: Findings suggest that for individuals with poor mental health, there are certain barriers to participation that are not felt as strongly by those without any mental health problems. Mapping the behaviour change domains to potential interventions, activities that focus on increasing perceived capabilities, providing social opportunities, and reinforcing both automatic and reflective motivations to engage has the potential to help to redress the imbalance in arts participation amongst those with poor mental health.

Cost-effectiveness analysis of the introduction of the pneumococcal conjugate vaccine (PCV-13) in the Egyptian national immunization program, 2013.

INTRODUCTION: Pneumonia is one of the most important causes of morbidity and mortality in children under 5 in Egypt, and the Ministry of Health of Egypt is considering introducing pneumococcal conjugate vaccine (PCV) in its national immunization program. We performed an economic analysis to evaluate the cost-effectiveness of this vaccine in Egypt and to provide the decision-makers with needed evidence. METHODS: The analysis was done using the TRIVAC model. Data included demographic characteristics, burden of disease, coverage and efficacy of the vaccine, health resource utilization, and costs of pneumococcal disease vaccination and treatment. Whenever possible, we used national or regional data. Two alternatives were compared: (1) general vaccination of children younger than 5 years with the 13-valent pneumococcal conjugate vaccine (PCV13), using a three-dose schedule without booster, and (2) no vaccination. Outcomes of 10 cohorts from birth to 5 years were analyzed. The study was performed from the governmental perspective and selected public health providers. RESULTS: In comparison to no vaccine, the introduction of PCV13 would be cost-effective, with an incremental cost-effectiveness ratio of US$ 3916 per disability-adjusted life-year (DALY) averted (government perspective). The total incremental cost of the PCV vaccination program (10 cohorts) would be approximately US$ 1.09 billion. Over the 10 cohorts, the program would avert 8583 pneumococcal deaths - 42% of all pneumococcal-related deaths. CONCLUSION: The introduction of PCV13 would be a good value for money from the government perspective. It would represent a high-impact public health intervention for Egypt and respond to the National Immunization Technical Advisory Group (NITAG) resolution on reducing pneumonia burden and overall child mortality. Strengthening surveillance will be critical to generating high-quality national data, improving future economic analyses that support evidence-based decisions for introducing vaccines and public health interventions, and to monitoring their impact.

Cost-effectiveness analysis of the introduction of rotavirus vaccine in Iran.

BACKGROUND: Although the mortality from diarrheal diseases has been decreasing dramatically in Iran, it still represents an important proportion of disease burden in children <5 years old. Rotavirus vaccines are among the most effective strategies against diarrheal diseases in specific epidemiological conditions. This study aimed to evaluate the cost-effectiveness of the introduction of rotavirus vaccine (3 doses of pentavalent RotaTeq (RV5)) in Iran, from the viewpoints of Iran's health system and society. METHODS: The TRIVAC decision support model was used to calculate total incremental costs, life years (LYs) gained, and disability-adjusted life years (DALYs) averted due to the vaccination program. Necessary input data were collected from the most valid accessible sources as well as a systematic review and meta-analysis on epidemiological studies. We used WHO guidelines to estimate vaccination cost. An annual discount rate of 3% was considered for both health gain and costs. A deterministic sensitivity analysis was performed for testing the robustness of the models results. RESULTS: Our results indicated that total DALYs potentially lost due to rotavirus diarrhea within 10 years would be 138,161, of which 76,591 could be prevented by rotavirus vaccine. The total vaccination cost for 10 cohorts was estimated to be US$ 499.91 million. Also, US$ 470.61 million would be saved because of preventing outpatient visits and inpatient admissions (cost-saving from the society perspective). We estimated a cost per DALY averted of US$ 2868 for RV5 vaccination, which corresponds to a highly cost-effective strategy from the government perspective. In the sensitivity analysis, all scenarios tested were still cost-saving or highly cost-effective from the society perspective, except in the least favorable scenario and low vaccine efficacy and disease incidence scenario. CONCLUSION: Based on the findings, introduction of rotavirus vaccine is a highly cost-effective strategy from the government perspective. Introducing the vaccine to the national immunization program is an efficient use of available funds to reduce child mortality and morbidity in Iran.

Evidence-based decision-making for vaccine introductions: Overview of the ProVac International Working Group's experience.

INTRODUCTION: Pan American Health Organization's (PAHO) ProVac Initiative aims to strengthen countries' technical capacity to make evidence-based immunization policy. With financial support from the Bill and Melinda Gates Foundation, PAHO established the ProVac International Working Group (IWG), a platform created for two years to transfer the ProVac Initiative's tools and methods to support decisions in non-PAHO regions. METHODS: In 2011, WHO Regional Offices and partner agencies established the IWG to transfer the ProVac framework for new vaccine decision support, including tools and trainings to other regions of the world. During the two year period, PAHO served as the coordinating secretariat and partner agencies played implementing or advisory roles. RESULTS: Fifty nine national professionals from 17 countries received training on the use of economic evaluations to aid vaccine policy making through regional workshops. The IWG provided direct technical support to nine countries to develop cost-effectiveness analyses to inform decisions. All nine countries introduced the new vaccine evaluated or their NITAGs have made a recommendation to the Ministry of Health to introduce the new vaccine. DISCUSSION: Developing countries around the world are increasingly interested in weighing the potential health impact due to new vaccine introduction against the investments required. During the two years, the ProVac approach proved valuable and timely to aid the national decision making processes, even despite the different challenges and idiosyncrasies encountered in each region. The results of this work suggest that: (1) there is great need and demand for technical support and for capacity building around economic evaluations; and (2) the ProVac method of supporting country-owned analyses is as effective in other regions as it has been in the PAHO region. CONCLUSION: Decision support for new vaccine introduction in low- and middle-income countries is critical to guiding the efficient use of resources and prioritizing high impact vaccination programs.

Strengthening national decision-making on immunization by building capacity for economic evaluation: Implementing ProVac in Europe.

BACKGROUND: For many years, low- and middle-income countries have made efforts to strengthen national decision-making on immunization. The Pan American Health Organization (PAHO) ProVac Initiative was established to help expedite the use of evidence-based decision-making around new vaccine introduction. This initiative provides training in user-friendly cost-effectiveness models and supports the development of country-led economic evaluations. Due to the success of the ProVac Initiative in the Americas, and following requests from countries from outside the Americas, the Bill & Melinda Gates Foundation funded a two-year pilot effort to expand the initiative to other world regions. Called the ProVac International Working Group (IWG), this endeavor took place in 2012 and 2013. It was coordinated by PAHO and carried out in collaboration with several international partners, including the Agence de Médecine Préventive (AMP), London School of Hygiene & Tropical Medicine (LSHTM), Program for Appropriate Technology in Health, Sabin Vaccine Institute, United States Centers for Disease Control and Prevention, and the World Health Organization (WHO). In the WHO European Region, technical support was provided by AMP, in close collaboration with the WHO Regional Office for Europe and other ProVac IWG partners. METHODS: In 2012, AMP, the WHO Regional Office for Europe, and other partners held a training workshop in Dubrovnik, Croatia, for 31 participants from four countries of the WHO European Region. The aim was to train health professionals in standard methods of economic evaluation and to assess regional demand for economic studies to support decision-making on immunization. AMP and the other organizations also supported four national cost-effectiveness studies in the WHO European Region. The assistance included country visits and support over a period of six months, the establishment of multidisciplinary teams of experts, ongoing training on the TRIVAC decision-support model for new-vaccine economic analysis, review of local evidence, recommending key data inputs, and support in presenting results to national decision makers. RESULTS: National cost-effectiveness studies were conducted in four countries: Albania (rotavirus vaccine [RV]), Azerbaijan (pneumococcal conjugate vaccine [PCV]), Croatia (PCV), and Georgia (PCV). All four countries improved their estimates of the burden of disease preventable by the new vaccines. National advisory bodies and ministries of health obtained economic evidence that helped Albania and Croatia to make decisions on introducing the new vaccines. Azerbaijan and Georgia used economic evidence to confirm previously made preliminary decisions to introduce PCV and make corresponding financial commitments. The study helped Albania to obtain access to affordable prices for rotavirus vaccines through participation in the UNICEF procurement mechanism for middle-income countries. Croatia was able to define the PCV price that would make its introduction cost-effective, and can use this figure as a basis for price negotiations. DISCUSSION: Despite some challenges due to competing national priorities, tight budgets for immunization, and lack of available national data, the ProVac IWG helped to build capacity of national health professionals, support decision-making for the introduction of new vaccines, and promote utilization of economic evidence for making decisions on immunization. This type of strong collaboration among international partners and countries should be scaled up, given that many other countries in the WHO European Region have expressed interest in receiving assistance from the ProVac IWG.

Evidence for lymphatics in the developing and adult human choroid.

PURPOSE: Lymphatics subserve many important functions in the human body including maintenance of fluid homeostasis, immune surveillance, and tumor metastasis. Our aim was to provide structural and phenotypic evidence of lymphatic-like structures in the human choroid, including details of its development. METHODS: Using multiple-marker immunohistochemistry (IHC), choroids from human fetal eyes (8-26 weeks gestation) and adults (17-74 years) were examined with lymphatic- and vascular-specific markers: prospero homeobox-1 (PROX-1), lymphatic vascular endothelium receptor-1 (LYVE-1), podoplanin, D2-40, endomucin, VEGF-C, vascular endothelial growth factor receptor-3 (VEGFR-3 or Flt4), UEA lectin, platelet endothelial cell adhesion molecule-1 (PECAM-1), CD34, and CD39. Transmission electron microscopy (TEM) was used to establish evidence for choroidal lymphatics, and to provide details of stratification and relative frequency of lymphatics compared to choroidal blood vessels. RESULTS: Immunohistochemistry and TEM indicated a central-to-peripheral topography of lymphatic formation, with numerous blind-ended lymph sacs just external to the choriocapillaris, as well as the presence of infrequent precollector and collector lymphatic channels. Characteristic ultrastructural features of lymphatics in adult human choroid included anchoring filaments, luminal flocculent protein but absence of erythrocytes, fragmented and/or absent basal lamina, absence of intracellular Weibel-Palade bodies, infrequent pericyte ensheathment, and lack of fenestrae. CONCLUSIONS: The system of blind-ended initial lymphatic segments seen just external to the fenestrated vessels of the choriocapillaris is ideally placed for recirculating extracellular fluid and strategically placed for immune surveillance. The presence of a system of lymphatic-like channels in the human choroid provides an anatomical basis for antigen presentation in the posterior eye, with a possible route from the eye to the sentinel lymph nodes, similar to that already described for anterior eye lymphatics.

The clinical effectiveness and cost-effectiveness of peginterferon alfa and ribavirin for the treatment of chronic hepatitis C in children and young people: a systematic review and economic evaluation.

BACKGROUND: Optimal therapy for children with chronic hepatitis C is unclear. Two treatment regimens are currently licensed in children. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of peginterferon alfa-2a (Pegasys®, Roche) and peginterferon alfa-2b [ViraferonPeg®, Merck Sharp & Dohme (MSD)] in combination with ribavirin (RBV), within their licensed indications, for the treatment of chronic hepatitis C virus (HCV) in children and young people aged 3-17 years. DATA SOURCES: Twelve electronic bibliographic databases, including The Cochrane Library, MEDLINE and EMBASE, were searched from inception to November 2012. Bibliographies of retrieved papers, key hepatitis C websites and symposia and manufacturers' submissions to the National Institute for Health and Care Excellence were also searched, and clinical experts were contacted. REVIEW METHODS: Systematic reviews of clinical effectiveness and cost-effectiveness were conducted, including studies of health-related quality of life (HRQoL), following standard guidelines to ensure methodological rigour. Clinical effectiveness studies were included if they were in children and young people aged 3-17 years with chronic compensated HCV of any severity, including those with human immunodeficiency virus co-infection and those who were treatment naive or had been previously treated. Eligible interventions were peginterferon alfa-2a or peginterferon alfa-2b, each in combination with RBV, compared against best supportive care (BSC) or against each other, and study designs were randomised controlled trials (RCTs) or non-RCTs, or uncontrolled cohort studies. Outcomes included sustained virological response (SVR) and adverse events. Previously published Markov state-transition economic models of chronic HCV in adults were adapted to estimate the cost-effectiveness of peginterferon alfa-2a and -2b (in combination with RBV), compared with BSC and with one another in children. The model extrapolated the impact of SVR on life expectancy, quality-adjusted life expectancy and lifetime costs. Uncertainty was explored through probabilistic and deterministic sensitivity analyses. RESULTS: Seven studies [two peginterferon alfa-2a and RBV (Copegus®, Roche), and five peginterferon alfa-2b and RBV (Rebetol®, MSD)] were included in the review of clinical effectiveness. Six were single-arm cohort studies and one was a RCT for which only those data for a single arm met the inclusion criteria. Overall, the studies were relatively small and of generally poor quality. SVR rates ranged from 53% to 66% (peginterferon alfa-2a) and 29% to 75% (peginterferon alfa-2b) (49% to 65% if excluding two studies with very small sample sizes). Rates of non-response and relapse were variable and adverse events were generally mild. No studies of cost-effectiveness or HRQoL in children and young people met the inclusion criteria. HRQoL, utilities and costs of treatment were therefore taken from studies of adults with chronic HCV. From this model, peginterferon alfa (-2a or -2b) in combination with RBV was more effective and had lower lifetime costs than BSC. Peginterferon alfa-2a had slightly lower lifetime costs and higher quality-adjusted life-years than peginterferon alfa-2b; therefore, peginterferon alfa-2b was dominated by peginterferon alfa-2a. Results were robust to changes in the sensitivity analyses. LIMITATIONS: There were few good quality studies and parameter data had to be taken from adult studies, which is a limitation of the work. CONCLUSIONS: Treatment of children and young people with peginterferon (alfa-2a or -2b) and RBV may be an effective therapy. Results from the independent Markov model suggest that peginterferon (alfa-2a or -2b) in combination with RBV is cost-effective compared with BSC. However, the available evidence is of poor quality. Future research into the impact of these treatments on growth and quality of life in children and young people is recommended. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002743. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Shortened peginterferon and ribavirin treatment for chronic hepatitis C.

BACKGROUND: Peginterferon alfa and ribavirin combination therapy is an effective treatment for many patients with chronic hepatitis C virus (HCV). Reducing the length of treatment may be advantageous. We performed a systematic review and economic evaluation to assess shorter treatment duration of this regimen. METHODS: We searched fourteen bibliographic databases (including The Cochrane Library, Medline, and Embase) from 2000 to October 2009 and consulted experts and drug manufacturers. Eligible articles were randomized controlled trials (RCTs) selected according to predefined criteria. We undertook an economic evaluation to assess the cost-effectiveness of shortened treatment versus standard treatment in the UK. RESULTS: Six trials were included. In the sub-group of patients who had low viral load (LVL) and a rapid virological response (RVR), there were no statistically significant differences in sustained virological response (SVR) rates between patients who received standard treatment (range, 83 percent to 100 percent) and those who received shortened courses (range 84 percent to 96 percent) (24 weeks for genotype 1, 16 weeks for genotype 2/3). Shortened treatment resulted in cost savings, but in some scenarios also resulted in poorer outcome, compared with standard treatment. This requires a judgment to be made on the value of the quality-adjusted life-year loss resulting from adopting a shorter treatment regimen, if shorter treatment is associated with a lower SVR than standard treatment duration. CONCLUSIONS: For chronic HCV patients who have LVL and achieve an RVR, shortened peginterferon and ribavirin combination therapy could be considered as a viable treatment option.

Evidence of hematopoietic differentiation, vasculogenesis and angiogenesis in the formation of human choroidal blood vessels.

Human fetal eyes 8-40 weeks gestation (WG) were examined using markers to hematopoietic stem cells (HSC), vascular precursor cells (VPC), monocytes/macrophages and endothelial cells (EC). Electron microscopy and bromo-deoxyuridene labeling were undertaken to confirm the existence of solid vascular cords and to demonstrate vasculogenesis and angiogenesis in developing choroidal tissue. Our results demonstrated that the earliest incipient choroid consisted of vimentin(+) mesenchymal precursor cells which downregulated vimentin expression with maturation. Our observations lead us to conclude that these vimentin(-)/CD34(+)/CD44(+)/CD133(+) HSCs then differentiated into three distinct lineages: single isolated CD34(-)/CD39(+) VPCs that formed solid vascular cords which lumenized and became lined with CD34(+) vascular ECs; CD34(--+)/CD14(+)/CD68(+) monocytes that differentiated into tissue macrophages; and CD133(+)/CD34(--+)/α-smooth muscle actin(+) mural precursor cells that matured into smooth muscle cells and pericytes. Blood vessel formation occurred throughout the whole choroid simultaneously, indicative of in situ differentiation. Vasculogenesis, as evidenced by lumenization of solid vascular cords, was responsible for the formation of the entire choroidal area with angiogenesis, in all three layers of the choroid, only adding to vascular density. These results suggest that formation of the human choroid involves three processes: HSC differentiation, vasculogenesis and angiogenesis. Since vasculogenesis takes place independently of VEGF(165), further insights regarding the molecular mechanisms of vasculogenesis are required to better inform future treatments of choroidal neovascularization.

Role of CD44+ stem cells in mural cell formation in the human choroid: evidence of vascular instability due to limited pericyte ensheathment.

PURPOSE: To examine mural cell differentiation and pericyte ensheathment during human choroidal vascular formation and into adulthood. METHODS: Triple- and double-labeled immunohistochemistry (alpha-smooth muscle actin [αSMA], desmin, NG2, calponin, caldesmon, CD44, CD34, and CD39) were applied to human fetal (8-32 weeks' gestation) and adult choroidal and retinal wholemounts and histologic cross-sections. Transmission electron microscopy (TEM) was also undertaken. RESULTS: Early in development CD44+ stem cells also stained with αSMA and CD39, suggesting a common precursor. At 12 weeks' gestation, αSMA+ mural precursor cells, confirmed by TEM, were found scattered and isolated over the primordial vascular tree. During development, αSMA+ cells formed a continuous sheath around large arterioles; in veins there were gaps in αSMA expression. The choriocapillaris had an extensive vascular bed but limited coverage by αSMA+ and NG2+ mural cells. Calponin was expressed only on large vessels, and no caldesmon was detected. Pericyte ensheathment of adult capillaries was 11% for choroid versus 94% for retina. Remarkably, choroidal pericytes had no visible intermediate filaments (IFs) on TEM, though IFs were present in retinal pericytes. Neither retinal nor choroidal pericytes stained with desmin. CONCLUSIONS: CD44+ stem cells are involved in the formation of mural cells in the human choroidal vasculature. A marked reduction in pericyte ensheathment of human choroidal vessels suggests a permanently open "plasticity window" and a predisposition to vascular instability and poor autoregulatory ability.

Neonatal parenteral nutrition hypersensitivity: a case report implicating bisulfite sensitivity in a newborn infant.

This report describes a case of parenteral nutrition hypersensitivity in a 37 weeks' gestation infant with congenital diaphragmatic hernia complicated by bowel necrosis and functional short bowel syndrome. The patient developed a rash with subsequent urticaria beginning on the 50th day of life. The reactions were confirmed with a positive rechallenge. After the amino acid solution was replaced with a non-bisulfite-containing product, the infant was able to continue to receive nutrition support through parenteral nutrition without recurrence of symptoms. It is speculated that the bisulfite additive in the amino acid solution may have interacted with the lipid emulsion to sensitize the patient.

In vivo characterization of astrocyte precursor cells (APCs) and astrocytes in developing rat retinae: differentiation, proliferation, and apoptosis.

PURPOSE: To characterize the timing of differentiation, antigenic expression, morphology, proliferative potential, and apoptosis during astrocyte differentiation in the rat retina in vivo. METHODS: Whole mounts of rat retinae from embryonic day (E) 13 to postnatal day (P) 21 and adults were examined utilizing combinations of Pax2, GFAP, vimentin, S100, and GS lectin. These markers were also combined with BrdU and TUNEL to identify proliferation and apoptosis of cells of the astrocytic lineage. RESULTS: Three distinct stages of astrocytic differentiation were identified: (i) Pax2+/vimentin+/GFAP(-) astrocyte precursor cell (APC), (ii) Pax2+/vimentin+/GFAP+ immature perinatal astrocytes, and (iii) Pax2+/vimentin(-)/GFAP+ mature perinatal astrocytes. An earlier transient site of astrocyte generation was detected from E13 to E15 at the ventricular surface, but unlike the majority of retinal astrocytes that migrate into the retina starting at E15-E16, this ventricular source of retinal astrocytes were restricted to a small rim surrounding the optic nerve head. APCs and perinatal astrocytes were highly proliferative and migratory. Significant numbers of perinatal astrocytes were lost because of apoptosis, which was matched closely to the retraction of excess capillary segments during postnatal maturation of the retinal vasculature. CONCLUSIONS: This study provides evidence of a second site of astrocyte generation at the ventricular zone early in embryonic development of the mammalian retinae. APCs are present from E16 to E20 only during perinatal development and are a highly migratory and proliferative cell. As the retina is considered a part of the central nervous system (CNS), this is the first in vivo characterization of cells of the astrocytic lineage in mammalian CNS development.

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development.

We asked whether the hypoxia-regulated factor, insulin-like growth factor binding protein-3 (IGFBP3), could modulate stem cell factor receptor (c-kit+), stem cell antigen-1 (sca-1+), hematopoietic stem cell (HSC), or CD34+ endothelial precursor cell (EPC) function. Exposure of CD34+ EPCs to IGFBP3 resulted in rapid differentiation into endothelial cells and dose-dependent increases in cell migration and capillary tube formation. IGFBP3-expressing plasmid was injected into the vitreous of neonatal mice undergoing the oxygen-induced retinopathy (OIR) model. In separate studies, GFP-expressing HSCs were transfected with IGFBP3 plasmid and injected into the vitreous of OIR mice. Administering either IGFBP3 plasmid alone or HSCs transfected with the plasmid resulted in a similar reduction in areas of vasoobliteration, protection of the developing vasculature from hyperoxia-induced regression, and reduction in preretinal neovascularization compared to control plasmid or HSCs transfected with control plasmid. In conclusion, IGFBP3 mediates EPC migration, differentiation, and capillary formation in vitro. Targeted expression of IGFBP3 protects the vasculature from damage and promotes proper vascular repair after hyperoxic insult in the OIR model. IGFBP3 expression may represent a physiological adaptation to ischemia and potentially a therapeutic target for treatment of ischemic conditions.

Inflammation and breakdown of the blood-retinal barrier during "physiological aging" in the rat retina: a model for CNS aging.

OBJECTIVE: To examine the possible contribution of inflammation and breakdown of the blood-brain barrier in the central nervous system (CNS) of physiologically aged rats showing cognitive decline. METHODS: Young (3- to 6-month-old) and aged (24- to 30-month-old) Wistar rats were assessed by the novel object recognition test. Vascular and inflammatory changes in the CNS were investigated in whole-mount preparations or sections of retinas from young adult or aged male Wistar rats. RESULTS: Aged rats showed a significant impairment in short-term memory compared with young adults. Deterioration of blood-retinal barrier function in aged rats was evidenced by leakage of intravascular tracer into the retinal parenchyma and reduced immunoreactivity for the tight junctional protein, occludin. Immunohistochemistry revealed the presence of major histocompatibility complex (MHC) class II-positive resident microglia, activated T cells, and monocyte-like cells in the retinal parenchyma of aged rats only. Microglia positive for the ED1 antigen, indicative of phagocytic activity, were also observed in these retinas. CONCLUSION: Breakdown of the blood-retinal barrier, MHC class II expression, microglial activation, and trafficking of activated T cells are associated with physiological aging. Such changes in the CNS may contribute to the pathogenesis of age-related cognitive decline.