Disabilities in Early Childhood: A Global Health Perspective.

Prior to the launch of the United Nations' Sustainable Development Goals (SDGs) in 2015, childhood disability was rarely considered an important subject in global health. The SDGs till 2030 now require that children under 5 years who are at risk of not benefitting from inclusive quality education are identified, monitored, and promptly supported. A new tool for identifying children who are not developmentally on track has been developed by UNICEF but has limited sensitivity for detecting children with disabilities due to reliance on parental assessment of child behavior in certain everyday situations. In this paper, we identified conditions that are commonly associated with developmental disabilities based on the International Classification of Diseases (ICD) codes and clarified the concept of "developmentally on track" as it relates to children with developmental disabilities and developmental delays. We summarized the latest evidence on the global burden of developmental disabilities in children under 5 years based on the diagnostic and functional approaches for measuring disabilities at the population level. We highlighted the global health context for addressing the needs of children with developmental disabilities and provided an overview of the opportunities and the role of pediatric caregivers in supporting children with developmental disabilities.

Measuring early child development in low and middle income countries: Investigating the validity of the early Human Capability Index.

Inclusion of early child development in the United Nations Sustainable Development Agenda raises issues of how this goal should be monitored, particularly in low resource settings. The aim of this paper was to explore the validity of the early Human Capability Index (eHCI); a population measure designed to capture the holistic development of children aged 3-5 years. Convergent, divergent, discriminant and concurrent validity were examined by exploring the associations between eHCI domains and child (sex, age, stunting status, preschool attendance) and family (maternal education, home learning environment) characteristics. Analyses were repeated using data from seven low and middle income countries: Brazil (n = 1810), China (n = 11421), Kiribati (n = 8339), Lao PDR (n = 7493), Samoa (n = 12191), Tonga (n = 6214), and Tuvalu (n = 549). Correlations and linear regressions provide evidence that within these country samples, the tool is capturing the aspects of early child development that it was designed to measure. Although the tool was intended to measure development of children aged 3-5 years, results suggest it can be validly applied to children aged 2-6 years. The eHCI is free, requires minimal implementation resources, captures development across domains and abilities, and is designed to allow cultural and contextual concepts to be included. The eHCI appears psychometrically robust in diverse country contexts and could enable evaluation of early years policies and programs, as well as monitoring of children's development to track progress towards the Sustainable Development Agenda.

Inequalities in early childhood care and development in low/middle-income countries: 2010-2018.

Background: Inequalities in early childhood development (ECD) tend to persist into adulthood and amplify across the life course. To date, little research on inequalities in early childhood care and development in low/middle-income countries has been available to guide governments, donors and civil society in identifying which young children and families should be targeted by policies and programmes to improve nurturing care that could prevent them from being left behind. Methods: Using data from 135 Demographic and Health Surveys and Multiple Indicator Cluster Surveys between 2010 and 2018, we assessed levels and trends of inequalities in exposure to risks of stunting or extreme poverty (under age 5; levels in 85 and trends in 40 countries), early attendance of early care and education programmes (36-59 months; 65 and 17 countries), home stimulation (36-59 months; 62 and 14 countries) and child development according to the Early Childhood Development Index (36-59 months; 60 and 13 countries). Inequalities within countries were measured as the absolute gap in three domains-child gender, household wealth and residential area-and compared across regions and country income groups. Results: 63% of children were not exposed to stunting or extreme poverty; 39% of 3-4-year olds attended early care and education; and 69% received a level of reported home stimulation defined as adequate. Sub-Saharan Africa had the lowest proportion of children not exposed to stunting or extreme poverty (45%), attending early care and education (24%) and receiving adequate home stimulation (47%). Substantial gaps in all indicators were found across country income groups, residential areas and household wealth categories. There were no significant reductions in gaps over time for a subset of countries with available data in two survey rounds. Conclusions: Available data indicate large inequalities in early experiences and outcomes. Efforts of reducing these inequalities must focus on the poorest families and those living in rural areas in the poorest countries. Improving and applying population-level measurements on ECD in more countries over time are important for ensuring equal opportunities for young children globally.

Blockade of OX40/OX40L pathway combined with ethylene-carbodiimide-fixed donor splenocytes induces donor-specific allograft tolerance in presensitized recipients.

BACKGROUND: Memory T cells (Tms) are the major barrier preventing long-term allograft survival in presensitized transplant recipients. The OX40/OX40L pathway is important in the induction and maintenance of Tms. METHODS: In this study, we added anti-OX40L mAb to ethylene-carbodiimide-fixed donor splenocytes (ECDI-SPs)-a method which is effective in inducing allograft tolerance in non-presensitized mouse heart transplant model. Recipient mice received heart transplantation after 6 weeks of donor skin presensitization and were treated with anti-OX40L mAb, ECDI-SPs or anti-OX40L mAb + ECDI-SPs, respectively. RESULTS: Our data showed that the combination of ECDI-SPs and anti-OX40L mAb induced donor-specific tolerance in skin-presensitized heart transplant recipients, with the mechanism for this being associated with suppression of Tms and upregulation of CD4+CD25+Foxp3+ T regulatory cells (Tregs). Importantly, CD25+ T-cell depletion in the combined therapy-treated recipients broke the establishment of allograft tolerance, whereas adoptive transfer of presensitization-derived T cells into tolerant recipients suppressed Tregs expansion and abolished established tolerance. CONCLUSIONS: Blockade of OX40/OX40L pathway in combination with ECDI-SPs appears to modulate the Tms/Tregs imbalance so as to create a protective milieu and induce graft tolerance in presensitized recipients.

ECDI-fixed donor splenocytes prolong skin allograft survival by promoting M2 macrophage polarization and inducing regulatory T cells.

Rejection is a common complication of allogeneic tissue transplantation. Fixation of splenocytes (SP) with 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (ECDI) induces immune tolerance in recipients post-transplantation; however, the mechanism underlying this effect remains unclear. Here, we determined the mechanisms of ECDI-fixed donor SP (ECDI-SP) in inducing tolerance in skin allograft transplantation. C57BL/6-recipient mice that received Balb/c full-thickness skin transplants with two infusions of donor-derived ECDI-SP, along with rapamycin showed superior skin allograft survival and lower inflammatory cell infiltration than mice that received rapamycin-only treatment. In ECDI-SP-treated mice, the levels of anti-inflammatory cytokines such as interleukin (IL)-10 in sera were markedly increased, whereas the expression of inflammatory cytokines was significantly suppressed. Splenic macrophages were significantly polarized to the alternative activated macrophage (M2) phenotype, with expansion of CD4+Foxp3+ regulatory T cells (Tregs) in the spleen and draining lymph nodes. Allostimulatory activity of ECDI-SP in vitro and donor-specific ex vivo hyporesponsiveness were observed. C57BL/6 macrophages engulfed allogeneic Balb/c-derived ECDI-SP, polarized to the M2 phenotype, with pronounced cAMP response element-binding (CREB) protein phosphorylation. By facilitating increased IL-10 expression, ECDI-SP induced M2 polarization and Treg production, inhibiting effector T-cell proliferation. Thus, ECDI-SP modulates macrophage M2 polarization by increasing CREB phosphorylation and promoting Treg production to suppress allogeneic skin graft rejection.

Reseach progress for ECDI-modified autoantigen peptides being used in autoimmune disease / 中国免疫学杂志

Ethylene carbodiimide (ECDI) is a chemical coupling agent,more and more studies have focused on the immune tolerance induced by administration of ethylene carbodiimide (ECDI)-fixed syngeneic splenocytes (Ag-SPs) coupled to peptides or to whole myelin proteins,in order to establish a novel and effective tolerance therapy for autoimmune diseases.The mechanisms and applications of immune tolerance induced by Ag-SPs in several kinds of common autoimmune diseases were summarized,and were compared with their counterparts in the traditional treatment.

The intravenous injection of oxidized LDL- or Apolipoprotein B100--Coupled splenocytes promotes Th1 polarization in wildtype and Apolipoprotein E--Deficient mice.

BACKGROUND: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis. METHODS AND RESULTS: OTII-transgenic mice that were treated with a single dose of 5 × 10(7) OVA-coupled splenocytes (OVA-SP), had decreased splenocyte proliferation, and lower IFNγ production in vitro upon antigen recall. However, in vivo CD4 cell activation was increased. To try lipoprotein-derived, "atherosclerosis-associated" antigens, we first tested human oxidized LDL. In wild type mice, an increase of IFNγ production upon in vitro recall was detected in the oxLDL-SP group. In Apolipoprotein E - deficient (ApoE-/-) mice that received oxLDL-SP every 5 weeks for 20 weeks, we did not find any difference of atherosclerotic plaque burden, but again increased IFNγ production. To overcome xenogenous limitations, we then examined the effects of mouse Apolipoprotein B100 peptides P3 and P6. ApoB100-SP treatment again promoted a more IFNγ pronounced response upon in vitro recall. Flow cytometry analysis of cytokine secreting spleen cells revealed CD4 positive T cells to be mainly the source for IFNγ. In ApoE-/- mice that were administered ApoB100-SP during 20 weeks, the atherosclerotic plaque burden in aortic roots as well as total aorta was unchanged compared to PBS treated controls. Splenocyte proliferation upon antigen recall was not significantly altered in ApoB100-SP treated ApoE-/- mice. CONCLUSION: Although we did not observe a relevant anti-atherosclerotic benefit, the treatment with antigen-coupled splenocytes in its present form already impacts the immune responses and deserves further exploration.

ECDI-fixed allogeneic splenocytes combined with α1-antitrypsin prolong survival of rat renal allografts.

Pre- and post-transplant infusions of donor splenocytes treated with 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (ECDI-SPs) induce donor-specific tolerance and prolong rat renal allograft survival. However, proinflammatory cytokine production during peritransplantation negates the effects of ECDI-SPs. Therefore, we reasoned that blocking proinflammatory cytokines would promote long-term ECDI-SP-induced allograft survival. We therefore examined the effects of infusing ECDI-SPs alone or in combination with a short course of α1-Antitrypsin (AAT) on the long-term outcomes of a rat kidney allograft model. The data showed that ECDI-SPs+AAT promote renal allograft survival compared with ECDI-SPs alone. This effect was accompanied by expansion of Foxp3+ Tregs, enhanced alloantigen-specific Treg function, and modulation of expression levels of proinflammatory cytokines IL-1ß, IL-6, TNF-α, and the anti-inflammatory cytokine IL-10. In conclusion, our strategy of combining ECDI-SPs and AAT provides a promising approach for inducing specific transplant tolerance.

Nanoparticle delivery of donor antigens for transplant tolerance in allogeneic islet transplantation.

Human islet cell transplantation is a promising treatment for type 1 diabetes; however, long-term donor-specific tolerance to islet allografts remains a clinically unmet goal. We have previously shown that recipient infusions of apoptotic donor splenocytes chemically treated with 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (donor ECDI-SP) can mediate long-term acceptance of full major histocompatibility complex (MHC)-mismatched murine islet allografts without the use of immunosuppression. In this report, we investigated the use of poly(lactide-co-glycolide) (PLG) particles in lieu of donor ECDI-SP as a synthetic, cell-free carrier for delivery of donor antigens for the induction of transplant tolerance in full MHC-mismatched murine allogeneic islet transplantation. Infusions of donor antigen-coupled PLG particles (PLG-dAg) mediated tolerance in ∼20% of recipient mice, and the distribution of cellular uptake of PLG-dAg within the spleen was similar to that of donor ECDI-SP. PLG-dAg mediated the contraction of indirectly activated T cells but did not modulate the direct pathway of allorecognition. Combination of PLG-dAg with a short course of low dose immunosuppressant rapamycin at the time of transplant significantly improved the tolerance efficacy to ∼60%. Furthermore, altering the timing of PLG-dAg administration to a schedule that is more feasible for clinical transplantation resulted in equal tolerance efficacy. Thus, the combination therapy of PLG-dAg infusions with peritransplant rapamycin represents a clinically attractive, biomaterials-based and cell-free method for inducing long-term donor-specific tolerance for allogeneic cell transplantation, such as for allogeneic islet transplantation.