Vascular Stem Cells in Diabetic Complications

Diabetes leads to a variety of secondary complications. At the heart of these complications lies endothelial cells (ECs) – cells that take up unregulated plasma glucose, experience various biochemical alterations, and provide the basis for whole organ vascular dysfunctions. With the purpose of generating new vascular networks for the treatment of these chronic complications, my initial work focused on vascular stem cells (VSCs). VSCs have the ability to differentiate into both endothelial (EPC) and mesenchymal (MPC) progenitor cells, both of which are necessary for the creation of stable and functional blood vessels. To establish whether these progenitor populations retain their integrity in diabetes, we investigated their cellular activity in a high glucose (HG) setting. Contrary to our expectations, EPCs evaded the negative effects of HG while MPCs displayed some functional alterations. Importantly, we noted MPCs in HG to be skewed towards the adipocyte lineage, while differentiation to both osteoblasts and chondrocytes was suppressed. MPC alterations exposed in our study are reminiscent of phenotypic changes that occur in the bone marrow of long-term diabetic patients. To elucidate the mechanism behind this alteration in MPC differentiation we examined the Wnt signaling pathway in a comprehensive manner. The results of this study have revealed a novel finding. We have demonstrated the autogenous upregulation of non-canonical Wnt11 in HG-treated MPCs, that signals through the Wnt/Ca2+/protein kinase C (PKC) pathway to stimulate adipogenesis. Increase in adipocytes in human diabetic marrow samples correlated with a decrease in the number of stem cells. We have also shown that enhanced adipogenesis in marrow samples may disrupt the stem cell niche by altering Angiopoeitin/Tie signaling axis. Taken together, targeting the conversion of stem cells to adipocytes could be an effective means to combat many chronic diabetic complications. Preventing adipogenesis may restore stem cell numbers in diabetic patients enabling endogenous repair

Vascular stem cells in diabetic complications: evidence for a role in the pathogenesis and the therapeutic promise

Long standing diabetes leads to structural and functional alterations in both the micro- and the macro-vasculature. Vascular endothelial cells (ECs) are the primary target of the hyperglycemia-induced adverse effects. Vascular stem cells that give rise to endothelial progenitor cells (EPCs) and mesenchymal progenitor cells (MPCs) represent an attractive target for cell therapy for diabetic patients. A number of studies have reported EPC dysfunction as a novel participant in the culmination of the diabetic complications. The controversy behind the identity of EPCs and the similarity between these progenitor cells to hematopoietic cells has led to conflicting results. MPCs, on the other hand, have not been examined for a potential role in the pathogenesis of the complications. These multipotent cells, however, do show a therapeutic role. In this article, we summarize the vascular changes that occur in diabetic complications highlighting some of the common features, the key findings that illustrate an important role of vascular stem cells (VSCs) in the pathogenesis of chronic diabetic complications, and provide mechanisms by which these cells can be used for therapy. © 2012 Keats and Khan; licensee BioMed Central Ltd

Vascular stem cells in diabetic complications: evidence for a role in the pathogenesis and the therapeutic promise

Long standing diabetes leads to structural and functional alterations in both the micro- and the macro-vasculature. Vascular endothelial cells (ECs) are the primary target of the hyperglycemia-induced adverse effects. Vascular stem cells that give rise to endothelial progenitor cells (EPCs) and mesenchymal progenitor cells (MPCs) represent an attractive target for cell therapy for diabetic patients. A number of studies have reported EPC dysfunction as a novel participant in the culmination of the diabetic complications. The controversy behind the identity of EPCs and the similarity between these progenitor cells to hematopoietic cells has led to conflicting results. MPCs, on the other hand, have not been examined for a potential role in the pathogenesis of the complications. These multipotent cells, however, do show a therapeutic role. In this article, we summarize the vascular changes that occur in diabetic complications highlighting some of the common features, the key findings that illustrate an important role of vascular stem cells (VSCs) in the pathogenesis of chronic diabetic complications, and provide mechanisms by which these cells can be used for therapy. © 2012 Keats and Khan; licensee BioMed Central Ltd

Switch from canonical to noncanonical Wnt signaling mediates high glucose-induced adipogenesis

Human bone marrow mesenchymal progenitor cells (MPCs) are multipotent cells that play an essential role in endogenous repair and the maintenance of the stem cell niche. We have recently shown that high levels of glucose, conditions mimicking diabetes, cause impairment of MPCs, resulting in enhanced adipogenesis and suppression of osteogenesis. This implies that diabetes may lead to reduced endogenous repair mechanisms through altering the differentiation potential of MPCs and, consequently, disrupting the stem cell niche. Phenotypic alterations in the bone marrow of long-term diabetic patients closely resemble this observation. Here, we show that high levels of glucose selectively enhance autogenous Wnt11 expression in MPCs to stimulate adipogenesis through the Wnt/protein kinase C noncanonical pathway. This novel mechanism may account for increased bone marrow adipogenesis, severe bone loss, and reduced vascular stem cells leading to chronic secondary complications of diabetes. Stem Cells 2014;32:1649-1660 © 2014 AlphaMed Press

The dietary intake and practices of adolescent girls in low- and middle-Income countries: A systematic review

In many low- and middle-income countries (LMICs) the double burden of malnutrition is high among adolescent girls, leading to poor health outcomes for the adolescent herself and sustained intergenerational effects. This underpins the importance of adequate dietary intake during this period of rapid biological development. The aim of this systematic review was to summarize the current dietary intake and practices among adolescent girls (10⁻19 years) in LMICs. We searched relevant databases and grey literature using MeSH terms and keywords. After applying specified inclusion and exclusion criteria, 227 articles were selected for data extraction, synthesis, and quality assessment. Of the included studies, 59% were conducted in urban populations, 78% in school settings, and dietary measures and indicators were inconsistent. Mean energy intake was lower in rural settings (1621 ± 312 kcal/day) compared to urban settings (1906 ± 507 kcal/day). Self-reported daily consumption of nutritious foods was low; on average, 16% of girls consumed dairy, 46% consumed meats, 44% consumed fruits, and 37% consumed vegetables. In contrast, energy-dense and nutrient-poor foods, like sweet snacks, salty snacks, fast foods, and sugar-sweetened beverages, were consumed four to six times per week by an average of 63%, 78%, 23%, and 49% of adolescent girls, respectively. 40% of adolescent girls reported skipping breakfast. Along with highlighting the poor dietary habits of adolescent girls in LMIC, this review emphasizes the need for consistently measured and standardized indicators, and dietary intake data that are nationally representativ

Progress and priorities for reproductive, maternal, newborn, and child health in Kenya: A countdown to 2015 country case study

Background: Progress in reproductive, maternal, newborn, and child health (RMNCH) in Kenya has been inconsistent over the past two decades, despite the global push to foster accountability, reduce child mortality, and improve maternal health in an equitable manner. Although several cross-sectional assessments have been done, a systematic analysis of RMNCH in Kenya was needed to better understand the push and pull factors that govern intervention coverage and influence mortality trends. As such, we aimed to determine coverage and impact of key RMNCH interventions between 1990 and 2015.Methods: We did a comprehensive, systematic assessment of RMNCH in Kenya from 1990 to 2015, using data from nationally representative Demographic Health Surveys done between 1989 and 2014. For comparison, we used modelled mortality estimates from the UN Inter-Agency Groups for Child and Maternal Mortality Estimation. We estimated time trends for key RMNCH indicators, as defined by Countdown to 2015, at both the national and the subnational level, and used linear regression methods to understand the determinants of change in intervention coverage during the past decade. Finally, we used the Lives Saved Tool (LiST) to model the effect of intervention scaleup by 2030.Findings: After an increase in mortality between 1990 and 2003, there was a reversal in all mortality trends from 2003 onwards, although progress was not substantial enough for Kenya to achieve Millennium Development Goal targets 4 or 5. Between 1990 and 2015, maternal mortality declined at half the rate of under-5 mortality, and changes in neonatal mortality were even slower. National-level trends in intervention coverage have improved, although some geographical inequities remain, especially for counties comprising the northeastern, eastern, and northern Rift Valley regions. Disaggregation of intervention coverage by wealth quintile also revealed wide inequities for several healthsystems-based interventions, such as skilled birth assistance. Multivariable analyses of predictors of change in family planning, skilled birth assistance, and full vaccination suggested that maternal literacy and family size are important drivers of positive change in key interventions across the continuum of care. LiST analyses clearly showed the importance of quality of care around birth for maternal and newborn survival.Interpretation: Intensified and focused efforts are needed for Kenya to achieve the RMNCH targets for 2030. Kenya must build on its previous progress to further reduce mortality through the widespread implementation of key preventive and curative interventions, especially those pertaining to labour, delivery, and the first day of life. Deliberate targeting of the poor, least educated, and rural women, through the scale-up of community-level interventions, is needed to improve equity and accelerate progress

Accelerating Kenya's progress to 2030: understanding the determinants of under-five mortality from 1990 to 2015.

INTRODUCTION: Despite recent gains, Kenya did not achieve its Millennium Development Goal (MDG) target for reducing under-five mortality. To accelerate progress to 2030, we must understand what impacted mortality throughout the MDG period. METHODS: Trends in the under-five mortality rate (U5MR) were analysed using data from nationally representative Demographic and Health Surveys (1989-2014). Comprehensive, mixed-methods analyses of health policies and systems, workforce and health financing were conducted using relevant surveys, government documents and key informant interviews with country experts. A hierarchical multivariable linear regression analysis was undertaken to better understand the proximal determinants of change in U5MR over the MDG period. RESULTS: U5MR declined by 50% from 1993 to 2014. However, mortality increased between 1990 and 2000, following the introduction of facility user fees and declining coverage of essential interventions. The MDGs, together with Kenya's political changes in 2003, ushered in a new era of policymaking with a strong focus on children under 5 years of age. External aid for child health quadrupled from 40 million in 2002 to 180 million in 2012, contributing to the dramatic improvement in U5MR throughout the latter half of the MDG period. Our multivariable analysis explained 44% of the decline in U5MR from 2003 to 2014, highlighting maternal literacy, household wealth, sexual and reproductive health and maternal and infant nutrition as important contributing factors. Children living in Nairobi had higher odds of child mortality relative to children living in other regions of Kenya. CONCLUSIONS: To attain the Sustainable Development Goal targets for child health, Kenya must uphold its current momentum. For equitable access to health services, user fees must not be reintroduced in public facilities. Support for maternal nutrition and reproductive health should be prioritised, and Kenya should acknowledge its changing demographics in order to effectively manage the escalating burden of poor health among the urban poor

Multiple-micronutrient supplementation in pregnant adolescents in low- and middle-income countries: a systematic review and a meta-analysis of individual participant data

Context Approximately 7.3 million births occur annually among adolescents in low- and middle-income countries. Pregnant adolescents constitute a nutritionally vulnerable group that could benefit from intervention to mitigate the mortality and adverse birth outcomes associated with adolescent pregnancy. Objective The aim of this systematic review and meta-analysis was to assess the following: (1) the effect of multiple-micronutrient (MMN) supplementation vs iron and folic acid (IFA) supplementation among adolescents on maternal morbidity, birth outcomes, and mortality outcomes, (2) the effects of MMN supplementation in adolescents compared with the effects in adult women, and (3) the effect modification, if any, of MMN supplementation by baseline and geographic characteristics of adolescents. Data Sources MEDLINE and Cochrane databases were searched, along with the reference lists of relevant reviews. Study Selection Multiple-micronutrient supplementation trials in pregnancy that were conducted in a low- or middle-income country and had included at least 100 adolescents (10–19 years of age) were eligible for inclusion. Two independent reviewers assessed study eligibility. Data Extraction Thirteen randomized controlled trials conducted in Africa and Asia were identified from 1792 reviews and 1578 original trials. Individual-level data was shared by study collaborators and was checked for completeness and extreme values. One- and two-stage individual participant data meta-analyses were conducted using data from randomized controlled trials of MMN supplementation. Results A total of 15 283 adolescents and 44 499 adult women with singleton births were included in the individual participant data meta-analyses of MMN supplementation vs IFA supplementation. In adolescents, MMN supplementation reduced low birth weight (1-stage OR = 0.87, 95%CI 0.77–0.97; 2-stage OR = 0.81; 95%CI 0.74–0.88), preterm birth (1-stage OR = 0.88, 95%CI 0.80–0.98; 2-stage OR = 0.86, 95%CI 0.79–0.95), and small-for-gestational-age births (1-stage OR = 0.90, 95%CI 0.81–1.00; 2-stage OR = 0.86, 95%CI 0.79–0.95) when compared with IFA supplementation. The effects of MMN supplementation did not differ between adolescents and older women, although a potentially greater reduction in small-for-gestational-age births was observed among adolescents. Effect modification by baseline characteristics and geographic region was inconclusive. Conclusions Multiple-micronutrient supplementation can improve birth outcomes among pregnant adolescents in low- and middle-income countries. Policy related to antenatal care in these settings should prioritize MMN supplementation over the currently recommended IFA supplementation for all pregnant women, especially adolescents

Indirect health sector actions and supportive strategies to prevent malnutrition

Purpose of review: Malnutrition is a pervasive problem that causes negative acute, long-term, and intergenerational consequences. As we have begun to move from efficacy to effectiveness trials of nutrition interventions, and further still to more holistic case study approaches to understanding how and why nutrition outcomes change over time, it has become clear that more emphasis on the \u27nutrition-sensitive\u27 interventions is required.Recent findings: In this article, we propose recategorizing the nutrition-specific and sensitive terminology into a new framework that includes direct and indirect health sector actions and supportive strategies that exist outside the health sector; an adjustment that will improve sector-specific planning and accountability. We outline indirect health sector nutrition interventions, with a focus on family planning and the evidence to support its positive link with nutrition outcomes. In addition, we discuss supportive strategies for nutrition, with emphasis on agriculture and food security, water, sanitation, and hygiene, and poverty alleviation and highlight some of the recent evidence that has contributed to these fields.Summary: Indirect health sector nutrition interventions and supportive strategies for nutrition will be critical, alongside direct health sector nutrition interventions, to reach global targets. Investments should be made both inside and outside the health sector