IL-10-conditioned dendritic cells, decommissioned for recruitment of adaptive immunity, elicit innate inflammatory gene products in response to danger signals

Dendritic cells (DCs) are the professional APCs of the immune system, enabling T cells to perceive and respond appropriately to potentially dangerous microbes, while also being able to maintain T cell tolerance toward self. In part, such tolerance can be determined by IL-10 released from certain types of regulatory T cells. IL-10 has previously been shown to render DCs unable to activate T cells and it has been assumed that this process represents a general block in maturation. Using serial analysis of gene expression, we show that IL-10 pretreatment of murine bone marrow-derived DCs alone causes significant changes in gene expression. Furthermore, these cells retain the ability to respond to Toll-like receptor agonists, but in a manner skewed toward the selective induction of mediators known to enhance local inflammation and innate immunity, among which we highlight a novel CXCR2 ligand, DC inflammatory protein-1. These data suggest that, while the presence of a protolerogenic and purportedly anti-inflammatory agent such as IL-10 precludes DCs from acquiring their potential as initiators of adaptive immunity, their ability to act as initiators of innate immunity in response to Toll-like receptor signaling is enhanced

National, regional, and global causes of mortality in 5-19-year-olds from 2000 to 2019 : a systematic analysis

Background: Investments in the survival of older children and adolescents (aged 5-19 years) bring triple dividends for now, their future, and the next generation. However, 1·5 million deaths occurred in this age group globally in 2019, nearly all from preventable causes. To better focus the attention of the global community on improving survival of children and adolescents and to guide effective policy and programmes, sound and timely cause of death data are crucial, but often scarce. Methods: In this systematic analysis, we provide updated time-series for 2000-19 of national, regional, and global cause of death estimates for 5-19-year-olds with age-sex disaggregation. We estimated separately for countries with high versus low mortality, by data availability, and for four age-sex groups (5-9-year-olds [both sexes], 10-14-year-olds [both sexes], 15-19-year-old females, and 15-19-year-old males). Only studies reporting at least two causes of death were included in our analysis. We obtained empirical cause of death data through systematic review, known investigator tracing, and acquisition of known national and subnational cause of death studies. We adapted the Bayesian Least Absolute Shrinkage and Selection Operator approach to address data scarcity, enhance covariate selection, produce more robust estimates, offer increased flexibility, allow country random effects, propagate coherent uncertainty, and improve model stability. We harmonised all-cause mortality estimates with the UN Inter-agency Group for Child Mortality Estimation and systematically integrated single cause estimates as needed from WHO and UNAIDS. Findings: In 2019, the global leading specific causes of death were road traffic injuries (115 843 [95% uncertainty interval 110 672-125 054] deaths; 7·8% [7·5-8·1]); neoplasms (95 401 [90 744-104 812]; 6·4% [6·1-6·8]); malaria (81 516 [72 150-94 477]; 5·5% [4·9-6·2]); drowning (77 460 [72 474-85 952]; 5·2% [4·9-5·5]); and diarrhoea (72 679 [66 599-82 002], 4·9% [4·5-5·3]). The leading causes varied substantially across regions. The contribution of communicable, maternal, perinatal, and nutritional conditions declined with age, whereas the number of deaths associated with injuries increased. The leading causes of death were diarrhoea (51 630 [47 206-56 235] deaths; 10·0% [9·5-10·5]) in 5-9-year-olds; malaria (31 587 [23 940-43 116]; 8·6% [6·6-10·4]) in 10-14-year-olds; self-harm (32 646 [29 530-36 416]; 13·4% [12·6-14·3]) in 15-19-year-old females; and road traffic injuries (48 757 [45 692-52 625]; 13·9% [13·3-14·3]) in 15-19-year-old males. Widespread declines in cause-specific mortality were estimated across age-sex groups and geographies in 2000-19, with few exceptions like collective violence. Interpretation: Child and adolescent survival needs focused attention. To translate the vision into actions, more investments in the health information infrastructure for cause of death and in the related life-saving interventions are needed

Endothelial Restoration of Receptor Activity-Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy.

RAMPs (receptor activity-modifying proteins) serve as oligomeric modulators for numerous G-protein-coupled receptors, yet elucidating the physiological relevance of these interactions remains complex. Ramp2 null mice are embryonic lethal, with cardiovascular developmental defects similar to those observed in mice null for canonical adrenomedullin/calcitonin receptor-like receptor signaling. We aimed to genetically rescue the Ramp2(-/-) lethality in order to further delineate the spatiotemporal requirements for RAMP2 function during development and thereby enable the elucidation of an expanded repertoire of RAMP2 functions with family B G-protein-coupled receptors in adult homeostasis. Endothelial-specific expression of Ramp2 under the VE-cadherin promoter resulted in the partial rescue of Ramp2(-/-) mice, demonstrating that endothelial expression of Ramp2 is necessary and sufficient for survival. The surviving Ramp2(-/-) Tg animals lived to adulthood and developed spontaneous hypotension and dilated cardiomyopathy, which was not observed in adult mice lacking calcitonin receptor-like receptor. Yet, the hearts of Ramp2(-/-) Tg animals displayed dysregulation of family B G-protein-coupled receptors, including parathyroid hormone and glucagon receptors, as well as their downstream signaling pathways. These data suggest a functional requirement for RAMP2 in the modulation of additional G-protein-coupled receptor pathways in vivo, which is critical for sustained cardiovascular homeostasis. The cardiovascular importance of RAMP2 extends beyond the endothelium and canonical adrenomedullin/calcitonin receptor-like receptor signaling, in which future studies could elucidate novel and pharmacologically tractable pathways for treating cardiovascular diseases

Epicardial-derived adrenomedullin drives cardiac hyperplasia during embryogenesis.

BACKGROUND: Growth promoting signals from the epicardium are essential for driving myocardial proliferation during embryogenesis. In adults, these signals become reactivated following injury and promote angiogenesis and myocardial repair. Therefore, identification of such paracrine factors could lead to novel therapeutic strategies. The multi-functional peptide adrenomedullin (Adm 5 gene, AM 5 protein) is required for normal heart development. Moreover, elevated plasma AM following myocardial infarction offers beneficial cardioprotection and serves as a powerful diagnostic and prognostic indication of disease severity. RESULTS: Here, we developed a new model of Adm overexpression by stabilizing the Adm mRNA through gene-targeted replacement of the endogenous 30 untranslated region. As expected, Admhi/hi mice express three-times more AM than controls in multiple tissues, including the heart. Despite normal blood pressures, Admhi/hi mice unexpectedly showed significantly enlarged hearts due to increased cardiac hyperplasia during development. The targeting vector was designed to allow for reversion to wild-type levels by means of Cre-mediated modification. Using this approach, we demonstrate that AM derived from the epicardium, but not the myocardium or cardiac fibroblast, is responsible for driving cardiomyocyte hyperplasia. CONCLUSIONS: AM is produced by the epicardium and drives myocyte proliferation during development, thus representing a novel and clinically relevant factor potentially related to mechanisms of cardiac repair after injury

Assessing health and well-being among older people in rural South Africa

Background: The population in developing countries is ageing, which is likely to increase the burden of noncommunicable diseases and disability. Objective: To describe factors associated with self-reported health, disability and quality of life (QoL) of older people in the rural northeast of South Africa. Design: Cross-sectional survey of 6,206 individuals aged 50 and over. We used multivariate analysis to examine relationships between demographic variables and measures of self-reported health (Health Status), functional ability (WHODASi) and quality of life (WHOQoL). Results: About 4,085 of 6,206 people eligible (65.8%) completed the interview. Women (Odds Ratio (OR) 1.30, 95% CI 1.09, 1.55), older age (OR2.59, 95% CI 1.97, 3.40), lower education (OR1.62, 95% CI 1.31,2.00), single status (OR1.18, 95% CI 1.01, 1.37) and not working at present (OR1.29, 95% CI 1.06, 1.59) were associated with a low health status. Women were also more likely to report a higher level of disability (OR1.38, 95% CI 1.14, 1.66), as were older people (OR2.92, 95% CI 2.25, 3.78), those with no education (OR1.57, 95% CI 1.26, 1.97), with single status (OR1.25, 95% CI 1.06, 1.46) and not working at present (OR1.33, 95% CI 1.06, 1.66). Older age (OR1.35, 95% CI 1.06, 1.74), no education (OR1.39, 95% CI 1.11, 1.73), single status (OR1.28, 95% CI 1.10, 1.49), a low household asset score (OR1.52, 95% CI 1.19, 1.94) and not working at present (OR1.32; 95% CI 1.07, 1.64) were all associated with lower quality of life. Conclusions: This study presents the first population-based data from South Africa on health status, functional ability and quality of life among older people. Health and social services will need to be restructured to provide effective care for older people living in rural South Africa with impaired functionality and other health problems

Comparison of the Therapeutic Effects of Human and Mouse Adipose-Derived Stem Cells in a Murine Model of Lipopolysaccharide-Induced Acute Lung Injury

Introduction. Adipose-derived stem cells (ASCs) have emerged as important regulators of inflammatory/immune responses in vitro and in vivo and represent attractive candidates for cell-based therapies for diseases that involve excessive inflammation. Acute lung injury (ALI) is an inflammatory condition for which treatment is mainly supportive due to lack of effective therapies. In this study, the therapeutic effects of ASC-based therapy were assessed in vivo by comparison of the anti-inflammatory properties of both human and murine ASCs in a mouse model of lipopolysaccharide (LPS)-induced ALI. Methods. Human ASCs (hASCs) or mouse ASCs (mASCs) were delivered to C57Bl/6 mice (7.5 x 105 total cells/mouse) by oropharyngeal aspiration (OA) four hours after the animals were challenged with lipopolysaccharide (15 mg/kg). Mice were sacrificed 24 and 72 hours after LPS exposure, and lung histology examined for evaluation of inflammation and injury. Bronchoalveolar lavage fluid (BALF) was analyzed to determine total and differential cell counts, total protein and albumin concentrations, and myeloperoxidase (MPO) activity. Cytokine expression in the injured lungs was measured at the steady-state mRNA levels and protein levels for assessment of the degree of lung inflammation. Results: Both human and mouse ASC treatments provided protective anti-inflammatory responses. There were decreased levels of leukocyte (for example neutrophil) migration into the alveoli, total protein and albumin concentrations in BALF, and MPO activity after the induction of ALI following both therapies. Additionally, cell therapy with both cell types effectively suppressed the expression of proinflammatory cytokines and increased the anti-inflammatory cytokine interleukin 10 (IL-10). Overall, the syngeneic mASC therapy had a more potent therapeutic effect than the xenogeneic hASC therapy in this model. Conclusions: Treatment with hASCs or mASCs significantly attenuated LPS-induced acute lung injury in mice. These results suggest a potential benefit for using an ASC-based therapy to treat clinical ALI and may possibly prevent the development of acute respiratory distress syndrome (ARDS)

Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals

Background Causes of mortality are a crucial input for health systems for identifying appropriate interventions for child survival. We present an updated series of cause-specific mortality for neonates and children younger than 5 years from 2000 to 2019. Methods We updated cause-specific mortality estimates for neonates and children aged 1-59 months, stratified by level (low, moderate, or high) of mortality. We made a substantial change in the statistical methods used for previous estimates, transitioning to a Bayesian framework that includes a structure to account for unreported causes in verbal autopsy studies. We also used systematic covariate selection in the multinomial framework, gave more weight to nationally representative verbal autopsy studies using a random effects model, and included mortality due to tuberculosis. Findings In 2019, there were 5·30 million deaths (95% uncertainty range 4·92-5·68) among children younger than 5 years, primarily due to preterm birth complications (17·7%, 16·1-19·5), lower respiratory infections (13·9%, 12·0-15·1), intrapartum-related events (11·6%, 10·6-12·5), and diarrhoea (9·1%, 7·9-9·9), with 49·2% (47·3-51·9) due to infectious causes. Vaccine-preventable deaths, such as for lower respiratory infections, meningitis, and measles, constituted 21·7% (20·4-25·6) of under-5 deaths, and many other causes, such as diarrhoea, were preventable with low-cost interventions. Under-5 mortality has declined substantially since 2000, primarily because of a decrease in mortality due to lower respiratory infections, diarrhoea, preterm birth complications, intrapartum-related events, malaria, and measles. There is considerable variation in the extent and trends in cause-specific mortality across regions and for different strata of all-cause under-5 mortality. Interpretation Progress is needed to improve child health and end preventable deaths among children younger than 5 years. Countries should strategize how to reduce mortality among this age group using interventions that are relevant to their specific causes of death. Funding Bill & Melinda Gates Foundation; WHO

Revitalizing child health: lessons from the past

Essential health, education and other service disruptions arising from the COVID-19 pandemic risk reversing some of the hard-won gains in improving child survival over the past 40 years. Although children have milder symptoms of COVID-19 disease than adults, pandemic control measures in many countries have disrupted health, education and other services for children, often leaving them without access to birth and postnatal care, vaccinations and early childhood preventive and treatment services. These disruptions mean that the SARS-CoV-2 virus, along with climate change and shifting epidemiological and demographic patterns, are challenging the survival gains that we have seen over the past 40 years. We revisit the initiatives and actions of the past that catalyzed survival improvements in an effort to learn how to maintain these gains even in the face of today's global challenges