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Objective: Excessive childhood adiposity is a risk factor for adverse metabolic health. The objective was to investigate associations of newborn body composition and cord C-peptide with childhood anthropometrics and explore whether these newborn measures mediate associations of maternal midpregnancy glucose and BMI with childhood adiposity.Research Design and Methods: Data on mother/offspring pairs (N = 4,832) from the epidemiological Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and HAPO Follow-up Study (HAPO FUS) were analyzed. Linear regression was used to study associations between newborn and childhood anthropometrics. Structural equation modeling was used to explore newborn anthropometric measures as potential mediators of the associations of maternal BMI and glucose during pregnancy with childhood anthropometric outcomes.Results: In models including maternal glucose and BMI adjustments, newborn adiposity as measured by the sum of skinfolds was associated with child outcomes (adjusted mean difference, 95% CI, P value) BMI (0.26, 0.12-0.39, <0.001), BMI z-score (0.072, 0.033-0.11, <0.001), fat mass (kg) (0.51, 0.26-0.76, <0.001), percentage of body fat (0.61, 0.27-0.95, <0.001), and sum of skinfolds (mm) (1.14, 0.43-1.86, 0.0017). Structural equation models demonstrated significant mediation by newborn sum of skinfolds and cord C-peptide of maternal BMI effects on childhood BMI (proportion of total effect 2.5% and 1%, respectively), fat mass (3.1%, 1.2%), percentage of body fat (3.6%, 1.8%), and sum of skinfolds (2.9%, 1.8%), and significant mediation by newborn sum of skinfolds and cord C-peptide of maternal glucose effects on child fat mass (proportion of total association 22.0% and 21.0%, respectively), percentage of body fat (15.0%, 18.0%), and sum of skinfolds (15.0%, 20.0%).Conclusions: Newborn adiposity is independently associated with childhood adiposity and, along with fetal hyperinsulinemia, mediates, in part, associations of maternal glucose and BMI with childhood adiposity. [ABSTRACT FROM AUTHOR]

The process of inflammation is orchestrated by macrophages, according to their state of differentiation: thus, classically activated (M1) macrophages initiate the process by elaborating proinflammatory cytokines and reactive oxygen species, whereas the latter phase is controlled by alternatively activated macrophages (M2) to resolve inflammation and promote tissue remodelling with the release of growth factors. In a simple human inflammatory response, such as acute crystal arthropathy, macrophages progress linearly through M1 and M2 phases; however, in chronic inflammatory responses, such as atherosclerosis and Diabetic Nephropathy (DN), both M1 and M2 macrophages may coexist, leading to persistent inflammation and fibrosis. A key macrophage receptor that regulates conversion from M1 to M2 is CD163, the hemoglobin scavenger receptor. Scavenging of hemoglobin:haptoglobin (Hb:Hp) complexes via CD163 leads to nuclear translocation of the transcription factor Nrf2 (NF-E2-related factor 2), upregulation of heme oxygenase (HO)-1 cytoprotective protein, and release of interleukin (IL)-10 anti-inflammatory cytokine; IL-10 is then linked in a positive feedback loop to further CD163 expression. The potency of this M1/M2 switching pathway is underscored by the fact that human Hp2 polymorphisms are associated with worsened clinical outcomes for diabetic complications, including DN. Parallel observations in animals show that HO-1 activation by hemin protects against DN in rodent models of diabetes. This review discusses the concept that Nrf2/HO-1 acts as a 'therapeutic funnel' through which a range of natural and synthetic anti-oxidants may drive M1 to M2 switching and improved kidney function in diabetes. We also discuss our observations on the evolution of M1/M2 phenotypes in a human model of wound healing which has presented intriguing potential drug targets for DN, such as eotaxin/CCR3., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Intravascular hemolysis may cause tissue injury directly or via a systemic inflammatory response. Under physiological conditions, extracorpuscular hemoglobin (Hb) is bound by haptoglobin(Hp) and the complex internalized via the hemoglobin scavenger receptor CD163 on monocytes, prior to catabolism via heme-oxygenase-1 (HO-1). Recently, a novel subset of CD68(pos)CD163(high)HLA-DR(low) macrophages with high expression of HO-1 was recognized in hemorrhagic areas of atherosclerotic plaques, distinct from CD68(pos)CD163(low)HLA-DR(high) foam cell macrophages with low- HO-1 content. Considering the hemolytic insult during CPB, we hypothesized that an equivalent compensatory CD163(high)HLA-DR(low) phenotype will evolve in circulating CD14(pos) monocytes post surgery., Methods: Twelve patients undergoing elective surgery with CPB were enrolled with informed consent.Whole-blood samples were collected in EDTA at predetermined time-points, pre- intra-, and postoperatively. Whole-blood was evaluated by three-color flow cytometry for expression of CD14, CD163, and HLA-DR; CD14(pos) cells were also permeabilized to detect intracellular HO-1 protein. Plasma [Hp-Hb] concentration was determined by ELISA., Results: A striking phenotypic switch from CD163(low)HLA-DR(high) preoperatively to CD163(high)HLA-DR(low) postoperatively at 24 h was observed on circulating CD14(pos) monocytes. Intracellular HO-1 protein was also significantly up-regulated at 24 h after declamping. These phenotypic changes were preceded by peak Hb-Hp levels observed at 2 h., Conclusion: We have shown for the first time, a phenotypic commitment of monocytes towards a protective CD14(pos)CD163(high)HLA-DR(low) population with increased intracellular HO-1 occurring in the circulation during the recovery phase of CPB. These findings have implications for monitoring of anti-inflammatory interventions and linkage to clinical outcomes., (© 2010 International Clinical Cytometry Society)