Offspring sex modifies the association between early-pregnancy adiposity and 2-year-old physical activity-The Glowing Study.

BACKGROUND: Rodent models suggest that in utero exposure to under and overnutrition programs offspring physical activity (PA) behaviors. Such nexus has not been established in humans. This study evaluated the association of early pregnancy maternal adiposity with offspring PA at age 2 years (2-yo-PA) taking into consideration prenatal and postnatal factors. METHODS: Women (n = 153) were enrolled early in pregnancy (<10 weeks). At enrollment, maternal adiposity [air displacement plethysmography, fat mass index (FMI, kg/m2)] and PA (accelerometers, activity counts) were measured, and age, race, and education self-reported. Gestational weight gain was measured at the research facility. Offspring birthweight and sex were self-reported. At age 2 years, parental feeding practices (child feeding questionnaire) were assessed, whereas anthropometrics (length and weight) and physical activity (accelerometers) were objectively measured. Offspring body mass index z-scores were calculated. Generalized linear regression analysis modeled the association of maternal FMI and 2-yo-PA [average activity counts (AC)4/day]. RESULTS: In bivariate associations, 2-yo-PA did not associate with maternal FMI (ß = -0.22, CI = -0.73 to 0.29, p = 0.398). However, maternal FMI interacted with offspring sex in association with 2-yo-PA. Specifically, 2-yo-PA was lower in girls (ß = -1.14, CI = -2.1 to -0.18, p = 0.02) compared to boys when maternal FMI was ≥7 kg/m2. When stratified by sex, 2-yo-PA of girls negatively associated with maternal FMI (ß = -0.82, CI = -1.43 to 0.29, p = 0.009) while no association was found between maternal FMI and boy's PA (ß = 0.32, CI = -0.38 to 1.01, p = 0.376). CONCLUSIONS: The association of 2-yo-PA and early pregnancy maternal adiposity was modified by offspring sex. Offspring's physical activity decreased with increasing early pregnancy adiposity maternal in girls but not boys in second parity dyads.

Effects of short-term supervised exercise training on liver fat in adolescents with obesity: a randomized controlled trial.

OBJECTIVE: The objective of this study was to quantify the effects of a 4-week, supervised, high-intensity interval training (HIIT) on intrahepatic triglyceride content (IHTG, percentage), cardiorespiratory fitness (CRF), and cardiometabolic markers in adolescents with obesity. METHODS: A total of 40 adolescents (age 13-18 y, BMI 36.7 ± 5.8 kg/m2 ) at risk for metabolic dysfunction-associated steatotic liver disease (MASLD) based on obesity and elevated Fibroscan measured controlled attenuation parameter (CAP) scores were randomized to HIIT three times a week for 4 weeks (n = 34) or observation (control; n = 6). Liver magnetic resonance imaging proton-density fat-fraction (MRI-PDFF), CAP, oral glucose tolerance test, serum alanine aminotransferase, dual-energy x-ray absorptiometry, and CRF tests were performed before and after intervention. Within- and between-group differences were compared. RESULTS: A total of 13 (38%) and 4 (66%) children had MASLD by MRI-PDFF (IHTG ≥ 5%) in the HIIT and control groups, respectively. The implemented HIIT protocol had no impact on CRF or IHTG (baseline 5.26%, Δ = -0.31 percentage points, 95% CI: -0.77 to 0.15; p = 0.179), but it decreased the 2-h glucose concentration (baseline 116 mg/dL, Δ = -11 mg/dL; 95% CI: -17.6 to -5.5; p < 0.001). When limiting the analysis to participants with MASLD (n = 17), HIIT decreased IHTG (baseline 8.81%, Δ = -1.05 percentage points, 95% CI: -2.08 to -0.01; p = 0.048). Between-group comparisons were not different. CONCLUSIONS: The implemented exercise protocol did not reduce IHTG, but it led to modest improvement in markers of cardiometabolic health.

Spatially patterned 3D model mimics key features of cancer metastasis to bone.

Bone is the most common target of metastasis in breast cancer and prostate cancer, leading to significant mortality due to lack of effective treatments. The discovery of novel therapies has been hampered by a lack of physiologically relevant in vitro models that can mimic key clinical features of bone metastases. To fill this critical gap, here we report spatially patterned, tissue engineered 3D models of breast cancer and prostate cancer bone metastasis which mimic bone-specific invasion, cancer aggressiveness, cancer-induced dysregulation of bone remodeling, and in vivo drug response. We demonstrate the potential of integrating such 3D models with single-cell RNA sequencing to identify key signaling drivers of cancer metastasis to bone. Together, these results validate that spatially patterned 3D bone metastasis models mimic key clinical features of bone metastasis and can serve as a novel research tool to elucidate bone metastasis biology and expedite drug discovery.

Elevated LDL-C, high blood pressure, and low peak V ˙ O2 associate with platelet mitochondria function in children-The Arkansas Active Kids Study.

Purpose: To evaluate the association of platelet (PL) mitochondria respiration with markers of cardiovascular health in children ages 7-10 years. Methods: PL mitochondrial respiration (n = 91) was assessed by high resolution respirometry (HRR): Routine (R) respiration, complex (C) I linked respiration (CI), and maximal uncoupled electron transport capacity of CII (CIIE) were measured. The respiratory control ratio (RCR) was calculated as the ratio of maximal oxidative phosphorylation capacity of CI and CI leak respiration (PCI/LCI). Peak V ˙ O2 (incremental bike test) and body composition (dual-energy X-ray absorptiometry) were measured. Multiple generalized linear regression analysis was used to model the association of measures by HRR with variables of interest: adiposity, low-density lipoprotein (LDL-C) and triglyceride (TG) status (normal vs. elevated) HOMA2-IR, blood pressure status (normal vs. high), and demographics. Results: R and CI-linked respiration positively associated with adiposity, high blood pressure (HBP), and peak V ˙ O2. R and CI-linked respiration had inverse association with age and elevated LDL-C. CIIE was higher in children with elevated LDL-C (log-ß = -0.54, p = 0.010). HBP and peak V ˙ O2 interacted in relation to RCR (log-ß = -0.01, p = 0.028). Specifically, RCR was lowest among children with HBP and low aerobic capacity (i.e., mean peak V ˙ O2 -1SD). HOMA2-IR did not associate with measures of PL mitochondria respiration. Conclusion: In PL, R and CI-linked mitochondrial respiration directly associate with adiposity, peak V ˙ O2 and HBP. Elevated LDL-C associates with lower CI-linked respiration which is compensated by increasing CII respiration. PL bioenergetics phenotypes in children associate with whole-body metabolic health status.

Obesity, but not glycemic control, predicts liver steatosis in children with type 1 diabetes.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD), the most common liver disease in children, is strongly associated with obesity and insulin resistance. Although type 1 diabetes (T1D) is characterized by insulin deficiency, increasing obesity rates among children with T1D is a major risk factor for NAFLD in this patient population. Predisposing factors for NAFLD in children with T1D are not known. STUDY DESIGN: This is a cross-sectional study comparing children with T1D across the range of body mass index (BMI) to the BMI-matched obese group without T1D. Hepatic steatosis was semi-quantitatively measured via the vibration-controlled transient elastogram (VCTE) method. Linear regression analysis was performed to assess the relationship between controlled-attenuated parameter (CAP) scores and clinical parameters. Receiver-operator curve (ROC) analysis was used to evaluate the diagnostic performance of several clinical parameters against NAFLD status determined via CAP. RESULTS: Two-thirds of subjects with obesity had CAP scores suggestive of NAFLD, while 16 % (n = 6) of T1D patients without obesity had elevated CAP. Obese subjects were different from non-obese subjects in many laboratory and clinical characteristics, regardless of T1D status. CAP score was significantly associated with BMI, HDL-Cholesterol (HDL-c), and HbA1c in all subjects as well as the T1D-only subgroup. Among subjects with obesity only, age, HDL-cand ALT were the most significant predictors. Diagnostic performance of BMI, HDL-c, and BMI/HDL ratio were in the good to the excellent range for predicting NAFLD among all subjects, while performance varied for T1D-only or obesity-only groups. CONCLUSION: The clinical and imaging findings of children with T1D and obesity are comparable to non-diabetic children with a similar degree of obesity. Obesity is the major risk factor for NAFLD in pediatric T1D. BMI, HDL-c, and BMI/HDL ratio may be helpful markers to determine further workup for NAFLD in children with T1D, particularly those with obesity.

A 3D Osteosarcoma Model with Bone-Mimicking Cues Reveals a Critical Role of Bone Mineral and Informs Drug Discovery.

Osteosarcoma (OS) is an aggressive bone cancer for which survival has not improved over three decades. While biomaterials have been widely used to engineer 3D soft-tissue tumor models, the potential of engineering 3D biomaterials-based OS models for comprehensive interrogation of OS pathology and drug discovery remains untapped. Bone is characterized by high mineral content, yet the role of bone mineral in OS progression and drug response remains unknown. Here, a microribbon-based OS model with bone-mimicking compositions is developed to elucidate the role of 3D culture and hydroxyapatite in OS signaling and drug response. The results reveal that hydroxyapatite in 3D is critical to support retention of OS signaling and drug resistance similar to patient tissues and mouse orthotopic tumors. The physiological relevance of this 3D model is validated using four established OS cell lines, seven patient-derived xenograft (PDX) cell lines and two animal models. Integrating 3D OS PDX models with RNA-sequencing identified 3D-specific druggable target, which predicts drug response in mouse orthotopic model. These results establish microribbon-based 3D OS models as a novel experimental tool to enable discovery of novel therapeutics that would be otherwise missed with 2D model and may serve as platforms to study patient-specific OS heterogeneity and drug resistance mechanisms.

Breastfeeding duration modifies the association between maternal weight status and offspring dietary palmitate oxidation.

BACKGROUND: Offspring of obese rodents develop a metabolic phenotype that favors fat deposition. Data regarding the impact of maternal obesity programing of offspring fuel usage in humans is scarce. OBJECTIVE: The objective of this study was to explore the association between maternal weight status and dietary palmitate oxidation (DPO) in 2-y-old offspring, taking into consideration potential confounders and modifiers. METHODS: Women (n = 56) were enrolled by the first trimester of gestation. Maternal physical activity (PA; measured with accelerometers) at enrollment and gestational weight gain (GWG) were measured. Offspring sex, race, and breastfeeding (BF) duration were self-reported. Human milk (HM) composition was determined at 6 mo postpartum. At age 2 y, dietary quality [healthy eating index (HEI)] and parental feeding practices [Child Feeding Questionnaire (CFQ)] were assessed. DPO in 2-y-olds (2-yo-DPO) was measured using deuterated palmitic acid. Generalized linear regression analysis was used to model the associations of 2-yo-DPO with maternal weight status [normal weight (NW), BMI <25 (in kg/m2) compared with excessive weight (EW), BMI ≥25]. RESULTS: DPO was higher in offspring of women with EW compared with NW (2.1 ± 1.2%/h compared with 1.4 ± 0.7%/h, P = 0.03). Maternal weight status interacted with BF duration in association with 2-yo-DPO (log ß: 0.05, P = 0.04). Specifically, 2-yo-DPO was higher in the EW compared with NW group if BF duration was ≥9 mo. HM insulin (log ß: 0.35, P = 0.002) and HM leptin (log ß: 0.81, P = 0.001) concentrations directly associated with 2-yo-DPO. PA (log ß: 0.06, P = 0.013), parental feeding restriction (log ß: 0.05, P < 0.0001), and male sex (log ß: 0.54, P < 0.001) were positively associated with 2-yo-DPO. HEI was negatively associated with 2-yo-DPO (log ß:-0.03, P < 0.0001). CONCLUSIONS: Higher 2-yo-DPO in offspring of women with EW compared with NW were driven by BF duration. Higher HM insulin and leptin concentrations in women with EW may explain these finding. More studies are needed to confirm these results. This trial was registered at clinicaltrials.gov as NCT03281850.

Cardiorespiratory Fitness Associates with Blood Pressure and Metabolic Health of Children-The Arkansas Active Kids Study.

INTRODUCTION: High blood pressure (HBP) in children causes preclinical damage to the heart and accelerates atherosclerosis. Current pharmacological treatments have limited ability to prevent end-organ damage, particularly that of the kidneys. A contrasting element between adult versus pediatric HPB treatment is the emphasis in adults on exercise regimens that target increments in cardiorespiratory fitness (CRF; peak oxygen consumption [V˙O2peak]). The aim of this study was to evaluate the association of CRF with blood pressure percentiles and blood pressure status in children with normal and excessive adiposity (NA vs EA). An exploratory aim was to measure associations of CRF with (a) other cardiovascular disease risk factors commonly found in children with HBP and (b) kidney function. METHODS: Children (n = 211) attended one study visit. CRF was measured using an incremental bike test and body composition by dual-energy x-ray absorptiometry. Fat-free mass (FFM) index was calculated as kilograms of FFM per square meter. Multiple logistic and linear regression analyses were used to model the probability of HBP and other variables of interest (plasma lipids, HOMA2-IR, alanine aminotransferase, and estimated glomerular filtration rate) against V˙O2peak. RESULTS: CRF interacted with adiposity status in predicting the probability of HBP. Each additional milliliter per minute per FFM index in V˙O2peak decreased the odds of HBP by 8% in the EA group only (odds ratio = 0.92, 95% confidence interval = 0.87-0.99). Systolic and diastolic blood pressure percentiles decreased, and estimated glomerular filtration rate increased with increasing CRF in both adiposity-level groups. HOMA2-IR and alanine aminotransferase decreased with increasing CRF in children with EA only. CONCLUSIONS: Higher CRF associated with decreased probability of clinical HBP, lower insulin resistance, and improved liver function in children with EA. Yet blood pressure percentiles and kidney function improved with increasing CRF irrespective of adiposity status.

Dietary Protein Requirements in Children: Methods for Consideration.

The current protein requirement estimates in children were largely determined from studies using the nitrogen balance technique, which has been criticized for potentially underestimating protein needs. Indeed, recent advances in stable isotope techniques suggests protein requirement as much as 60% higher than current recommendations. Furthermore, there is not a separate recommendation for children who engage in higher levels of physical activity. The current evidence suggests that physical activity increases protein requirements to support accretion of lean body masses from adaptations to exercise. The indicator amino acid oxidation and the 15N-end product methods represent alternatives to the nitrogen balance technique for estimating protein requirements. Several newer methods, such as the virtual biopsy approach and 2H3-creatine dilution method could also be deployed to inform about pediatric protein requirements, although their validity and reproducibility is still under investigation. Based on the current evidence, the Dietary Reference Intakes for protein indicate that children 4-13 years and 14-18 years require 0.95 and 0.85 g·kg-1·day-1, respectively, based on the classic nitrogen balance technique. There are not enough published data to overturn these estimates; however, this is a much-needed area of research.

Fibroblast Growth Factor-21 to Adiponectin Ratio: A Potential Biomarker to Monitor Liver Fat in Children With Obesity.

Background: There is a pressing need for effective and non-invasive biomarkers to track intrahepatic triglyceride (IHTG) in children at-risk for non-alcoholic fatty liver disease (NAFLD), as standard-of-care reference tools, liver biopsy and magnetic resonance imaging (MRI), are impractical to monitor the course disease. Objective: We aimed to examine the association between serum fibroblast growth factor (FGF)-21 to adiponectin ratio (FAR) and IHTG as assessed by MRI in children with obesity. Methods: Serum FGF21 and adiponectin levels and IHTG were measured at two time points (baseline, 6 months) in obese children enrolled in a clinical weight loss program. The association between percent change in FAR and IHTG at final visit was examined using a multiple linear regression model. Results: At baseline, FAR was higher in the subjects with NAFLD (n = 23, 35.8 ± 41.9 pg/ng) than without NAFLD (n = 35, 19.8 ± 13.7 pg/ng; p = 0.042). Forty-eight subjects completed both visits and were divided into IHTG loss (≥1% reduction than baseline), no change (within ±1% change), and gain (≥1% increase than baseline) groups. At 6 months, the percent change in FAR was different among the three groups (p = 0.005). Multiple linear regression showed a positive relationship between percent change in FAR and the final liver fat percent in sex and pubertal stage-similar subjects with NAFLD at baseline (slope coefficient 6.18, 95% CI 1.90-10.47, P = 0.007), but not in those without NAFLD. Conclusions: Higher value in percent increase in FAR is positively associated with higher level of IHTG percent value at 6 months in children with baseline NAFLD. FAR could be a potential biomarker to monitor the changes in IHTG in children with NAFLD.

Changes in Polyphenolics during Storage of Products Prepared with Freeze-Dried Wild Blueberry Powder.

Wild blueberry (WBB) powder can be added to the formulation of foods to encourage consumption of health-promoting polyphenolics, but the stability of polyphenolics throughout storage is important. We determined the stability of polyphenolics in five products (ice pop, oatmeal bar, graham cracker cookie, juice, and gummy product) prepared with WBB powder. Samples stored at 21 °C, 4.4 °C, or -20 °C (ice pops only) were analyzed at 0, 2, 4, 6, and 8 weeks for polyphenolic content and percent polymeric color. Total anthocyanins decreased over storage and storage temperatures in all products. However, the ice pop and the refrigerated juice both retained over 90% of their initial total anthocyanin content. The refrigerated oatmeal bar also showed good retention of anthocyanins (86%), but the gummy product retained only 43% and 51% when stored at 4.4 °C or 21 °C, respectively. The lower amount of polyphenolic compounds recovered in the gummies stored at 4.4 °C compared to 21 °C may be attributed to reduced extraction efficiency as a result of gel hardening at refrigerated temperature. Chlorogenic acid and flavonols were generally more stable than anthocyanins throughout storage.

Divergent Changes in Serum Branched-Chain Amino Acid Concentrations and Estimates of Insulin Resistance throughout Gestation in Healthy Women.

BACKGROUND: Branched-chain amino acid (BCAA) concentrations in the blood have been correlated with insulin resistance, but this relation throughout gestation (period in which insulin resistance typically increases) is unclear. OBJECTIVE: The objective of this study was to determine the associations between changes in BCAA concentrations and estimates of insulin resistance throughout gestation. METHODS: Serum BCAA (Leu, Ile, Val) concentrations and insulin resistance/sensitivity [i.e., homeostatic model assessment-2 of insulin resistance (HOMA2-IR), estimated metabolic clearance rate (MCR) of glucose, and estimated first- and second-phase insulin responses] were assessed at early (EP; 8.5 ± 0.2 wk) and/or late (LP; 29.2 ± 0.8 wk) pregnancy in 53 healthy women from the Glowing cohort. Adjusted Spearman correlations were used to evaluate the association between BCAA and insulin resistance/sensitivity measures at EP and LP, adjusted for body fat percentage and gestational weight gain (GWG). A multiple linear regression analysis was used to assess the association between changes in HOMA2-IR and BCAAs throughout gestation. Groups were made post hoc based on the mean percentage change (10% decrease) in Leu throughout gestation, creating a group with a ≥10% decrease in LeuLP-EP (BELOW) and a <10% decrease in LeuLP-EP (ABOVE), and Student's t tests were performed to assess differences between groups. RESULTS: Leu and Ile concentrations positively correlated with HOMA2-IR at both time points, but these relations at EP disappeared/weakened when adjusted for body fat percentage. From EP to LP, the change in Leu (LeuLP-EP) was negatively associated with the change in HOMA2-IR (HOMA2-IRLP-EP) (ß = -0.037, P = 0.006). MCR was lower in the BELOW group compared with the ABOVE group, whereas there was no difference in HOMA2-IR between groups. CONCLUSIONS: In this pregnancy cohort, BCAA concentrations decreased throughout gestation, whereas the mean insulin resistance did not change. These data do not support a connection between changes in blood BCAA concentrations and estimates of insulin resistance in pregnant women. This trial is registered at clinicaltrials.gov as NCT01131117.

Maternal Adiposity is Associated with Fat Mass Accretion in Female but not Male Offspring During the First 2 Years of Life.

OBJECTIVE: This study investigated which antenatal and postnatal factors determine offspring adiposity during the first 2 years of life. METHODS: Participants were mother and child pairs (N = 224). Offspring percent fat mass (%FM) was obtained using quantitative nuclear magnetic resonance at 11 time points between ages 0.5 and 24 months. Independent variables included race, age, gestational weight gain, first-trimester %FM, delivery mode, gestational measures of resting energy expenditure, respiratory exchange ratio, physical activity, serum cytokines and lipids, and dietary intake for the mothers, as well as sex, birth weight and length, breastfeeding duration, and physical activity at age 2 years for the children. Linear mixed models were used to construct the best-fitted models for the entire cohort and for each sex. RESULTS: Maternal %FM (P = 0.006), high-density lipoprotein (HDL) (P < 0.001), and breastfeeding duration (P = 0.023) were positively associated with female offspring adiposity, whereas maternal dietary fiber intake (P = 0.016) had a negative association. Birth weight (P = 0.004), maternal HDL (P = 0.013), and breastfeeding duration (P = 0.015) were all positively associated with male offspring adiposity. CONCLUSIONS: Antenatal and postnatal factors differentially impact male and female offspring adiposity during the first 2 years of life.

Parental adiposity differentially associates with newborn body composition.

BACKGROUND: Maternal obesity increases offspring's obesity risk. However, studies have not often considered maternal metabolic and exercise patterns as well as paternal adiposity as potential covariates. OBJECTIVE: To assess the relationship between parental and newborn adiposity. METHODS: Participants were mother-child pairs (n = 209) and mother-father-offspring triads (n = 136). Parental (during gestation) and offspring (2 weeks old) percent fat mass (FM) were obtained using air displacement plethysmography. Maternal race, age, resting energy expenditure (indirect calorimetry), physical activity (accelerometry), gestational weight gain (GWG), gestational age (GA), delivery mode, infant's sex and infant feeding method were incorporated in multiple linear regression analyses. The association between parental FM and offspring insulin-like growth factor 1 (IGF-1) was assessed at age 2 years. RESULTS: Maternal adiposity was positively-associated with male (ß = 0.11, P = .015) and female (ß = 0.13, P = .008) infant FM, whereas paternal adiposity was negatively-associated with male newborn adiposity (ß = -0.09, P = .014). Breastfeeding, female sex, GA and GWG positively associated with newborn adiposity. Vaginal and C-section delivery methods associated with greater adiposity than vaginal induced delivery method. Plasma IGF-1 of 2-year-old boys and girls positively associated with their respective fathers' and mothers' FM. CONCLUSIONS: Maternal and paternal adiposity differentially associate with newborn adiposity. The mechanisms of this finding remain to be determined.

Tissue-engineered 3D models for elucidating primary and metastatic bone cancer progression.

Malignant bone tumors are aggressive neoplasms which arise from bone tissue or as a result of metastasis. The most prevalent types of cancer, such as breast, prostate, and lung cancer, all preferentially metastasize to bone, yet the role of the bone niche in promoting cancer progression remains poorly understood. Tissue engineering has the potential to bridge this knowledge gap by providing 3D in vitro systems that can be specifically designed to mimic key properties of the bone niche in a more physiologically relevant context than standard 2D culture. Elucidating the crucial components of the bone niche that recruit metastatic cells, support tumor growth, and promote cancer-induced destruction of bone tissue would support efforts for preventing and treating these devastating malignancies. In this review, we summarize recent efforts focused on developing in vitro 3D models of primary bone cancer and bone metastasis using tissue engineering approaches. Such 3D in vitro models can enable the identification of effective therapeutic targets and facilitate high-throughput drug screening to effectively treat bone cancers. STATEMENT OF SIGNIFICANCE: Biomaterials-based 3D culture have been traditionally used for tissue regeneration. Recent research harnessed biomaterials to create 3D in vitro cancer models, with demonstrated advantages over conventional 2D culture in recapitulating tumor progression and drug response in vivo. However, previous work has been largely limited to modeling soft tissue cancer, such as breast cancer and brain cancer. Unlike soft tissues, bone is characterized with high stiffness and mineral content. Primary bone cancer affects mostly children with poor treatment outcomes, and bone is the most common site of cancer metastasis. Here we summarize emerging efforts on engineering 3D bone cancer models using tissue engineering approaches, and future directions needed to further advance this relatively new research area.

A comparative study of mitochondrial respiration in circulating blood cells and skeletal muscle fibers in women.

Skeletal muscle mitochondrial respiration is thought to be altered in obesity, insulin resistance, and type 2 diabetes; however, the invasive nature of tissue biopsies is an important limiting factor for studying mitochondrial function. Recent findings suggest that bioenergetics profiling of circulating cells may inform on mitochondrial function in other tissues in lieu of biopsies. Thus, we sought to determine whether mitochondrial respiration in circulating cells [peripheral blood mononuclear cells (PBMCs) and platelets] reflects that of skeletal muscle fibers derived from the same subjects. PBMCs, platelets, and skeletal muscle (vastus lateralis) samples were obtained from 32 young (25-35 yr) women of varying body mass indexes. With the use of extracellular flux analysis and high-resolution respirometry, mitochondrial respiration was measured in intact blood cells as well as in permeabilized cells and permeabilized muscle fibers. Respiratory parameters were not correlated between permeabilized muscle fibers and intact PBMCs or platelets. In a subset of samples (n = 12-13) with permeabilized blood cells available, raw measures of substrate (pyruvate, malate, glutamate, and succinate)-driven respiration did not correlate between permeabilized muscle (per mg tissue) and permeabilized PBMCs (per 106 cells); however, complex I leak and oxidative phosphorylation coupling efficiency correlated between permeabilized platelets and muscle (Spearman's ρ = 0.64, P = 0.030; Spearman's ρ = 0.72, P = 0.010, respectively). Our data indicate that bioenergetics phenotypes in circulating cells cannot recapitulate muscle mitochondrial function. Select circulating cell bioenergetics phenotypes may possibly inform on overall metabolic health, but this postulate awaits validation in cohorts spanning a larger range of insulin resistance and type 2 diabetes status.

Clearance of Indocyanine Green in Severe Pediatric Burns.

BACKGROUND: Clearance of indocyanine green dye (ICGc) reflects sinusoidal perfusion and hepatocyte cell membrane function. Thus, ICGc is a reflection of the functional reserve of intact hepatocytes. The purpose of this study was to identify predictors of ICGc in severely burned children during the acute hospitalization and at the time of discharge from the intensive care unit (ICU). A secondary aim was to determine the relationship between liver size and patient ICGc. METHODS: Twenty-six children (0.8-17 years old) with 35% or greater total body surface area burned (%TBSA-B) were included. Assessment of ICGc (in milliliters per minute per meter squared) was done during the acute hospitalization (median: 6 days after admission, median: 14 days postburn) and at the time of discharge from the ICU (median: 19 days after admission, median: 27 days postburn). Age, TBSA-B, % third-degree burns, inhalation injury, preexisting chronic malnutrition, hematocrit, liver dysfunction, and time from burn injury were incorporated in multiple linear regressions as predictive variables of ICGc. Only variables with p < 0.05 were retained in the final models. RESULTS: Time from injury and age were the strongest predictors of ICGc during the acute admission but not at the time of discharge from the ICU. Time from injury was negatively associated with ICGc, whereas age was positively associated. At the time of discharge from the ICU, ICGc was increased in proportion to the %TBSA-B, whereas inhalation injury and preexisting chronic malnutrition were associated with lower ICGc. There was no correlation between change-to-predicted liver length and ICGc. CONCLUSIONS: The intrinsic ability of the liver to extract ICG from plasma was lower in younger burned patients during the acute admission and in those with preexisting chronic malnutrition and inhalation injury at the time of discharge from the ICU. LEVEL OF EVIDENCE: Prognostic/Epidemiologic, level III.

Mineralized Biomaterials Mediated Repair of Bone Defects Through Endogenous Cells.

Synthetic biomaterials that create a dynamic calcium (Ca2+)-, phosphate (PO43-) ion-, and calcium phosphate (CaP)-rich microenvironment, similar to that found in native bone tissue, have been shown to promote osteogenic commitment of stem cells in vitro and in vivo. The intrinsic osteoconductivity and osteoinductivity of such biomaterials make them promising bone grafts for the treatment of bone defects. We thus aimed to evaluate the potential of mineralized biomaterials to induce bone repair of a critical-sized cranial defect in the absence of exogenous cells and growth factors. Our results demonstrate that the mineralized biomaterial alone can support complete bone formation within critical-sized bone defects through recruitment of endogenous cells and neo-bone tissue formation in mice. The newly formed bone tissue recapitulated many key characteristics of native bone such as formation of bone minerals reaching similar bone mineral density, presence of bone-forming osteoblasts and tartrate-resistant acid phosphatase-expressing osteoclasts, as well as vascular networks. Biomaterials that recruit endogenous cells and provide a tissue-specific microenvironment to modulate cellular behavior and support generation of functional tissues are a key step forward in moving bench-side tissue engineering approaches to the bedside. Such tissue engineering strategies could eventually pave the path toward readily available therapies that significantly reduce patient cost of care and improve overall clinical outcomes.

Hydrogels as Extracellular Matrix Analogs.

The extracellular matrix (ECM) is the non-cellular component of tissue that provides physical scaffolding to cells. Emerging studies have shown that beyond structural support, the ECM provides tissue-specific biochemical and biophysical cues that are required for tissue morphogenesis and homeostasis. Hydrogel-based platforms have played a key role in advancing our knowledge of the role of ECM in regulating various cellular functions. Synthetic hydrogels allow for tunable biofunctionality, as their material properties can be tailored to mimic those of native tissues. This review discusses current advances in the design of hydrogels with defined physical and chemical properties. We also highlight research findings that demonstrate the impact of matrix properties on directing stem cell fate, such as self-renewal and differentiation. Recent and future efforts towards understanding cell-material interactions will not only advance our basic understanding, but will also help design tissue-specific matrices and delivery systems to transplant stem cells and control their response in vivo.

Predictors of muscle protein synthesis after severe pediatric burns.

BACKGROUND: Following a major burn, skeletal muscle protein synthesis rate increases but is often insufficient to compensate for massively elevated muscle protein breakdown rates. Given the long-term nature of the pathophysiologic response to burn injury, we hypothesized that muscle protein synthesis rate would be chronically elevated in severely burned children. The objectives of this study were to characterize muscle protein synthesis rate of burned children over a period of 24 months after injury and to identify predictors that influence this response. METHODS: A total of 87 children with 40% or greater total body surface area (TBSA) burned were included. Patients participated in stable isotope infusion studies at 1, 2, and approximately 4 weeks after burn and at 6, 12, and 24 months after injury to determine skeletal muscle protein fractional synthesis rate. Generalized estimating equations with log link normal distribution were applied to account for clustering of patients and control for patient characteristics. RESULTS: Patients (8 ± 6 years) had large (62, 51-72% TBSA) and deep (47% ± 21% TBSA third degree) burns. Muscle protein fractional synthesis rate was elevated throughout the first 12 months after burn compared with established values from healthy young adults. Muscle protein fractional synthesis rate was lower in boys, in children older than 3 years, and when burns were greater than 80% TBSA. CONCLUSION: Muscle protein synthesis is elevated for at least 1 year after injury, suggesting that greater muscle protein turnover is a component of the long-term pathophysiologic response to burn trauma. Muscle protein synthesis is highly affected by sex, age, and burn size in severely burned children. These findings may explain the divergence in net protein balance and lean body mass in different populations of burn patients. LEVEL OF EVIDENCE: Prognostic study, level III.