Showing papers by "Shriners Hospitals for Children - Galveston published in 2014"

Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

Abstract: Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT+) men and five BAT-negative (BAT−) men under thermoneutral conditions and after prolonged (5–8 h) cold exposure (CE) The two groups were similar in age, BMI, and adiposity CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT+ group only These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans

Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia

Abstract: Background Human bone marrow-derived mesenchymal stem (stromal) cells (hMSCs) improve survival in mouse models of acute respiratory distress syndrome (ARDS) and reduce pulmonary oedema in a perfused human lung preparation injured with Escherichia coli bacteria. We hypothesised that clinical grade hMSCs would reduce the severity of acute lung injury (ALI) and would be safe in a sheep model of ARDS. Methods Adult sheep (30–40 kg) were surgically prepared. After 5 days of recovery, ALI was induced with cotton smoke insufflation, followed by instillation of live Pseudomonas aeruginosa (2.5×10 11 CFU) into both lungs under isoflurane anaesthesia. Following the injury, sheep were ventilated, resuscitated with lactated Ringer9s solution and studied for 24 h. The sheep were randomly allocated to receive one of the following treatments intravenously over 1 h in one of the following groups: (1) control, PlasmaLyte A, n=8; (2) lower dose hMSCs, 5×10 6 hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10×10 6 hMSCs/kg, n=4. Results By 24 h, the PaO 2 /FiO 2 ratio was significantly improved in both hMSC treatment groups compared with the control group (control group: PaO 2 /FiO 2 of 97±15 mm Hg; lower dose: 288±55 mm Hg (p=0.003); higher dose: 327±2 mm Hg (p=0.003)). The median lung water content was lower in the higher-dose hMSC-treated group compared with the control group (higher dose: 5.0 g wet/g dry [IQR 4.9–5.8] vs control: 6.7 g wet/g dry [IQR 6.4–7.5] (p=0.01)). The hMSCs had no adverse effects. Conclusions Human MSCs were well tolerated and improved oxygenation and decreased pulmonary oedema in a sheep model of severe ARDS. Trail registration number: NCT01775774 for Phase 1. NCT02097641 for Phase 2.

Early rehabilitative exercise training in the recovery from pediatric burn.

Abstract: AB Purpose: The purpose of this study was to determine the effects of early outpatient exercise on muscle mass, function, and fractional synthetic rate in severely burned children. Methods: Forty-seven children with >=40% total body surface area burn performed a 12-wk standard of care rehabilitation (SOC, n = 23) or rehabilitative exercise training (RET, n = 24) immediately after hospital discharge. Dual-energy x-ray absorptiometry was used to assess lean body mass (LBM) at discharge, posttreatment, and 12 months post-burn. Muscle function was evaluated with a Biodex Isokinetic Dynamometer, and peak aerobic fitness (V[spacing dot above]O2peak) was measured using a modified Bruce treadmill protocol posttreatment. Stable isotope infusion studies were performed in a subset of patients (SOC, n = 13; RET, n = 11) at discharge and posttreatment to determine mixed-muscle fractional synthetic rate. Results: Relative peak torque (RET, 138 +/- 9 N[middle dot]m[middle dot]kg-1, vs SOC, 106 +/- 9 N[middle dot]m[middle dot]kg-1) and V[spacing dot above]O2peak (RET, 32 +/- 1 mL[middle dot]kg-1[middle dot]min-1, vs SOC, 28 +/- 1 mL[middle dot]kg-1[middle dot]min-1) were greater at posttreatment with RET compared with those with SOC. In addition, RET increased whole-body (9% +/- 2%) and leg (17% +/- 3%) LBM compared with SOC. Furthermore, the percentage change in whole-body (18% +/- 3%) and leg (31% +/- 4%) LBM from discharge to 12 months post-burn was greater with RET compared to SOC. Muscle fractional synthetic rate decreased from discharge to posttreatment in both groups (6.9% +/- 1.1% per day vs 3.4 +/- 0.4% per day); however, no differences were observed between treatment groups at each time point. Conclusions: Early outpatient exercise training implemented at hospital discharge represents an effective intervention to improve muscle mass and function after severe burn injury.

Predictors of insulin resistance in pediatric burn injury survivors 24 to 36 months postburn.

Abstract: Burn injury is a dramatic event with acute and chronic consequences including insulin resistance. However, factors associated with insulin resistance have not been previously investigated. The purpose of this study was to identify factors associated with long-term insulin resistance in pediatric burn injury survivors. The study sample consisted of 61 pediatric burn injury survivors 24 to 36 months after the burn injury, who underwent an oral glucose tolerance test. To assess insulin resistance, the authors calculated the area under the curve for glucose and insulin. The diagnostic criteria of the American Diabetes Association were used to define individuals with impaired glucose metabolism. Additional data collected include body composition, anthropometric measurements, burn characteristics, and demographic information. The data were analyzed using multivariate linear regression analysis. Approximately 12% of the patients met the criteria for impaired glucose metabolism. After adjusting for possible confounders, burn size, age, and body fat percentage were associated with the area under the curve for glucose (P < .05 for all). Time postburn and lean mass were inversely associated with the area under the curve for glucose (P < .05 for both). Similarly, older age predicted higher insulin area under the curve. The results indicate that a significant proportion of pediatric injury survivors suffer from glucose abnormalities 24 to 36 months postburn. Burn size, time postburn, age, lean mass, and adiposity are significant predictors of insulin resistance in pediatric burn injury survivors. Clinical evaluation and screening for abnormal glucose metabolism should be emphasized in patients with large burns, older age, and survivors with high body fat.

Effect of glycyrrhizin on pseudomonal skin infections in human-mouse chimeras

Abstract: In our previous studies, peripheral blood lineage(-)CD34(+)CD31(+) cells (CD31(+) IMC) appearing in severely burned patients have been characterized as inhibitor cells for the production of β-defensins (HBDs) by human epidermal keratinocytes (NHEK). In this study, the effect of glycyrrhizin on pseudomonal skin infections was studied in a chimera model of thermal injury. Two different chimera models were utilized. Patient chimeras were created in murine antimicrobial peptide-depleted NOD-SCID IL-2rγ(null) mice that were grafted with unburned skin tissues of severely burned patients and inoculated with the same patient peripheral blood CD31(+) IMC. Patient chimera substitutes were created in the same mice that were grafted with NHEK and inoculated with experimentally induced CD31(+) IMC. In the results, both groups of chimeras treated with glycyrrhizin resisted a 20 LD50 dose of P. aeruginosa skin infection, while all chimeras in both groups treated with saline died within 3 days of the infection. Human antimicrobial peptides were detected from the grafted site tissues of both groups of chimeras treated with glycyrrhizin, while the peptides were not detected in the same area tissues of controls. HBD-1 was produced by keratinocytes in transwell-cultures performed with CD31(+) IMC and glycyrrhizin. Also, inhibitors (IL-10 and CCL2) of HBD-1 production by keratinocytes were not detected in cultures of patient CD31(+) IMC treated with glycyrrhizin. These results indicate that sepsis stemming from pseudomonal grafted site infections in a chimera model of burn injury is controllable by glycyrrhizin. Impaired antimicrobial peptide production at the infection site of severely burned patients may be restored after treatment with glycyrrhizin.

Comparison of bolus injection and constant infusion methods for measuring muscle protein fractional synthesis rate in humans.

Abstract: Background The use of stable isotope tracer techniques to measure muscle protein fractional synthesis rate (FSR) has been well established and widely used. The most common method that has been utilized so far is a primed constant infusion (CI) method, which requires 3–4 h of tracer infusion. However, recently our group has developed a bolus injection (BI) method, which requires an injection of bolus of tracer and can be completed within 1 h. In this study, we compared calf (gastrocnemius) muscle protein FSR measured using these two different methods — CI and BI.

Lineage−CD34+CD31+ Cells That Appear in Association with Severe Burn Injury Are Inhibitory on the Production of Antimicrobial Peptides by Epidermal Keratinocytes

Abstract: Antimicrobial peptides are major host defense effectors against Pseudomonas aeruginosa skin infections. Due to the lack of such peptide production, severely burned hosts are greatly susceptible to P. aeruginosa burn wound infection. β-Defensin (HBD) production by normal human epidermal keratinocytes (NHEK) was inhibited by lineage−CD34+ cells isolated from peripheral blood of severely burned patients. Lineage−CD34+ cells obtained from severely burned patients were characterized as CD31+, while healthy donor lineage−CD34+ cells were shown to be CD31− cells. Lineage−CD34+CD31− cells did not show any inhibitory activities on HBD-1 production by NHEK. CCL2 and IL-10 released from lineage−CD34+CD31+ cells were shown to be inhibitory on the peptide production by NHEK, while these soluble factors were not produced by lineage−CD34+CD31− cells. After treatment with a mixture of mAbs for CCL2 and IL-10, the culture fluids of lineage−CD34+CD31+ cells did not show any inhibitory activities on HBD-1 production by NHEK. Lineage−CD34+CD31+ cells that appear in association with burn injuries play a role on the inhibition of antimicrobial peptide production by skin keratinocytes through the production of CCL2 and IL-10.