Skeletal Muscle Bioenergetics in Critical Limb Ischemia and Diabetes.

INTRODUCTION: Mitochondrial dysfunction is implicated in the metabolic myopathy accompanying peripheral artery disease (PAD) and critical limb ischemia (CLI). Type-2 diabetes mellitus (T2DM) is a major risk factor for PAD development and progression to CLI and may also independently be related to mitochondrial dysfunction. We set out to determine the effect of T2DM in the relationship between CLI and muscle mitochondrial respiratory capacity and coupling control. METHODS: We studied CLI patients undergoing revascularization procedures or amputation, and non-CLI patients with or without T2DM of similar age. Mitochondrial respiratory capacity and function were determined in lower limb permeabilized myofibers by high-resolution respirometry. RESULTS: Fourteen CLI patients (65 ± 10y) were stratified into CLI patients with (n = 8) or without (n = 6) T2DM and were compared to non-CLI patients with (n = 18; 69 ± 5y) or without (n = 19; 71 ± 6y) T2DM. Presence of CLI but not T2DM had a marked impact on all mitochondrial respiratory states in skeletal muscle, adjusted for the effects of sex. Leak respiration (State 2, P < 0.025 and State 4o, P < 0.01), phosphorylating respiration (P < 0.001), and maximal respiration in the uncoupled state (P < 0.001), were all suppressed in CLI patients, independent of T2DM. T2DM had no significant effect on mitochondrial respiratory capacity and function in adults without CLI. CONCLUSIONS: Skeletal muscle mitochondrial respiratory capacity was blunted by ∼35% in patients with CLI. T2DM was not associated with muscle oxidative capacity and did not moderate the relationship between muscle mitochondrial respiratory capacity and CLI.

Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration.

Viral-mediated in vivo gene delivery methods currently dominate among therapeutic strategies within the clinical and experimental settings, albeit with well documented limitations arising from immunologic constraints. In this study, we demonstrate the utility of nonviral hepatotropic in vivo gene delivery of unpackaged expression constructs, including one encoding fibroblast growth factor 21 (FGF21). FGF21 is an important hepatokine whose expression positively correlates with therapeutic outcomes across various animal models of obesity. Our data demonstrate that FGF21 expression can be restored into the livers of immunocompetent FGF21 knockout mice for at least 2 weeks after a single injection with an FGF21 expression plasmid. In wild-type C57BL6/J mice, in vivo transfection with an FGF21-expressing plasmid induced weight loss, decreased adiposity, and activated thermogenesis in white fat within 2 weeks. Furthermore, in vivo FGF21 gene delivery protected C57BL6/J mice against diet-induced obesity by decreasing adiposity and increasing uncoupling protein 1-dependent thermogenesis in brown fat and by boosting respiratory capacity in subcutaneous and perigonadal white fat. Together, the data illustrate a facile and effective methodology for delivering prolonged protein expression specifically to the liver. We contend that this method will find utility in basic science research as a practical means to enhance in vivo studies characterizing liver protein function. We further believe our data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease. SIGNIFICANCE STATEMENT: This study presents a valuable method for nonviral gene delivery in mice that improves upon existing techniques. The data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease and will likely enhance in vivo studies characterizing liver protein function.

Mild burn amplifies the locomotive depression in demyelinated mice without muscle pathophysiological changes.

INTRODUCTION: Patients with mild burns take most accounts, however, the impact of mild burns is less known. Nerve destruction leads to muscle atrophy. We posit that even mild burn injury could worsen demyelinated nerves related to muscle pathophysiological impairment. METHODS: Young adult C57BL/6 (male, n = 60) mice were randomly fed with either a 0.2% cuprizone diet or a regular rodent diet for 4 weeks. At week 5, all mice were then grouped into mild scald burn with 10% TBSA and sham injury groups. Mice received animal behavior tests and in situ muscle isometric force measurement before euthanasia for tissue collection. RESULTS: Total horizontal ambulation and vertical activity were significantly reduced in mice with mild burn injury (p<0.05). Mice with the cuprizone diet had significantly less time to fall than those with the regular diet on day 7 after burn (p<0.05). No significant difference was found in gastrocnemius tissue weight among the groups, nor muscle isometric tensions (all p>0.05). The cuprizone diet increased the maximal phosphorylating respiration in mice muscle mitochondria (p<0.05). The muscle protein expressions of caspase 3, Fbx-32, and Murf1 significantly increased in mice with the cuprizone diet 3 days after burn (p<0.05). The signal expression of S100B significantly increased in mice with the cuprizone diet, and its expression was even greater on day 7 after burn injury. (p<0.05). CONCLUSION: The cuprizone diet-induced locomotion and cognitive disorders were amplified by the mild burn injury in mice, which is associated with muscle intracellular signal alterations. However, mild burn injury does not cause mouse muscle weight loss and function impairment. The potential risk of pre-existed neural impairment could be aware when patients encounter even small or mild burns.

The association between body mass index and physical function in adult burn survivors: A Burn Model System National Database study.

INTRODUCTION: An area of rehabilitation research in burns is the impact of co-morbidities on disease trajectory. Obesity is a comorbidity of increasing public health concern, but its role remains controversial regarding burn injury and physical recovery. Our aim was to evaluate the association between body mass index (BMI) categories as a measure of obesity at discharge and self-reported physical function (PF) during recovery of adult burn survivors. METHODS: This is a retrospective study on data collected by four major US burn centers, which contribute to the Burn Model System National Database. The data included BMI obtained at hospital discharge and self-reported PF-mobility, using the PROMIS measures assessed at 6, 12, and 24 months after burn. Subjects were classified into weight status categories based on BMI: underweight (BMI <18.5), normal weight (18.5 ≤ BMI <25), overweight (25 ≤ BMI <30), obesity class 1 (30 ≤ BMI <35), obesity class 2 (35 ≤ BMI <40), and obesity class 3 (BMI ≥40). Mixed-effects linear regression models were used to assess the association between BMI categories and PF scores over time, adjusted for patient and injury characteristics. RESULTS: A total of 496 adult burn patients aged 47 ± 16 years were included, with mean total body surface area (TBSA) burned of 18 ± 19 % and mean BMI at discharge of 28 ± 7 kg/m2. PROMIS PF scores significantly improved over time in the recovery phase after burn (time effect, p < 0.001). Compared to overweight burn patients, normal-underweights exhibited lower PF score by an average of 4.06 units (p = 0.001) but scores increased linearly by an estimated 0.17 units per month (p = 0.01) over the 24 months after discharge. Similarly, compared to overweight burn patients, class 1 obese reported lower PF score by a mean 2.67 units (p = 0.07) but PF increased linearly by 0.15 units per month (p = 0.07) over the 24 months after discharge. These findings were independent of the effects of age at discharge, sex, TBSA burned, and hand and leg burn. CONCLUSION: Being overweight was associated with improved and faster recovery of PF scores compared to normal, underweight, and obese burn patients during long-term recovery. Hence, our data suggests that long-term recovery and restoration of PF in adult burn survivors is not compromised by a small excess in body weight.

Enzymatic Debridement in Geriatric Burn Patients-A Reliable Option for Selective Eschar Removal.

The treatment of geriatric burn patients represents a major challenge in burn care. The objective of this study was to evaluate the efficacy of enzymatic debridement (ED) in geriatric burn patients. Adult patients who received ED for treatment of mixed pattern and full thickness burns (August 2017-October 2022) were included in this study and grouped in the younger (18-65 years) and geriatric (≥65 years) groups. Primary outcome was a necessity of surgery subsequent to ED. Both groups (patient characteristics, surgical and non-surgical treatment) were compared. Multiple logistic and linear regression models were used to identify the effect of age on the outcomes. A total of 169 patients were included (younger group: 135 patients, geriatric group: 34 patients). The burn size as indicated by %TBSA (24.2 ± 20.4% vs. 26.8 ± 17.1%, p = 0.499) was similar in both groups. The ASA (2.5 ± 1.1 vs. 3.4 ± 1.1, p < 0.001) and ABSI scores (6.1 ± 2.8 vs. 8.6 ± 2.3, p < 0.001) were significantly higher in the geriatric group. The %TBSA treated with ED (5.4 ± 5.0% vs. 4.4 ± 4.3%, p = 0.245) were similar in both groups. The necessity of additional surgical interventions (63.0 % vs. 58.8 %, p = 0.763) and the wound size debrided and grafted (2.9 ± 3.5% vs. 2.2 ± 2.1%; p = 0.301) were similar in both groups. Regression models yielded that age did not have an effect on efficacy of ED. We showed that ED is reliable and safe to use in geriatric patients. Age did not have a significant influence on the surgical outcomes of ED. In both groups, the size of the grafted area was reduced and, in many patients, surgery was avoided completely.

A comparison of the changes in cardiac output and systemic vascular resistance during exercise following high-fat meals containing DHA or EPA.

Long-chain n-3 PUFA can lower blood pressure (BP) but their acute effects on cardiac output, BP and systemic vascular resistance (SVR) in response to dynamic exercise are uncertain. We compared the effects of high-fat meals rich in EPA (20 : 5n-3), DHA (22 : 6n-3) or oleic acid (control) on cardiac output, BP and SVR in response to exercise stress testing. High-fat meals (50 g fat) containing high-oleic sunflower oil enriched with 4·7 g of either EPA or DHA v. control (high-oleic sunflower oil only) were fed to twenty-two healthy males using a randomised cross-over design. Resting measurements of cardiac output, heart rate and BP were made before and hourly over 5 h following the meal. A standardised 12 min exercise test was then conducted with further measurements made during and post-exercise. Blood samples were collected at fasting, 5 h postprandially and immediately post-exercise for the analysis of lipid, glucose and 8-isoprostane-F2α (8-iso-PGF2α). Plasma concentrations of EPA and DHA increased by 0·22 mmol/l 5 h following the EPA and DHA meals, respectively, compared with the control (P < 0·001). Resting cardiac output and 8-iso-PGF2α increased similarly following all meals and there were no significant differences in cardiac output during exercise between the meals. SVR was lower at 5 h and during exercise following the DHA but not EPA meal, compared with the control meal, by 4·9 % (95 % CI 1·3, 8·4; P < 0·01). Meals containing DHA appear to differ from EPA with regard to their effects on cardiovascular haemodynamics during exercise.

Nuclear Factor Erythroid 2-Related Factor 2 Activation and Burn-Induced Cardiac Dysfunction.

BACKGROUND: Our previous studies have found that burn injury induces cardiac dysfunction through interruption of the antioxidant-response element (ARE) pathway in cardiac mitochondria. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator that activates many antioxidant enzymes. Oltipraz (Olti) is a Nrf2 activator and a well-known inducer of NQO1 along with other enzymes that comprise the Nrf2-associated antioxidants. We propose that Nrf2 activation will induce the ARE pathway, leading to abrogation of burn-induced cardiac dysfunction. STUDY DESIGN: In this study, we investigated the effect of Nrf2-deficiency in mice on burn-induced cardiac dysfunction. Wild-type (WT) and Nrf2-deficient mice received 30% total body surface area burn injury and were treated with or without Olti and then harvested at 3 hours and 24 hours post burn (3 hpb and 24 hpb). RESULTS: As expected, Nrf2-deficient mice exhibited exacerbated cardiac dysfunction after burn injury, as measured by Vevo 2100 echocardiography. Electron microscopy showed that Nrf2 depletion worsened burn injury-induced cardiac mitochondrial damage. In addition, Nrf2 depletion increased cardiac mitochondrial dysfunction and myocardial fibrosis after burn injury. Treatment with Olti ameliorated the heart dysfunction in burned Nrf2-/+ mice, improved cardiac mitochondrial structure and oxidative phosphorylation, as well as decreased cardiac fibrosis. These results suggest that Nrf2 and its downstream targets modulate cardiac function after burn injury. CONCLUSIONS: In summary, Nrf2 depletion worsens cardiac dysfunction after burn injury. Nrf2 activation, with a drug such as Olti, offers a promising therapeutic strategy for abrogating burn-induced cardiac dysfunction.

Strength of association between body mass index and physical function scores in paediatric burn patients: A National Institute on Disability, Independent Living, and Rehabilitation Research Burn Model System study.

OBJECTIVE: Increased body weight has been associated with reduced muscle wasting in the early catabolic phase after a severe burn. Yet, overweight and obese non-burn children often exhibit impaired musculoskeletal function, which may lead to poor physical function (PF). We aimed to determine the association between body mass index (BMI) at discharge and self-reported PF and caregiver proxy-reported PF during recovery of burned children. MATERIALS AND METHODS: This is a retrospective multisite longitudinal study in paediatric burn patients ((8-17 y old at time of burn). PF outcome measures were self-reported mobility, proxy-reported mobility, and upper extremity PF evaluated using PROMIS measures at 6-, 12-, and 24-months after injury. Primary exposure variable was BMI-for-age at discharge. RESULTS: A total of 118 paediatric patients, aged 11.7 ± 3.3 y, with burns covering 37.6 ± 18.8% of their total body surface area (TBSA) and BMI-for-age of 23.1 ± 5.4 kg/m2 at discharge were analyzed. BMI at discharge was not significantly associated with self-reported mobility scores 6 months after burn (beta coefficient =-0.23, p = 0.31), had a positive effect on mobility at 12 months (beta = 0.46, p = 0.05), and no effect at 24 months after injury (beta=-0.10, p = 0.60), when adjusted for burn size. BMI did not have a significant effect on proxy-reported mobility or upper extremity PF. CONCLUSION: A greater BMI at discharge was associated with improved self-reported PF at 12 months after burn but not at 6 months or 24 months, which suggests a faster recovery of PF in paediatric patients of larger body weight. Our data suggests that a larger body weight does not compromise the recovery of PF after burn.

Supervised Resistance Training on Functional Capacity, Muscle Strength and Vascular Function in Peripheral Artery Disease: An Updated Systematic Review and Meta-Analysis.

Supervised resistance training appears to be a promising alternative exercise modality to supervised walking in patients with peripheral artery disease (PAD). This meta-analysis examined the efficacy of supervised RT for improving walking capacity, and whether adaptations occur at the vascular and/or skeletal muscle level in PAD patients. We searched Medline, CINAHL, Scopus, and Cochrane Central Register of Controlled Trials databases for randomized controlled trials (RCTs) in PAD patients testing the effects of supervised RT for ≥4 wk. on walking capacity, vascular function, and muscle strength. Pooled effect estimates were calculated and evaluated using conventional meta-analytic procedures. Six RCTs compared supervised RT to standard care. Overall, supervised RT prolonged claudication onset distance during a 6-min walk test (6-MWT) (101.7 m (59.6, 143.8), p < 0.001) and improved total walking distance during graded treadmill walking (SMD: 0.67 (0.33, 1.01), p < 0.001) and the 6-MWT (49.4 m (3.1, 95.6), p = 0.04). Five RCTS compared supervised RT and supervised intermittent walking, where the differences in functional capacity between the two exercise modalities appear to depend on the intensity of the exercise program. The insufficient evidence on the effects of RT on vascular function and muscle strength permitted only limited exploration. We conclude that RT is effective in prolonging walking performance in PAD patients. Whether RT exerts its influence on functional capacity by promoting blood flow and/or enhancing skeletal muscle strength remains unclear.

Cafeteria Diet Impacts the Body Weight and Energy Expenditure of Brown Norway Rats in an Apparent Age Dependent Manner, but Has no Effect on Muscle Anabolic Sensitivity to Nutrition.

While obesity blunts the ability of muscle to mount a protein synthetic response to an amino acid infusion in older adults, it is unclear if this insensitivity to nutrition persists long term and in response to complete foods is unknown. To address this, young (2 months old) and old (17-20 months old) Brown Norway rats were randomized to receive either chow or a 12 wk diet of calorie-dense human foods. At wk 10 drinking water was supplemented with 2% heavy water, followed 2 weeks later by a flooding dose of [2H5]-phenylalanine and an oral leucine bolus, allowing the short and long-term effects of age and diet on muscle protein synthesis rates to be determined. The experimental diet increased energy intake in both young (7.4 ± 0.9%) and old (18.2 ± 1.8%) animals (P < 0.01), but only led to significant increases in body weight in the former (young: 10.2 ± 3.0% (P < 0.05) and old: 3.1 ± 5.1% (NS) vs. age-matched controls). Notably, energy expenditure in response to the cafeteria diet was increased in old animals only (chow: 5.1 ± 0.4; cafe: 8.2 ± 1.6 kcal.kg b.w-1.h-1; P < 0.05). Gastrocnemius protein fractional synthetic rates in response to either an acute leucine bolus or two weeks of feeding were equivalent across groups irrespective of age or diet. Rodents in old age appear capable of preventing weight gain in response to a calorie-dense diet by increasing energy expenditure while maintaining the anabolic sensitivity of muscle to nutrition; the mechanisms of which could have important implications for the aging obese human.

Postprandial lipaemia does not affect resting haemodynamic responses but does influence cardiovascular reactivity to dynamic exercise.

Postprandial lipaemia impairs endothelial function, possibly by changes in oxidative stress, but whether this affects cardiac output and/or systemic vascular resistance (SVR) at rest and in response to dynamic exercise remains uncertain. The present study set out to investigate the effects of a high-fat meal (HFM) v. a low-fat, high-carbohydrate meal (HCM) on cardiac output and SVR. A HFM (50 g fat) and an isoenergetic HCM (5 g fat) were randomly fed to thirty healthy adults using a crossover design. Cardiac output, heart rate and blood pressure (BP) were measured, and stroke volume and SVR were calculated over a 3 h rest following the meal, during exercise 3 h postprandially and for 45 min post-exercise. Blood samples were collected at fasting, 3 h postprandially and immediately post-exercise. Plasma TAG increased by 63.8 % 3 h following the HFM, and NEFA fell by 94.1% 3 h after the HCM. There was a 9.8% rise in plasma 8-isoprostane-F2alpha concentration following the HFM, and a 6.2% fall following the HCM. Cardiac output increased postprandially, but the difference between meals at rest or exercise was not statistically significant. The HFM resulted in a 3.2 mmHg (95% CI 0.7, 5.7) smaller increase in exercise mean arterial BP compared with the HCM due to a greater fall in exercise SVR. Postprandial lipaemia induced by a HFM does not affect cardiac output and/or SVR at rest, but it blunts the increase in BP during exercise.

Brown adipose tissue recruitment in a rodent model of severe burns.

BACKGROUND: Severe burns results in a prolonged hypermetabolic response. Brown adipose tissue (BAT), abundant in uncoupling protein 1 (UCP1), plays a key role in non-shivering thermogenesis. We set out to determine if BAT is recruited in response to severe burns. METHODS: Male balb-c mice underwent scald burns on approximately 20-25% of their total body surface. BAT was harvested from the interscapular fat pad of sham and burned mice at 3h, 24h, 4 days, and 10 days after injury. High-resolution respirometry was used to determine mitochondrial respiratory function in BAT. BAT protein concentration, and mitochondrial enzyme activity were also determined. RESULTS: Respiration increased in BAT of burned mice, peaking at 24h after injury (after injury, P<0.001). While UCP1 independent respiration was not significantly altered by burn, UCP1 dependent respiration increased >2-fold at 24h after injury when compared to the 3h and sham group (P<0.01). Normalized to citrate synthase activity, total uncoupled (P<0.05) and UCP1 dependent (P<0.01) respiration remained elevated at 24h after injury. CONCLUSIONS: We show a time-dependent recruitment of rodent BAT in response to severe burns. Given recent reports that humans, including patients with severe burns, have functional BAT, these data support a role for BAT in the hypermetabolic response to severe burns.

The Influence of Obesity on Treatment and Outcome of Severely Burned Patients.

Obesity and the related medical, social, and economic impacts are relevant multifactorial and chronic conditions that also have a meaningful impact on outcomes following a severe injury, including burns. In addition to burn-specific difficulties, such as adequate hypermetabolic response, fluid resuscitation, and early wound coverage, obese patients also present with common comorbidities, such as arterial hypertension, diabetes mellitus, or nonalcoholic fatty liver disease. In addition, the pathophysiologic response to severe burns can be enhanced. Besides the increased morbidity and mortality compared to burn patients with normal weight, obese patients present a challenge in fluid resuscitation, perioperative management, and difficulties in wound healing. The present work is an in-depth review of the current understanding of the influence of obesity on the management and outcome of severe burns.

Determinants of skeletal muscle protein turnover following severe burn trauma in children.

BACKGROUND & AIMS: Burns remain the fifth cause of non-fatal pediatric injuries globally, with muscle cachexia being a hallmark of the stress response to burns. Burn-induced muscle wasting is associated with morbidity, yet the determinants of muscle protein catabolism in response to burn trauma remains unclear. Our objective was to determine the effect of patient and injury characteristics on muscle protein kinetics in burn patients. METHODS: This retrospective, observational study was performed using protein kinetic data from pediatric patients who had severe burns (>30% of the total body surface area burned) and underwent cross-limb stable isotope infusions between 1999 and 2008 as part of prospective clinical trials. Mixed multiple regression models were used to assess associations between patient/injury characteristics and muscle protein fractional synthesis rate (FSR), net balance (NB), and rates of phenylalanine appearance (Ra; index of protein breakdown) and disappearance (Rd; index of protein synthesis) across the leg. RESULTS: A total of 268 patients who underwent 499 studies were analyzed. Increasing time post injury was associated with greater FSR (p < 0.001) and NB (p = 0.01). Males were more catabolic than females (as indicated by lower NB, p = 0.04 and greater Ra, p = 0.008), a consequence of higher protein breakdown rather than lower synthesis. Increasing burn size was associated with higher protein synthesis rate (as indicated by higher FSR, p = 0.019) and higher protein breakdown rates (as indicated by greater Ra, p = 0.001). FSR was negatively associated with age (p < 0.001). CONCLUSIONS: Data from this large patient cohort show that injury severity, sex, and time post injury influence skeletal muscle wasting in burned children. These findings suggest that individual patient characteristics should be considered when devising therapies to improve the acute care and rehabilitation of burn survivors.

Quantification of an Exercise Rehabilitation Program for Severely Burned Children: The Standard of Care at Shriners Hospitals for Children®-Galveston.

Currently, there are no clear guidelines for the implementation of rehabilitative exercise training (RET) in burned individuals. Therefore, we quantified the training logs for exercise intensity, frequency, and duration of 6 weeks of this program to develop a basic framework for outpatient RET in patients recovering from severe burns. Thirty-three children (11 female, [mean ± SD] 12 ± 3 years, 145 ± 18 cm, 40 ± 11 kg, 49 ± 31 BMI percentile) with severe burns (49 ± 15% total body surface area burned, with 35 ± 22% third-degree burns) completed our 6-week resistance and aerobic exercise training program. Cardiorespiratory fitness (peak VO2), strength, power, and lean body mass (LBM) were measured before and after RET. Outcome measures were analyzed as a relative percentage of values in age- and sex-matched nonburned children (11 female, 12 ± 3 years, 154 ± 20 cm, 49 ± 22 kg, 56 ± 25 BMI percentile). At discharge, burned children had lower LBM (77% of age-sex-matched nonburn values), peak torque (53%), power (62%), and cardiorespiratory fitness (56%). After 6 weeks of training, LBM increased by 5% (82% of nonburn values), peak torque by 18% (71%), power by 20% (81%), and cardiorespiratory fitness by 18% (74%; P < .0001 for all). Quantification of data in exercise training logs suggested that physical capacity can be improved by aerobic exercise training performed at five metabolic equivalents (>70% of peak VO2) at least 3 days/week and 150 minutes/week and by resistance training performed at volume loads (reps × sets × weight) of 131 kg for the upper body and 275 kg for the lower body for 2 days/week. We present for the first time the quantification of our RET and provide clear exercise prescription guidelines specific to children with severe burn injury.

Natural Compound Oridonin Inhibits Endotoxin-Induced Inflammatory Response of Activated Hepatic Stellate Cells.

Hepatic stellate cells (HSCs) play an important role in hepatic fibrogenesis and inflammatory modulation. Endotoxin is dramatically increased in portal venous blood after serious injury and can contribute to liver damage. However, the mechanism underlying endotoxin's effects on HSCs remains largely unknown. Oridonin is a bioactive diterpenoid isolated from Rabdosia rubescens that exhibits anti-inflammatory properties in different tissues. In the present study, we determined the effects of oridonin on endotoxin-induced inflammatory response and signaling pathways in vitro. The production of proinflammatory cytokines in activated human HSCs line LX-2 was measured by ELISA and Western blots. Immunofluorescence and nuclear fractionation assay were used to determine NF-κB activity. Oridonin treatment significantly inhibited LPS-induced proinflammatory cytokines IL-1ß, IL-6, and MCP-1 production as well as cell adhesion molecules ICAM-1 and VCAM-1. Additionally, oridonin blocked LPS-induced NF-κB p65 nuclear translocation and DNA binding activity. Oridonin prevented LPS-stimulated NF-κB regulator IKKα/ß and IκBα phosphorylation and IκBα degradation. Combined treatment of oridonin and an Hsp70 substrate binding inhibitor synergistically suppressed LPS-stimulated proinflammatory cytokines and NF-κB pathway activation. Therefore, oridonin inhibits LPS-stimulated proinflammatory mediators through IKK/IκBα/NF-κB pathway. Oridonin could be a promising agent for a hepatic anti-inflammatory.

Children with severe burns display no sex differences in exercise capacity at hospital discharge or adaptation after exercise rehabilitation training.

BACKGROUND AND OBJECTIVE: Females have a 50% increased risk of death from burn injury compared to males. However, whether exercise capacity and exercise induced training adaptations differ between burned boys and girls is unknown. This project tested the hypothesis that girls with burns have lower exercise capacity and different exercise induced training adaptations. METHODS: Twenty-five girls were matched to 26 boys (mean, 95%CI; years 13 [12,14], cm 151 [143,161], kg 54 [45,63]; each P>0.05) for burn injury (% total body surface area burn, 54 [45,62]; P=0.82). Lean body mass (LBM), strength (peak torque) and cardiorespiratory fitness (peak VO2) were normalized to kg LBM and compared as a percentage of age-sex matched non-burned children (n=26 boys, years 13 [12,14]; n=25 girls, years 13 [12,14]) at discharge (DC) and after aerobic and resistance rehabilitation exercise training (RET). RESULTS: Using a 2-way factorial ANOVA (group×time), we found both groups had similar 11% change in LBM (87.3% of non-burned values [82.2,92.3]) and after the RET (92.8% [87.2,98.3]; main effect, time P<0.0001). Peak torque increased similarly by 16% in both groups (% of age-sex matched non-burned DC, 55.9 [51.3,60.5]; after RET, 77.5 [72.1,82.9]; main effect, time P<0.0001). Likewise, peak VO2 increased in both groups by 15% (% of age-sex matched non-burned DC, 56.8 [52.4,61.2] to RET, 72.2 [67.6,76.8]; main effect, time; P<0.0001). Burned children exercise at greater percentage of their peak VO2 and peak HR compared to non-burned children (Interaction, group×time, P<0.0001). CONCLUSION: The burn injury does not have sex-dependent effects on LBM or exercise capacity in severely burn injured children. Differences in relative peak VO2 and peak HR suggest the need for burn specific exercise programs for improving the efficacy of a rehabilitation program.

Correlation between invasive and noninvasive blood pressure measurements in severely burned children.

INTRODUCTION: Accurate blood pressure monitoring is essential for burn management, with the intra-arterial line method being the gold standard. Here we evaluated agreement between cuff and intra-arterial line methods. METHODS: Data from burned children admitted from 1997 to 2016 were retrospectively reviewed. Simultaneously collected intra-arterial and cuff measurements were cross-matched and linear regression performed to assess agreement for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP). RESULTS: We identified 9969 matches for SBP, DBP, and MAP in 872 patients (579 male) aged 8±5years with burns covering 52±20% of the total body surface area and a hospitalization lasting 33±31 days. Intra-arterial lines had a complication rate of 1%. The mean bias (95% CI) between methods was 1.3 (0.5, 2.1) mm Hg for SBP, -6.4 (-7.0, -5.7) mmHg for DBP, and -5.8 (-6.4, -5.3) mmHg for MAP. The standard deviation of the bias (95% limit of agreement) was 12.1 (-22.5, 25.1) mmHg for SBP, 9.9 (-25.8, 13.0) mmHg for DBP, and 8.7 (-22.8, 11.1) mmHg for MAP. CONCLUSIONS: Cuff measurements vary widely from those of intra-arterial lines, which have a low complication rate. Intra-arterial lines are advisable when tight control of the hemodynamic response is essential.

Skeletal Muscle Mitochondrial Function is Determined by Burn Severity, Sex, and Sepsis, and is Associated With Glucose Metabolism and Functional Capacity in Burned Children.

BACKGROUND: Restoring normal mitochondrial function represents a new target for strategies aimed at mitigating the stress response to severe burn trauma and hastening recovery. Our objective was to investigate the determinants of skeletal muscle mitochondrial respiratory capacity and function and its association with glucose metabolism and functional capacity in burned children. METHODS: Data from burned children enrolled in the placebo arm of an ongoing prospective clinical trial were analyzed. Mitochondrial respiratory capacity was determined in permeabilized myofibers by high-resolution respirometry on at least one occasion per participant. In subsets of patients, glucose kinetics and cardiorespiratory fitness (VO2peak) were also determined. Mixed multiple regression models were used to identify the determinants of mitochondrial respiratory function and to assess the relationship between mitochondrial respiration and both glucose control and functional capacity (VO2peak). MAIN RESULTS: Increasing full-thickness burn size was associated with greater adjusted coupled (ATP-producing) respiration, adjusted for age, sex, sepsis, and time of testing (P < 0.01; n = 55, obs = 97). Girls had on average 23.3% lower coupled respiration (adjusted mean and 95% confidence of interval [CI], -7.1; -12.6 to -1.7 pmol/s/mg; P < 0.025) and 29.8% lower respiratory control than boys (adjusted mean and 95% CI, -0.66; -1.07 to -0.25; P < 0.01; n = 55, obs = 97). The presence of sepsis was associated with lower respiration coupled to ATP production by an average of 25.5% compared with nonsepsis (adjusted mean and 95% CI, -6.9; -13.0 to -0.7 pmol/s/mg; P < 0.05; n = 55, obs = 97), after adjustment for age, sex, full-thickness burn size, and time of testing. During a hyperinsulinemic euglycemic clamp, hepatic glucose release was associated with greater coupled respiration and respiratory control (P < 0.05; n = 42, obs = 73), independent of age, sepsis, full-thickness burn size, and time postinjury testing. Coupled respiration was positively associated with VO2peak after adjustment for age, full-thickness burn size, and time of exercise testing (P < 0.025; n = 18, obs = 25). CONCLUSIONS: Burn severity, sex, and sepsis influence skeletal muscle mitochondrial function in burned children. Glucose control and functional capacity are associated with altered mitochondrial respiratory function in muscle of burn survivors, highlighting the relationship of altered muscle bioenergetics with the clinical sequelae accompanying severe burn trauma.

Association between nocturnal sleep duration, body fatness, and dietary intake in Greek women.

OBJECTIVE: We investigated the association of nocturnal sleep duration with body fatness, energy, and macronutrient intake in female adults. METHODS: Thirty healthy Greek women 30-60 y of age and under no medication were recruited for an observational, cross-sectional study in Athens, Greece, in 2005. Participants' height, weight, skinfold thickness, and waist and hip circumferences were measured. All subjects completed a Sleep Habits Questionnaire and a 7-d sleep diary to estimate nocturnal sleep duration. Two 24-h dietary recall interviews were conducted to assess dietary intake. RESULTS: Nocturnal sleep duration was negatively associated with body fatness (r = -0.614, P < 0.001) and body mass index (r = -0.401, P < 0.05). Each 1-h decrease in nocturnal sleep duration was associated with a significant increase in body fat of 2.8% (95% confidence interval -4.6 to -1.0) when the effects of age and energy intake were held constant. A weak positive association between sleep duration and saturated fat was observed (r = 0.392, P < 0.05). However, no significant association of sleep duration with certain central obesity indices, energy intake, or a preference for fat or carbohydrate consumption was found. CONCLUSION: The present study identifies an independent negative association of nocturnal sleep duration with body fatness. Therefore, the shorter the sleep duration, the greater is the body fatness. The hypothesis that sleep duration is associated with energy intake and a preference for fat or carbohydrate consumption was not supported.