Transient Elastography-Based Liver Profiles in a Hospital-Based Pediatric Population in Japan

Background & Aims

The utility of transient elastography (FibroScan) is well studied in adults but not in children. We sought to assess the feasibility of performing FibroScans and the characteristics of FibroScan-based liver profiles in Japanese obese and non-obese children.

Methods

FibroScan examinations were performed in pediatric patients (age, 1–18 yr) who visited Osaka City University Hospital. Liver steatosis measured by controlled attenuation parameter (CAP), and hepatic fibrosis evaluated as the liver stiffness measurement (LSM), were compared among obese subjects (BMI percentile ≥90%), non-obese healthy controls, and non-obese patients with liver disease.

Results

Among 214 children examined, FibroScans were performed successfully in 201 children (93.9%; median, 11.5 yr; range, 1.3–17.6 yr; 115 male). CAP values (mean±SD) were higher in the obese group (n = 52, 285±60 dB/m) compared with the liver disease (n = 40, 202±62, P<0.001) and the control (n = 107, 179±41, P<0.001) group. LSM values were significantly higher in the obese group (5.5±2.3 kPa) than in the control (3.9±0.9, P<0.001), but there were no significant differences in LSM between the liver disease group (5.4±4.2) and either the obese or control group. LSM was highly correlated with CAP in the obese group (ρ = 0.511) but not in the control (ρ = 0.129) or liver disease (ρ = 0.170) groups.

Conclusions

Childhood obesity carries a high risk of hepatic steatosis associated with increased liver stiffness. FibroScan methodology provides simultaneous determination of CAP and LSM, is feasible in children of any age, and is a non-invasive and effective screening method for hepatic steatosis and liver fibrosis in Japanese obese children.     

Placenta Growth Factor in Eyes with Neovascular Glaucoma Is Decreased after Intravitreal Ranibizumab Injection

Purpose

To evaluate changes in the concentrations of placental growth factor (PlGF) and vascular endothelial growth factor-A (VEGF-A) in aqueous humor of patients with neovascular glaucoma (NVG) before and after an intravitreal injection of ranibizumab (IVR) and to determine the underlying correlation between the levels.

Methods

The prospective interventional comparative study involved 20 eyes of 20 patients with surgery-required advanced NVG and 20 control subjects from January 2013 to November 2013. The NVG eyes received the IVR treatment before glaucoma surgery. Aqueous humor was collected at the time of the IVR injection (pre- IVR) and at the time of antiglaucomatous surgery (post-IVR). Aqueous humor was also collected at the time of cataract surgery in normal control. Aqueous humor and plasma VEGF-A and PlGF levels were measured with an enzyme-linked immunosorbent assay methods, respectively.

Results

The mean aqueous humor PlGF and VEGF-A concentrations in the pre-IVR eyes were significantly higher than in those of the control subjects (p<0.001), whereas the plasma levels showed no significant difference. There was a statistically significant correlation between the aqueous humor PlGF and the VEGF-A concentration (r = 0.612, p = 0.003). The mean aqueous humor PlGF in the post-IVR eyes dramatically decreased from 1078.36 ± 755.83 to 177.64 ± 151.73 pg/mL (p<0.001). The VEGF-A level showed a similar trend from 3697.64 ± 2104.47 pg/mL to 183.54 ± 130.35 pg/mL (p<0.001).

Conclusions

Aqueous humor concentrations of VEGF-A and PlGF were significantly elevated in the eyes with NVG, and there was a positive correlation between the levels. After an IVR treatment, VEGF-A and PlGF were significantly decreased in NVG eyes.     

Myocardial Integrated Backscatter in Obese Adolescents: Associations with Measures of Adiposity and Left Ventricular Deformation

Background

Myocardial fibrosis has been proposed to play an important pathogenetic role in left ventricular (LV) dysfunction in obesity. This study tested the hypothesis that calibrated integrated backscatter (cIB) as a marker of myocardial fibrosis is altered in obese adolescents and explored its associations with adiposity, LV myocardial deformation, and metabolic parameters.

Methods/Principal Findings

Fifty-two obese adolescents and 38 non-obese controls were studied with conventional and speckle tracking echocardiography. The average cIB of ventricular septum and LV posterior wall was measured. In obese subjects, insulin resistance as estimated by homeostasis model assessment (HOMA-IR) and glucose tolerance were determined. Compared with controls, obese subjects had significantly greater cIB of ventricular septum (-16.8±7.8 dB vs -23.2±7.8 dB, p<0.001), LV posterior wall (-20.5±5.6 dBvs -25.0±5.1 dB, p<0.001) and their average (-18.7±5.7 dB vs -24.1±5.0 dB, p<0.001). For myocardial deformation, obese subjects had significantly reduced LV longitudinal systolic strain rate (SR) (p = 0.045) and early diastolic SR (p = 0.015), and LV circumferential systolic strain (p = 0.008), but greater LV longitudinal late diastolic SR (p<0.001), and radial early (p = 0.037) and late (p = 0.002) diastolic SR than controls. For the entire cohort, myocardial cIB correlated positively with body mass index (r = 0.45, p<0.001) and waist circumference (r = 0.45, p<0.001), but negatively with LV circumferential systolic strain (r = -0.23, p = 0.03) and systolic SR (r = -0.25, p = 0.016). Among obese subjects, cIB tended to correlate with HOMA-IR (r = 0.26, p = 0.07).

Conclusion

Obese adolescents already exhibit evidence of increased myocardial fibrosis, which is associated with measures of adiposity and impaired LV circumferential myocardial deformation.     

Alcohol and Exercise Affect Declining Kidney Function in Healthy Males Regardless of Obesity: A Prospective Cohort Study

Background

Although lifestyle is associated with metabolic syndrome and cardiovascular diseases, there has been no sufficient evidence of lifestyles on incident chronic kidney disease (CKD). The purpose of this prospective cohort study is to investigate the effects of lifestyles on kidney function in healthy people.

Methods

A total of 7473 healthy people were enrolled in this Saitama Cardiometabolic Disease and Organ Impairment Study, Japan. Data on alcohol consumption, exercise frequency, and sleep duration were collected. The outcome event was incident CKD or decrease in estimated glomerular filtration rate (eGFR) by >25% in 3 years.

Results

Subjects were classified into four groups according to body mass index and gender. Mean ± standard deviation of age was 38.8±10.5 years; eGFR, 78.1±15.2 ml/min/1.73m². In the male groups, multivariate logistic regression models showed that the outcome events were associated with a small amount of alcohol consumed (20 to 140g of alcohol/week) (ref. more than 140g of alcohol/week); non-obese male, adjusted odds ratio 1.366 (95% confidence interval, 1.086, 1.718); obese male (body mass index ≥25), 1.634 (1.160, 2.302); and with frequent exercise (twice a week or more) (ref. no exercise); non-obese male, 1.417 (1.144, 1.754); obese male, 1.842 (1.317, 2.577). Sleep duration was not associated with the outcome events.

Conclusion

These findings suggest that, regardless of obesity, a small amount of alcohol consumed and high exercise frequency were associated with the increased risk of loss of kidney function in the male groups.     

Relationship between Obesity and Massive Transfusion Needs in Trauma Patients,and Validation of TASH Score in Obese Population: A Retrospective Study on 910 Trauma Patients

Background

Prediction of massive transfusion (MT) is challenging in management of trauma patients. However, MT and its prediction were poorly studied in obese patients. The main objective was to assess the relationship between obesity and MT needs in trauma patients. The secondary objectives were to validate the Trauma Associated Severe Hemorrhage (TASH) score in predicting MT in obese patients and to use a grey zone approach to optimize its ability to predict MT.

Methods and Findings

An observational retrospective study was conducted in a Level I Regional Trauma Center Trauma in obese and non-obese patients. MT was defined as ≥10U of packed red blood cells in the first 24h and obesity as a BMI≥30kg/m². Between January 2008 and December 2012, 119 obese and 791 non-obese trauma patients were included. The rate of MT was 10% (94/910) in the whole population. The MT rate tended to be higher in obese patients than in non-obese patients: 15% (18/119, 95%CI 9‒23%) versus 10% (76/791, 95%CI 8‒12%), OR, 1.68 [95%CI 0.97‒2.92], p = 0.07. After adjusting for Injury Severity Score (ISS), obesity was significantly associated with MT rate (OR, 1.79[95%CI 1.00‒3.21], p = 0.049). The TASH score was higher in the obese group than in the non-obese group: 7(4–11) versus 5(2–10)(p<0.001). The area under the ROC curves of the TASH score in predicting MT was very high and comparable between the obese and non-obese groups: 0.93 (95%CI, 0.89‒0.98) and 0.94 (95%CI, 0.92‒0.96), respectively (p = 0.80). The grey zone ranged respectively from 10 to 13 and from 9 to 12 in obese and non obese patients, and allowed separating patients at low, intermediate or high risk of MT using the TASH score.

Conclusions

Obesity was associated with a higher rate of MT in trauma patients. The predictive performance of the TASH score and the grey zones were robust and comparable between obese and non-obese patients.     

Acute Dietary Nitrate Supplementation and Exercise Performance in COPD: A Double-Blind,Placebo-Controlled,Randomised Controlled Pilot Study

Background

Dietary nitrate supplementation can enhance exercise performance in healthy people, but it is not clear if it is beneficial in COPD. We investigated the hypotheses that acute nitrate dosing would improve exercise performance and reduce the oxygen cost of submaximal exercise in people with COPD.

Methods

We performed a double-blind, placebo-controlled, cross-over single dose study. Subjects were randomised to consume either nitrate-rich beetroot juice (containing 12.9mmoles nitrate) or placebo (nitrate-depleted beetroot juice) 3 hours prior to endurance cycle ergometry, performed at 70% of maximal workload assessed by a prior incremental exercise test. After a minimum washout period of 7 days the protocol was repeated with the crossover beverage.

Results

21 subjects successfully completed the study (age 68±7years; BMI 25.2±5.5kg/m²; FEV₁ percentage predicted 50.1±21.6%; peak VO₂ 18.0±5.9ml/min/kg). Resting diastolic blood pressure fell significantly with nitrate supplementation compared to placebo (-7±8mmHg nitrate vs. -1±8mmHg placebo; p = 0.008). Median endurance time did not differ significantly; nitrate 5.65 (3.90–10.40) minutes vs. placebo 6.40 (4.01–9.67) minutes (p = 0.50). However, isotime oxygen consumption (VO₂) was lower following nitrate supplementation (16.6±6.0ml/min/kg nitrate vs. 17.2±6.0ml/min/kg placebo; p = 0.043), and consequently nitrate supplementation caused a significant lowering of the amplitude of the VO₂-percentage isotime curve.

Conclusions

Acute administration of oral nitrate did not enhance endurance exercise performance; however the observation that beetroot juice caused reduced oxygen consumption at isotime suggests that further investigation of this treatment approach is warranted, perhaps targeting a more hypoxic phenotype.

Trial Registration

ISRCTN Registry ISRCTN66099139     

Individualized Exercise Training at Maximal Fat Oxidation Combined with Fruit and Vegetable-Rich Diet in Overweight or Obese Women: The LIPOXmax-Réunion Randomized Controlled Trial

Objectives

Lifestyle combined interventions are a key strategy for preventing type-2 diabetes (T2DM) in overweight or obese subjects. In this framework, LIPOXmax individualized training, based on maximal fat oxidation [MFO], may be a promising intervention to promote fat mass (FM) reduction and prevent T2DM. Our primary objective was to compare three training programs of physical activity combined with a fruit- and vegetable-rich diet in reducing FM in overweight or obese women.

Design and setting

A five months non-blinded randomized controlled trial (RCT) with three parallel groups in La Réunion Island, a region where metabolic diseases are highly prevalent.

Subjects

One hundred and thirty-six non-diabetic obese (body mass index [BMI]: 27–40 kg/m²) young women (aged 20–40) were randomized (G1: MFO intensity; G2: 60% of VO₂-peak intensity; G3: free moderate-intensity at-home exercise following good physical practices).

Outcomes

Anthropometry (BMI, bodyweight, FM, fat-free mass), glucose (fasting plasma glucose, insulin, HOMA-IR) and lipid (cholesterol and triglycerides) profiles, and MFO values were measured at month-0, month-3 and month-5.

Results

At month-5, among 109 women assessed on body composition, the three groups exhibited a significant FM reduction over time (G1: -4.1±0.54 kg; G2: -4.7±0.53 kg; G3: -3.5±0.78 kg, p<0.001, respectively) without inter-group differences (p = 0.135). All groups exhibited significant reductions in insulin levels or HOMA-IR index, and higher MFO values over time (p<0.001, respectively) but glucose control improvement was higher in G1 than in G3 while MFO values were higher in G1 than in G2 and G3. Changes in other outcome measures and inter-group differences were not significant.

Conclusion

In our RCT the LIPOXmax intervention did not show a superiority in reducing FM in overweight or obese women but is associated with higher MFO and better glucose control improvements. Other studies are required before proposing LIPOXmax training for the prevention of T2DM in overweight or obese women.

Trial Registration

ClincialTrials.gov NCT01464073     

The Cannabinoid Receptor 2 Q63R Variant Modulates the Relationship between Childhood Obesity and Age at Menarche

Background

The ovary is an important site where gene variants modulate pubertal timing. The cannabinoid receptor 2 (CB2) is expressed in the ovary, plays a role in folliculogenesis and ovulation, and can be modulated by estrogens. Obesity is strictly associated with early menarche and is characterized by sex hormone and endocannabinoid derangement.

Aim

In this study, we investigated the role of the CB2 receptor in determining the age at menarche in obese girls.

Methods

We studied a cohort of 240 obese girls (age 11.9±3 years; BMI z-score 2.8±0.8). The age at menarche (if it had already occurred) was recorded at the time of the visit or via phonecall. The CNR2 rs35761398 polymorphism, which leads to the CB2 Q63R variant, was detected by the TaqMan assay.

Results

In total, 105 patients were homozygous for the R63-coding allele (RR), 113 were QR and 22 were QQ. Variance analysis revealed a significantly earlier age of menarche in subjects carrying the Q63 allele, which was also found after adjusting for BMI z-score (11±1.2 vs. 11.6±1.2 years, p = 0.0003). Logistic regression analysis demonstrated that patients homozygous for the Q allele had a 2.2-fold higher risk (odds ratio = 2.2; CI1.1–3.4; p = 0.02) of presenting with an early menarche (age at menarche <12 years).

Conclusion

We demonstrated for the first time the association between the CB2 Q63R functional variant and the age at menarche in a cohort of Italian obese girls.     

Effect of Oral Glucose Administration on Rebound Growth Hormone Release in Normal and Obese Women: The Role of Adiposity,Insulin Sensitivity and Ghrelin

Context

Metabolic substrates and nutritional status play a major role in growth hormone (GH) secretion. Uncovering the mechanisms involved in GH secretion following oral glucose (OG) administration in normal and obese patients is a pending issue.

Objective

The aim of this study was to investigate GH after OG in relation with adiposity, insulin secretion and action, and ghrelin secretion in obese and healthy women, to further elucidate the mechanism of GH secretion after OG and the altered GH secretion in obesity.

Participants and Methods

We included 64 healthy and obese women. After an overnight fast, 75 g of OG were administered; GH, glucose, insulin and ghrelin were obtained during 300 minutes. Insulin secretion and action indices and the area under the curve (AUC) were calculated for GH, glucose, insulin and ghrelin. Univariate and multivariate linear regression analyses were employed.

Results

The AUC of GH (μg/L•min) was lower in obese (249.8±41.8) than in healthy women (490.4±74.6), P=0.001. The AUC of total ghrelin (pg/mL•min) was lower in obese (240995.5±11094.2) than in healthy women (340797.5±37757.5), P=0.042. There were significant correlations between GH secretion and the different adiposity, insulin secretion and action, and ghrelin secretion indices. After multivariate analysis only ghrelin AUC remained a significant predictor for fasting and peak GH.     

Monitoring Cell Death in Regorafenib-Treated Experimental Colon Carcinomas Using Annexin-Based Optical Fluorescence Imaging Validated by Perfusion MRI

Objective

To investigate annexin-based optical fluorescence imaging (OI) for monitoring regorafenib-induced early cell death in experimental colon carcinomas in rats, validated by perfusion MRI and multiparametric immunohistochemistry.

Materials and Methods

Subcutaneous human colon carcinomas (HT-29) in athymic rats (n = 16) were imaged before and after a one-week therapy with regorafenib (n = 8) or placebo (n = 8) using annexin-based OI and perfusion MRI at 3 Tesla. Optical signal-to-noise ratio (SNR) and MRI tumor perfusion parameters (plasma flow PF, mL/100mL/min; plasma volume PV, %) were assessed. On day 7, tumors underwent immunohistochemical analysis for tumor cell apoptosis (TUNEL), proliferation (Ki-67), and microvascular density (CD31).

Results

Apoptosis-targeted OI demonstrated a tumor-specific probe accumulation with a significant increase of tumor SNR under therapy (mean Δ +7.78±2.95, control: -0.80±2.48, p = 0.021). MRI detected a significant reduction of tumor perfusion in the therapy group (mean ΔPF -8.17±2.32 mL/100 mL/min, control -0.11±3.36 mL/100 mL/min, p = 0.036). Immunohistochemistry showed significantly more apoptosis (TUNEL; 11392±1486 vs. 2921±334, p = 0.001), significantly less proliferation (Ki-67; 1754±184 vs. 2883±323, p = 0.012), and significantly lower microvascular density (CD31; 107±10 vs. 182±22, p = 0.006) in the therapy group.

Conclusions

Annexin-based OI allowed for the non-invasive monitoring of regorafenib-induced early cell death in experimental colon carcinomas, validated by perfusion MRI and multiparametric immunohistochemistry.     

Patterns of Circulating Fibroblast Growth Factor 21 in Subjects with and without Type 2 Diabetes

Background

Fibroblast growth factor 21 (FGF21) exerts wide-range effects on carbohydrate and lipid metabolism. However, its perturbation in type 2 diabetes mellitus (T2DM) remains elusive. Besides, previous human studies in T2DM simply investigated fasting or stimulated levels of FGF21. The current study sought to evaluate the temporal changes of circulating FGF21 in subjects with and without T2DM.

Methods

Ten patients with T2DM and 16 normal controls (NC) were recruited. Participants were categorized as obese (BMI≥25 kg/m²) or lean (BMI<25 kg/m²). Blood samples were drawn every 30 min within 7 hours (8 a.m.-3 p.m.). Serum FGF21, blood glucose, insulin, free fatty acids (FFAs) and adiponectin were measured in all subjects.

Results

The peak levels of FGF21 were observed in the fasting state (8 a.m.) both in T2DM and NC groups (267.35 ±158.72 ng/L vs. 178.93±121.37 ng/L, P = 0.096). FGF21 AUC did not differ significantly between the two groups (T2DM: 949.4±471.47 ng/L; NC: 883.13±561.40 ng/L, P = 0.770). Obese subjects had higher FGF21 levels than lean ones in patients either with or without T2DM. The pattern of FFAs closely resembled that of FGF21. Correlation analysis showed that temporal levels of FGF21 were significantly related to FFAs (r = 0.749, P = 0.002),but not blood glucose, insulin or adiponectin (all P> 0.05).

Conclusions

These findings suggest that the pattern of circulating FGF21 does not differ significantly between T2DM and NC,although T2DM patients showed a trend toward higher fasting FGF21 than healthy subjects. The pattern of circulating FFAs is significantly associated with that of FGF21.     

Blockade of Thrombopoietin Reduces Organ Damage in Experimental Endotoxemia and Polymicrobial Sepsis

Background and Purpose

Thrombopoietin (TPO), a growth factor primarily involved in thrombopoiesis may also have a role in the pathophysiology of sepsis. In patients with sepsis, indeed, TPO levels are markedly increased, with disease severity being the major independent determinant of TPO concentrations. Moreover, TPO increases and correlates with ex vivo indices of platelet activation in patients with burn injury upon sepsis development, and may contribute to depress cardiac contractility in septic shock. Still, the role of TPO in sepsis pathophysiology remains controversial, given the protective role of TPO in other experimental disease models, for instance in doxorubicin-induced cardiotoxicity and myocardial ischemia/reperfusion injury. The aim of our study was to define the contribution of TPO in the development of organ damage induced by endotoxemia or sepsis, and to investigate the effects of inhibiting TPO in these conditions.

Methods

We synthesized a chimeric protein able to inhibit TPO, mTPOR-MBP, and studied its effect in two murine experimental models, acute endotoxemia and cecal ligation and puncture (CLP) model.

Results

In both models, TPO levels markedly increased, from 289.80±27.87 pg/mL to 465.60±45.92 pg/mL at 3 hours in the LPS model (P<0.01), and from 265.00±26.02 pg/mL to 373.70±26.20 pg/mL in the CLP model (P<0.05), respectively. Paralleling TPO levels, also platelet-monocyte aggregates increased, from 32.86±2.48% to 46.13±1.39% at 3 hours in the LPS model (P<0.01), and from 43.68±1.69% to 56.52±4.66% in the CLP model (P<0.05). Blockade of TPO by mTPOR-MBP administration reduced histological damage in target organs, namely lung, liver, and gut. In particular, neutrophil infiltration and lung septal thickening were reduced from a score of 1.86±0.34 to 0.60±0.27 (P<0.01) and from 1.43±0.37 to 0.40±0.16 (P<0.05), respectively, in the LPS model at 3 hours, and from a score of 1.75±0.37 to 0.38±0.18 (P<0.01) and from 1.25±0.31 to 0.13±0.13 (P<0.001), respectively, in the CLP model. Similarly, the number of hepatic microabscesses was decreased from 14.14±1.41 to 3.64±0.56 in the LPS model at 3 hours (P<0.001), and from 1.71±0.29 to 0.13±0.13 in the CLP model (P<0.001). Finally, the diameter of intestinal villi decreased from 90.69±3.95 μm to 70.74±3.60 μm in the LPS model at 3 hours (P<0.01), and from 74.29±4.29 μm to 57.50±1.89 μm in the CLP model (P<0.01). This protective effect was associated with the blunting of the increase in platelet-monocyte adhesion, and, on the contrary, with increased platelet-neutrophil aggregates in the circulation, which may be related to decreased neutrophil sequestration into the inflamed tissues. Conversely, circulating cytokine levels were not significantly changed, in both models, by mTPOR-MBP administration.

Conclusion

Our results demonstrate that TPO participates in the development of organ damage induced by experimental endotoxemia or polymicrobial sepsis via a mechanism involving increased platelet-leukocyte adhesion, but not cytokine release, and suggest that blocking TPO may be useful in preventing organ damage in patients affected by systemic inflammatory response or sepsis.     

Obesity Is Associated with Lower Coronary Microvascular Density

Background

Obesity is associated with diastolic dysfunction, lower maximal myocardial blood flow, impaired myocardial metabolism and increased risk of heart failure. We examined the association between obesity, left ventricular filling pressure and myocardial structure.

Methods

We performed histological analysis of non-ischemic myocardium from 57 patients (46 men and 11 women) undergoing coronary artery bypass graft surgery who did not have previous cardiac surgery, myocardial infarction, heart failure, atrial fibrillation or loop diuretic therapy.

Results

Non-obese (body mass index, BMI, ≤30 kg/m², n=33) and obese patients (BMI >30 kg/m², n=24) did not differ with respect to myocardial total, interstitial or perivascular fibrosis, arteriolar dimensions, or cardiomyocyte width. Obese patients had lower capillary length density (1145±239, mean±SD, vs. 1371±333 mm/mm³, P=0.007) and higher diffusion radius (16.9±1.5 vs. 15.6±2.0 μm, P=0.012), in comparison with non-obese patients. However, the diffusion radius/cardiomyocyte width ratio of obese patients (0.73±0.11 μm/μm) was not significantly different from that of non-obese patients (0.71±0.11 μm/μm), suggesting that differences in cardiomyocyte width explained in part the differences in capillary length density and diffusion radius between non-obese and obese patients. Increased BMI was associated with increased pulmonary capillary wedge pressure (PCWP, P<0.0001), and lower capillary length density was associated with both increased BMI (P=0.043) and increased PCWP (P=0.016).

Conclusions

Obesity and its accompanying increase in left ventricular filling pressure were associated with lower coronary microvascular density, which may contribute to the lower maximal myocardial blood flow, impaired myocardial metabolism, diastolic dysfunction and higher risk of heart failure in obese individuals.     

Effect of Acute Intermittent CPAP Depressurization during Sleep in Obese Patients

Background

Obstructive Sleep Apnea (OSA) describes intermittent collapse of the airway during sleep, for which continuous positive airway pressure (CPAP) is often prescribed for treatment. Prior studies suggest that discontinuation of CPAP leads to a gradual, rather than immediate return of baseline severity of OSA. The objective of this study was to determine the extent of OSA recurrence during short intervals of CPAP depressurization during sleep.

Methods

Nine obese (BMI = 40.4 ± 3.5) subjects with severe OSA (AHI = 88.9 ± 6.8) adherent to CPAP were studied during one night in the sleep laboratory. Nasal CPAP was delivered at therapeutic (11.1 ± 0.6 cm H₂0) or atmospheric pressure, in alternating fashion for 1-hour periods during the night. We compared sleep architecture and metrics of OSA during CPAP-on and CPAP-off periods.

Results

8/9 subjects tolerated CPAP withdrawal. The average AHI during CPAP-on and CPAP-off periods was 3.6 ± 0.6 and 15.8 ± 3.6 respectively (p<0.05). The average 3% ODI during CPAP-on and CPAP-off was 4.7 ± 2 and 20.4 ± 4.7 respectively (p<0.05). CPAP depressurization also induced more awake (p<0.05) and stage N1 (p<0.01) sleep, and less stage REM (p<0.05) with a trend towards decreased stage N3 (p = 0.064).

Conclusion

Acute intermittent depressurization of CPAP during sleep led to deterioration of sleep architecture but only partial re-emergence of OSA. These observations suggest carryover effects of CPAP.     

The Effect of Exercise Intensity on Endothelial Function in Physically Inactive Lean and Obese Adults

Purpose

To examine the effects of exercise intensity on acute changes in endothelial function in lean and obese adults.

Methods

Sixteen lean (BMI <25, age 23±3 yr) and 10 obese (BMI >30, age 26±6 yr) physically inactive adults were studied during 3 randomized admissions [control (C, no exercise), moderate-intensity exercise (M, @ lactate threshold (LT)) and high-intensity exercise (H, midway between LT and VO₂peak) (30 min)]. Endothelial function was assessed by flow-mediated dilation (FMD) at baseline and 1, 2, and 4 h post-exercise.

Results

RM ANCOVA revealed significant main effects for group, time, and group x condition interaction (p<0.05). A diurnal increase in FMD was observed in lean but not obese subjects. Lean subjects exhibited greater increases in FMD than obese subjects (p = 0.0005). In the obese group a trend was observed for increases in FMD at 2- and 4-hr after M (p = 0.08). For lean subjects, FMD was significantly elevated at all time points after H. The increase in FMD after H in lean subjects (3.2±0.5%) was greater than after both C (1.7±0.4%, p = 0.015) and M (1.4±0.4%, p = 0.002). FMD responses of lean and obese subjects significantly differed after C and H, but not after M.

Conclusion

In lean young adults, high-intensity exercise acutely enhances endothelial function, while moderate-intensity exercise has no significant effect above that seen in the absence of exercise. The FMD response of obese adults is blunted compared to lean adults. Diurnal variation should be considered when examining the effects of acute exercise on FMD.     

Resveratrol Does Not Influence Metabolic Risk Markers Related to Cardiovascular Health in Overweight and Slightly Obese Subjects: A Randomized,Placebo-Controlled Crossover Trial

Background

In vitro and animal studies have shown positive effects of resveratrol on lipid and lipoprotein metabolism, but human studies specifically designed to examine these effects are lacking.

Objective

The primary outcome parameter of this study in overweight and slightly obese subjects was the effect of resveratrol on apoA-I concentrations. Secondary outcome parameters were effects on other markers of lipid and lipoprotein metabolism, glucose metabolism, and markers for inflammation and endothelial function.

Design

This randomized, placebo-controlled crossover study was conducted in 45 overweight and slightly obese men (n = 25) and women (n = 20) with a mean age of 61 ± 7 years. Subjects received in random order resveratrol (150 mg per day) or placebo capsules for 4 weeks, separated by a 4-week wash-out period. Fasting blood samples were collected at baseline and at the end of each intervention period.

Results

Compliance was excellent as indicated by capsule count and changes in resveratrol and dihydroresveratrol concentrations. No difference between resveratrol and placebo was found in any of the fasting serum or plasma metabolic risk markers (mean ± SD for differences between day 28 values of resveratrol vs. placebo: apoA-I; 0.00 ± 0.12 g/L (P = 0.791), apoB100; -0.01 ± 0.11 g/L (P = 0.545), HDL cholesterol; 0.00 ± 0.09 mmol/L (P = 0.721), LDL cholesterol -0.03 ± 0.57 mmol/L (P = 0.718), triacylglycerol; 0.10 ± 0.54 mmol/L (P = 0.687), glucose; -0.08 ± 0.28 mmol/L (P = 0.064), insulin; -0.3 ± 2.5 mU/L (P = 0.516)). Also, no effects on plasma markers for inflammation and endothelial function were observed. No adverse events related to resveratrol intake were observed.

Conclusion

150 mg of daily resveratrol intake for 4 weeks does not change metabolic risk markers related to cardiovascular health in overweight and slightly obese men and women. Effects on glucose metabolism warrant further study.

Trial Registration

ClinicalTrials.gov NCT01364961     

Magnetic Resonance Imaging Determined Visceral Fat Reduction Associates with Enhanced IL-10 Plasma Levels in Calorie Restricted Obese Subjects

Background

Obesity is characterized by a low grade chronic inflammation state. Indeed circulating pro-inflammatory cytokines, such as TNF-α and IL-6, are elevated in obese subjects, while anti-inflammatory cytokines, such as IL-10, appear to be reduced. Cytokines profile improves after weight loss, but how visceral or subcutaneous fat loss respectively affect pro- or anti-inflammatory cytokines plasma levels has not been precisely assessed. Therefore in the present study we correlated changes in circulating cytokine profile with quantitative changes in visceral and subcutaneous adipose tissue depots measured by an ad hoc Magnetic Resonance Imaging (MRI) protocol before and after weight loss.

Materials and Methods

In 14 obese subjects, MRI determination of visceral and subcutaneous fat and plasma glucose, insulin, TNF-α IL-6, and IL-10 measurements were performed before and after a caloric restriction induced weight loss of at least 5% of the original body weight.

Results

Weight loss improved insulin sensitivity (QUICKI Index: 0.35±0.03 vs 0.37±0.04; P<0.05), increased IL-10 (3.4±1.9 vs 4.6±1.0 pg/mL; P<0.03), and reduced TNF-α and IL-6 plasma levels (2.5±1.3 vs 1.6±1.5 pg/mL, P<0.0015, 2.3±0.4 vs 1.6±0.6 pg/mL, P<0.02 respectively). A significant correlation was observed between the amount of visceral fat loss and the percentage reduction in both TNF-α (r = 0.56, p<0.05) and IL-6 (r = 0.19 p<0.05) plasma levels. In a multiple regression analysis, the amount of visceral fat loss independently correlated with the increase in IL-10 plasma levels.

Conclusion

The reduction in visceral adipose tissue is the main driver of the improved inflammatory profile induced by weight loss.     

Relationship between Inflammatory Cytokines and Indices of Cardiac Dysfunction following Intense Endurance Exercise

Objectives

Pro-inflammatory cytokines have been noted to increase following exercise but their relationship to exercise-induced cardiac dysfunction has not previously been investigated. We sought to evaluate whether exercise-induced cardiac dysfunction was associated with increases in cytokines, particularly the pro-inflammatory cytokines IL-1β, IL-12p70 and TNFα, which have been most implicated in cardiac pathology.

Methods

40 well-trained endurance athletes underwent evaluation prior to and immediately following one of four endurance sporting events ranging from 3 to 11 hours duration. Cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNFα) were analyzed by flow cytometry from serum samples collected within 50 minutes of race completion. Cardiac troponin (cTnI) and B-type natriuretic peptide were combined with an echocardiographic assessment of cardiac function, and a composite of cTnI > 0.04 μg/L, BNP increase > 10 ng/L and a decrease in right ventricular ejection (RVEF) > 10% were prospectively defined as evidence of myocardial dysfunction.

Results

Relative to baseline, IL-6 IL-8 and IL-10 increased 8.5-, 2.9-, and 7.1-fold, respectively, P<0.0001. Thirty-one (78%), 19 (48%) and 18 (45%) of the athletes met the pre-specified criteria for significant cTnI, BNP and RVEF changes, respectively. TNFα, IL-12p70 were univariate predictors of ΔRVEF and ΔBNP whilst none of the anti-inflammatory cytokines were significantly associated with these measures. Ten athletes (25%, all athletes competing in the endurance event of longest duration) met criteria for exercise-induced myocardial dysfunction. In these 10 athletes with myocardial dysfunction, as compared to those without, there was significantly greater post-race expression of the pro-inflammatory cytokines IL-12p70 (8.1±3.8pg/ml vs. 2.5±2.6pg/ml, P<0.0001) and TNFα (6.5±3.1pg/ml vs. 2.0±2.5pg/ml, P<0.0001).

Conclusion

Cardiac dysfunction following intense endurance exercise was associated with increased expression of pro-inflammatory cytokines. This does not prove a causal relationship but provides rationale for further investigations into whether inflammation mediates exercise-induced myocardial dysfunction.     

Interactive Video Game Cycling Leads to Higher Energy Expenditure and Is More Enjoyable than Conventional Exercise in Adults

Background

Despite the widely accepted health benefits of regular physical activity, only a small percentage of the population meets the current recommendations. The reasons include a wide use of technology and a lack of enjoyment while exercising. The purpose of this study was to compare the physiological, perceptual and enjoyment responses between a single bout of (I) conventional cycling and (II) interactive cycling video game at a matched workload.

Methods

A cross-sectional study in 34 healthy participants was performed. Initially, participants completed an incremental maximal cycling test to measure peak oxygen uptake and to determine ventilatory threshold. In random order, participants carried out a 30 min interactive cycling trial and a 30 min conventional cycling trial at 55% of peak power output. During the trials, oxygen uptake and energy expenditure were measured by open-circuit spirometry and heart rate was measured by radiotelemetry. RPE and enjoyment were measured every 10 minutes with Borg scale and a modified PACES scale.

Results

Interactive cycling resulted in a significantly greater %V̇O₂Reserve (68.2% ± 9.2% vs 64.7% ± 8.1%), rate of energy expenditure (505.8±75.2 vs 487.4±81.2 j·kg^-1·min^-1), and enjoyment (63.4% ± 17 vs 42% ± 13.6), P&lt;0.05. Participants were working at a higher intensity in relation to the individual’s ventilatory threshold during the interactive cycling video game trial (M = 11.86, SE = 3.08) than during the Conventional cycling trial (M = 7.55, SE = 3.16, t(33) = -2.69, P&lt;0.05, r = .42). No significant differences were found for heart rate reserve (72.5 ± 10.4 vs 71.4±10.1%) and RPE (13.1 ± 1.8 vs 13.2 ± 1.7).

Conclusion

Interactive cycling games can be a valid alternative to conventional exercise as they result in a higher exercise intensity than conventional cycling and a distraction from aversive cognitive and physiological states at and above the ventilatory threshold.     

Elevated Serum Level of IL-35 Associated with the Maintenance of Maternal-Fetal Immune Tolerance in Normal Pregnancy

Objectives

IL-35 is a novel inhibitory cytokine. In this study, we investigate the serum levels of inhibitory cytokines IL-35, IL-10 and TGF-β in both normal pregnancies and non-pregnant females, and whether IL-35 is associated with the pathogenesis of recurrent spontaneous abortion. We also try to elucidate the relationships of IL-35 with estrogen and alpha-fetoprotein (AFP).

Methods

The levels of IL-35, IL-10, TGF-β, estradiol (E2), unconjugated estriol (uE3) and AFP were analyzed in 120 normal pregnancies, 40 women suffering recurrent spontaneous abortion, 40 postpartum healthy women and 40 non-pregnant women by enzyme-linked immunosorbent assay (ELISA). The correlations between inhibitory cytokines, estrogen and AFP were assessed with the Spearman rank correlation coefficient.

Results

Data are expressed as median and percentiles (Q1, Q3).The level of serum IL-35 in normal pregnancies was significantly higher than that in non-pregnant women [333.6 (59.32, 1391) pg/mL vs. 123.9 (8.763, 471.7) pg/mL; P < 0.001]. A significantly higher level of TGF-β was observed in the first trimester only as compared to non-pregnant women [473.4 (398.0, 580.5) pg/mL vs. 379.7 (311.0, 441.3) pg/mL, P < 0.01]. The difference in serum IL-10 level between pregnant women and non-pregnant women was not significant [8.602 (5.854, 12.89) pg/mL vs. 9.339 (5.691, 12.07) pg/mL; P > 0.05]. The level of serum IL-35 in recurrent spontaneous abortion was significantly lower than that in normal early pregnancy [220.4 (4.951, 702.0) pg/mL vs. 386.5 (64.37, 1355) pg/mL; P < 0.05]. The higher IL-35 level in first trimester pregnant women correlated with E2 (r = 0.3062, P < 0.01) and AFP (r = 0.3179, P < 0.01).

Conclusion

Serum levels of IL-35 increased in normal pregnancy and decreased in recurrent spontaneous abortion. Increased IL-35 correlated with estrogen and AFP levels in early pregnancy. IL-35 is becoming recognized as an active player in the maintenance of a successful pregnancy, but this is not the case for IL-10 or TGF-β.