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1.  Low doses of caffeine reduce heart rate during submaximal cycle ergometry 
The purpose of this study was to examine the cardiovascular effects of two low-levels of caffeine ingestion in non habitual caffeine users at various submaximal and maximal exercise intensities.
Nine male subjects (19–25 yr; 83.3 ± 3.1 kg; 184 ± 2 cm), underwent three testing sessions administered in a randomized and double-blind fashion. During each session, subjects were provided 4 oz of water and a gelatin capsule containing a placebo, 1.5 mg/kg caffeine, or 3.0 mg/kg caffeine. After thirty minutes of rest, a warm-up (30 Watts for 2 min) the pedal rate of 60 rpm was maintained at a steady-state output of 60 watts for five minutes; increased to 120 watts for five minutes and to 180 watts for five minutes. After a 2 min rest the workload was 180 watts for one minute and increased by 30 watts every minute until exhaustion. Heart rate (HR) was measured during the last 15-seconds of each minute of submaximal exercise. Systolic blood pressure (BP) was measured at rest and during each of the three sub-maximal steady state power outputs. Minute ventilation (VE), Tidal volume (VT), Breathing frequency (Bf), Rating of perceived exertion (RPE), Respiratory exchange ratio (RER), and Oxygen consumption (VO2) were measured at rest and during each minute of exercise.
Caffeine at 1.5 and 3.0 mg/kg body weight significantly lowered (p < 0.05) HR during all three submaximal exercise intensities compared to placebo (range – 4 to 7 bpm lower) but not at rest or maximal exercise. BP was significantly higher (p < 0.05) at rest and after the 3 mg/kg caffeine vs placebo (116 ± 13 vs 123 ± 10 mm Hg). Neither dose of caffeine had any effect on BP during submaximal exercise. Caffeine had no effect on VE, VT, VO2, RPE, maximal power output or time to exhaustion.
In non habitual caffeine users it appears that consuming a caffeine pill (1.5 & 3.0 mg/kg) at a dose comparable to 1–3 cups of coffee lowers heart rate during submaximal exercise but not at near maximal and maximal exercise. In addition, this caffeine dose also only appears to affect systolic blood pressure at rest but not during cycling exercise.
PMCID: PMC2164943  PMID: 17925021
Biology of Sport  2014;31(2):139-144.
This study investigated the effects of obesity and ambient temperature on physiological responses and markers of oxidative stress to submaximal exercise in obese and lean people. Sixteen healthy males were divided into an obese group (n=8, %fat: 27.00±3.00%) and a lean group (n=8, %fat: 13.85±2.45%). Study variables were measured during a 60 min submaximal exercise test at 60% VO2max in a neutral (21±1°C) and a cold (4±1°C) environment. Heart rate, blood lactate, rectal temperature, serum levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured at rest, during exercise and in recovery. Heart rate of both groups was significantly lower (P<0.05) in the cold than the warm environment, but there were no significant differences between the two groups. Serum SOD activity increased to a significantly greater extent (P<0.05) in the cold than the neutral environment, and remained elevated for longer during exercise in the obese group than the lean group. Serum MDA level during submaximal exercise was not significantly different between conditions or groups. Cold stress in exercise may challenge antioxidant defence mechanisms in obese subjects, but lipid peroxidation remains unchanged.
PMCID: PMC4042661  PMID: 24899779
oxidative stress; cold; obese; physiological response; exercise
3.  Randomised, controlled walking trials in postmenopausal women: the minimum dose to improve aerobic fitness? 
Background: The American College of Sports Medicine recommends 20–60 minutes of aerobic exercise three to five days a week at an intensity of 40/50–85% of maximal aerobic power (VO2MAX) reserve, expending a total of 700–2000 kcal (2.93–8.36 MJ) a week to improve aerobic power and body composition.
Objective: To ascertain the minimum effective dose of exercise.
Methods: Voluntary, healthy, non-obese, sedentary, postmenopausal women (n = 121), 48–63 years of age, were randomised to four low dose walking groups or a control group; 116 subjects completed the study. The exercise groups walked five days a week for 24 weeks with the following intensity (% of VO2MAX) and energy expenditure (kcal/week): group W1, 55%/1500 kcal; group W2, 45%/1500 kcal; group W3, 55%/1000 kcal; group W4, 45%/1000 kcal. VO2MAX was measured in a direct maximal treadmill test. Submaximal aerobic fitness was estimated as heart rates at submaximal work levels corresponding to 65% and 75% of the baseline VO2MAX. The body mass index (BMI) was calculated and percentage of body fat (F%) estimated from skinfolds.
Results: The net change (the differences between changes in each exercise group and the control group) in VO2MAX was 2.9 ml/min/kg (95% confidence interval (CI) 1.5 to 4.2) in group W1, 2.6 ml/min/kg (95% CI 1.3 to 4.0) in group W2, 2.4 ml/min/kg (95% CI 0.9 to 3.8) in group W3, and 2.2 ml/min/kg (95% CI 0.8 to 3.5) in group W4. The heart rates in standard submaximal work decreased 4 to 8 beats/min in all the groups. There was no change in BMI, but the F% decreased by about 1% unit in all the groups.
Conclusions: Walking (for 24 weeks) at moderate intensity 45% to 55% of VO2MAX, with a total weekly energy expenditure of 1000–1500 kcal, improves VO2MAX and body composition of previously sedentary, non-obese, postmenopausal women. This dose of exercise apparently approaches the minimum effective dose.
PMCID: PMC1724503  PMID: 12055113
4.  The role of obesity in the immune response during sepsis 
Nutrition & Diabetes  2014;4(9):e137-.
Sepsis is one of the most important causes of mortality in the developed world, where almost two-thirds of the population suffer from obesity. Therefore, the coexistence of both conditions has become frequent in clinical practice and a growing number of clinical studies attempts to examine the potential effect of obesity on sepsis with controversial results up to now. The present study investigates how obesity influences the immune response of septic patients, by assessing the number and activation state of adipose tissue macrophages, serum and adipose tissue tumor necrosis factor-alpha (TNFα) levels and plasma oxidative stress markers.
The study included 106 patients, divided into four groups (control n=26, obesity n=27, sepsis n=27 and sepsis and obesity n=26). The number of macrophages in subcutaneous and visceral adipose tissue (SAT and VAT) and their subtypes (M1 and M2) were defined with immunohistochemical staining techniques under light microscopy. TNFα mRNA levels were determined in SAT and VAT using real-time reverse transcription-PCR. Serum levels of TNFα were determined with sandwich enzyme-linked immunosorbent assay. Plasma oxidative stress was evaluated using selective biomarkers (thiobarbituric acid-reactive substances (TBARS), protein carbonyls and total antioxidant capacity (TAC)).
Sepsis increased the total number of macrophages and their M2 subtype in (VAT), whereas obesity did not seem to affect the concentration of macrophages in fat. Obesity increased TNFα mRNA levels (P<0.05) in VAT as well as the plasma TBARS (P<0.001) and protein carbonyls (P<0.001) in septic patients. The plasma TAC levels were decreased and the serum TNFα levels were increased in sepsis although they were not influenced by obesity.
Obesity is associated with elevated TNFα adipose tissue production and increased oxidative stress biomarkers, promoting the proinflammatory response in septic patients.
PMCID: PMC4183975  PMID: 25244356
5.  Plasma adipokine and inflammatory marker concentrations are altered in obese, as opposed to non-obese, type 2 diabetes patients 
Elevated plasma free fatty acid (FFA), inflammatory marker, and altered adipokine concentrations have been observed in obese type 2 diabetes patients. It remains unclear whether these altered plasma concentrations are related to the diabetic state or presence of obesity. In this cross-sectional observational study, we compare basal plasma FFA, inflammatory marker, and adipokine concentrations between obese and non-obese type 2 diabetes patients and healthy, non-obese controls. A total of 20 healthy, normoglycemic males (BMI <30 kg/m2), 20 non-obese (BMI <30 kg/m2) and 20 obese (BMI >35 kg/m2) type 2 diabetes patients were selected to participate in this study. Groups were matched for age and habitual physical activity level. Body composition, glycemic control, and exercise performance capacity were assessed. Basal blood samples were collected to determine plasma leptin, adiponectin, resistin, tumor necrosis factor α (TNFα), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP) and FFA concentrations. Plasma FFA, inflammatory marker (hsCRP, IL-6, TNFα), adipokine (adiponectin, resistin, leptin), and triglyceride concentrations did not differ between non-obese diabetes patients and healthy, normoglycemic controls. Plasma FFA, IL-6, hsCRP, leptin, and triglyceride levels were significantly higher in the obese diabetes patients when compared with the healthy normoglycemic controls (P < 0.05). Furthermore, plasma hsCRP and leptin levels were significantly higher in the obese versus non-obese diabetes patients (P < 0.05). Significant correlations between plasma parameters and glycemic control were observed, but disappeared after adjusting for trunk adipose tissue mass. Elevated plasma leptin, hsCRP, IL-6, and FFA concentrations are associated with obesity and not necessarily with the type 2 diabetic state.
PMCID: PMC2874484  PMID: 20131064
Obesity; Diabetes; Adipokines; Inflammation; Fat mass
6.  Plasma levels of soluble tumor necrosis factor-α receptors are related to total and LDL-cholesterol in lean, but not in obese subjects 
Tumor necrosis factor-α (TNFα) is a mediator of insulin resistance. Plasma levels of soluble TNFα receptors (sTNFR1 and sTNFR2) probably reflect paracrine action of the cytokine. TNFα is also a regulator of lipid metabolism, however, data about impact of obesity on the relationships between TNFα and plasma lipids remain controversial.
The purpose of the present study was to examine the associations of TNFα system with plasma lipids in lean and obese subjects with normal glucose metabolism.
We examined 63 subjects, 33 lean (BMI<25 kg × m-2) and 30 with marked overweight or obesity (BMI>27.8 kg × m-2). Anthropometric and biochemical parameters were measured. Oral glucose tolerance test and euglycemic hyperinsulinemic clamp were also performed.
Obese subjects were markedly more insulin resistant and had higher levels of both TNFα receptors. Total (TC) and LDL-cholesterol (LDL-C), triglycerides (TG) and non-esterified fatty acids (NEFA) were also higher in the obese group. In obese subjects, both receptors were significantly related to TG and HDL-cholesterol (HDL-C), while sTNFR2 was also associated with NEFA. All those correlations disappeared after controlling for insulin sensitivity. In lean subjects, both receptors were related to TC, HDL-C and LDL-C. In that group, sTNFR1 predicted values of all those parameters independently of BMI, plasma glucose and insulin, and insulin sensitivity.
We conclude that TNFα receptors are associated with plasma lipids in different way in lean and in obese subjects. TNFα system is probably important in determining cholesterol levels in lean subjects, while in obese this effect might be masked by other metabolic abnormalities.
PMCID: PMC1524944  PMID: 16803616
7.  Effect of walking exercise on abdominal fat, insulin resistance and serum cytokines in obese women 
The purpose of the study was to investigate the effect of 12-week walking exercise on abdominal fat, insulin resistance and serum cytokines in obese women.
Following baseline measurements, obese women (N = 20) who met obesity criterion of BMI at 25 kg/m2 or greater were randomly assigned to the control (n = 10) or exercise groups (n = 10). Women assigned to the exercise group participated in a walking exercise (with an intensity of 50-60% of predetermined VO2max, a frequency of 3 days per week and duration of 50-70 minutes targeting 400 kcal of energy expenditure per session) for 12 weeks, while women assigned to the control group maintained their sedentary lifestyle. After the 12-week walking intervention, post-test measurements were conducted using the same procedure as the baseline measurement. Analyses of variance with repeated measures were used to evaluate any significant time by group interactions for the measured variables.
With respect to body fat parameters, significant time-by-group interactions were found in the abdominal subcutaneous (p = < 0.001) and visceral adipose tissues (p = 0.011). The exercise group had significant reductions in both subcutaneous and visceral adiposity, and the control group had no significant changes in those parameters. Similarly, there were significant time by group interactions in fasting glucose (p = 0.008), HOMA-IR (p = 0.029), serum TNF-α (p = 0.027), and IL-6 (p = 0.048) such that the exercise group had significant reductions in those parameters, with no such significant changes found in the control group. The exercise group also had a significant increase in serum adiponectin (p = 0.002), whereas the control group had no significant change in the parameter.
In summary, the current findings suggest that walking exercise can provide a safe and effective lifestyle strategy against abdominal obesity and serum insulin resistance markers in obese women.
PMCID: PMC4241903  PMID: 25566464
Abdominal adiposity; insulin resistance index; serum cytokines
8.  Effect of a twelve week exercise programme on cardio-respiratory and body composition variables in non-obese young and middle-aged females 
This study investigated the effect of a 12-week exercise programme consisting of jogging, calistnenics, and recreational activities on the cardiorespiratory function and body composition of 15 young and 15 middle-aged nonobese women 21-32 and 34-57 years, respectively. The exercise programme was 3 days per week for an average of 45 minutes each session. Pre- and post-programme data were obtained on: age, height, total body weight, resting heart rate, systolic and diastolic blood pressure, vital capacity, submaximal heart rate, supra-iliac skinfold, thigh skinfold, waist girth, cup size, body density, and percent fat. The t-test was used to test the difference between the young and middle-aged groups before and after the exercise programme and to test the pre- and post-programme mean values of each group. No differences between the groups or changes due to the exercise programme were observed on total body weight. No significant cardiorespiratory differences were found between the two groups at either test period, however, the young group decreased significantly (p < .01) in submaximal HR and the middle-aged group decreased significantly in resting (p < .01) and submaximal (p < .001) HR illustrating the positive effect of the programme. No significant body composition differences were found between the two groups at the pre-test. At the post-test the middle-aged group had a significantly (p < .10) larger thigh skinfold thickness than the young group. The young group did not change significantly on body composition measures from pre- to post-test. In contrast, the middle-aged group increased significantly in body density (p < .01) and decreased in percent body fat (p < .01) due to a significant (p < .01) reduction in supra-iliac skinfold thickness from 21.67 ± 2.35 to 18.13 ± 2.08 mm. The data were compared with data from other studies using similar age groups. The pre-test percent fat of the young group (25.07 ± .74) was similar to values reported in other studies. The middle-aged group had a relatively lower fat percentage (27.46 ± 1.58) compared with other middle-aged groups.
PMCID: PMC1859622  PMID: 630177
9.  Comparison of Active and Electrostimulated Recovery Strategies After Fatiguing Exercise 
The purpose of this study was to compare an electrostimulated to an active recovery strategy after a submaximal isometric fatiguing exercise. Nineteen healthy men completed three sessions (separated by at least 4 weeks) which included a knee extensors provocation exercise consisting of 3 sets of 25 isometric contractions. Contraction intensity level was fixed respectively at 60%, 55% and 50% of previously determined maximal voluntary contraction for the first, second and third sets. This provocation exercise was followed by either an active (AR) recovery (25 min pedaling on a cycle ergometer), an electrostimulated (ESR) recovery (25-min continuous and non-tetanic (5 Hz) stimulation of the quadriceps) or a strictly passive recovery (PR). Peak torques of knee extensors and subjective perception of muscle pain (VAS, 0-10) were evaluated before (pre-ex), immediately after the provocation exercise (post-ex), after the recovery period (post-rec), as well as 75 minutes (1h15) and one day (24h) after the exercise bout. Time course of peak torque was similar among the different recovery modes: ~ 75% of initial values at post-ex, ~ 90% at post-rec and at 1h15. At 24h, peak torque reached a level close to baseline values (PR: 99.1 ± 10.7%, AR: 105.3 ± 12.2%, ESR: 104.4 ± 10.5%). VAS muscle pain scores decreased rapidly between post-ex and post-rec (p < 0.001); there were no significant differences between the three recovery modes (p = 0.64). In conclusion, following a submaximal isometric knee extension exercise, neither electrostimulated nor active recovery strategies significantly improved the time course of muscle function recovery.
Key pointsThree sets of submaximal isometric contractions at 60%, 55% and 50% of MVC induced an early fatigue without DOMS but did not lead to exhaustion.In comparison with passive recovery, active and electrostimulated recovery did not lead to significantly higher MVC torques 24h after the exercise bout.No significant differences were demonstrated between the effects of passive, active and electrostimulated recoveries on muscle pain after repeated submaximal isometric contractions.
PMCID: PMC3761726  PMID: 24149681
Electrical stimulation; muscle recovery; isometric contraction; muscle fatigue
10.  Mechanical and Magnetic Resonance Imaging Changes Following Eccentric or Concentric Exertions 
Prior work has shown that changes in mechanical parameters and magnetic resonance imaging (MRI) parameters occur following submaximal eccentric activity but it is unclear whether similar changes occur following submaximal concentric activity. This study compared mechanical response parameters and MRI relaxation parameters following submaximal concentric or eccentric exertions.
This single site, randomized study investigated in-vivo changes in human upper limb dynamic mechanical properties following exposure to short term repetitive submaximal eccentric or concentric exertions. Eighteen subjects were assigned to either an eccentric or concentric group and exercised for 30 minutes at 50% of isometric forearm maximum voluntary contraction. Changes in strength, symptom intensity, MRI T2 relaxation measurements, which are indicative of edema, and dynamic mechanical parameters (stiffness, effective mass, and damping) were ascertained prior to exercise, one hour after, and 24 hours later.
Strength decreased following exercise (P < 0.01), however only the eccentric exercise group exhibited a reduction in mechanical stiffness (55%, P <0.01) and damping (31%, P < 0.05), and an increase (17%, P < 0.05) in MRI T2 relaxation time.
The changes in mechanical parameters and MRI findings following repetitive submaximal eccentric activity could negatively impact the ability of the arm to react to rapid forceful loading during repetitive industrial work activities and may result in increased strain on the upper limb. Similar changes were not observed following concentric exercise.
PMCID: PMC2581652  PMID: 18485551
Mechanical parameters; stiffness; forearm; submaximal eccentric exertions; MRI
11.  Substrate utilization during submaximal exercise in children with a severely obese parent 
We have reported a reduction in fatty acid oxidation (FAO) at the whole-body level and in skeletal muscle in severely obese (BMI ≥ 40 kg/m2) individuals; this defect is retained in cell culture suggesting an inherent component. The purpose of the current study was to determine if an impairment in whole-body fatty acid oxidation (FAO) was also evident in children with a severely obese parent.
Substrate utilization during submaximal exercise (cycle ergometer) was determined in children ages 8–12 y with a severely obese parent (OP, n = 13) or two lean/non-obese (BMI range of 18 to 28 kg/m2) parents (LP, n = 13). A subgroup of subjects (n = 3/group) performed 4 weeks of exercise training with substrate utilization measured after the intervention.
The children did not differ in age (LP vs. OP, respectively) (10.7 ± 0.5 vs. 10.2 ± 0.5 y), BMI percentile (65.3 ± 5.2 vs. 75.9 ± 7), Tanner Stage (1.4 ± 0.2 vs. 1.5 ± 0.2), VO2peak (40.3 ± 2.7 vs. 35.6 ± 2.6 ml/kg/min) or physical activity levels (accelerometer). At the same absolute workload of 15 W (~38% VO2peak), RER was significantly (P ≤ 0.05) lower in LP vs. OP (0.83 ± 0.02 vs. 0.87 ± 0.01) which was reflected in a reduced reliance on FAO for energy production in the OP group (58.6 ± 5.1 vs. 43.1 ± 4.0% of energy needs during exercise from FAO). At a higher exercise intensity (~65% VO2peak) there were no differences in substrate utilization between LP and OP. After exercise training RER tended to decrease (P = 0.06) at the 15 W workload, suggesting an increased reliance on FAO regardless of group.
These findings suggest that the decrement in FAO with severe obesity has an inherent component that may be overcome with exercise training.
PMCID: PMC3422990  PMID: 22571243
Bariatric surgery; Class III obesity; Exercise; Fat oxidation; Skeletal muscle
12.  The Effect of Submaximal Exercise Preceded by Single Whole-Body Cryotherapy on the Markers of Oxidative Stress and Inflammation in Blood of Volleyball Players 
The aim of the study was to determine the effect of single whole-body cryotherapy (WBC) session applied prior to submaximal exercise on the activity of antioxidant enzymes, the concentration of lipid peroxidation products, total oxidative status, and the level of cytokines in blood of volleyball players. The study group consisted of 18 male professional volleyball players, who were subjected to extremely cold air (−130°C) prior to exercise performed on cycloergometer. Blood samples were taken five times: before WBC, after WBC procedure, after exercise preceded by cryotherapy (WBC exercise), and before and after exercise without WBC (control exercise). The activity of catalase statistically significantly increased after control exercise. Moreover, the activity of catalase and superoxide dismutase was lower after WBC exercise than after control exercise (P < 0.001). After WBC exercise, the level of IL-6 and IL-1β was also lower (P < 0.001) than after control exercise. The obtained results may suggest that cryotherapy prior to exercise may have some antioxidant and anti-inflammatory properties. The relations between the level of studied oxidative stress and inflammatory markers may testify to the contribution of reactive oxygen species in cytokines release into the blood system in response to exercise and WBC.
PMCID: PMC3893756  PMID: 24489985
13.  A higher response of plasma neuropeptide Y, growth hormone, leptin levels and extracellular glycerol levels in subcutaneous abdominal adipose tissue to Acipimox during exercise in patients with bulimia nervosa: single-blind, randomized, microdialysis study 
Neuropeptide Y (NPY) is an important central orexigenic hormone predominantly produced by the hypothalamus, and recently found to be secreted in adipose tissue (AT). Acipimox (Aci) inhibits lipolysis in AT and reduces plasma glycerol and free fatty acid (FFA) levels. Exercise and Aci are enhancers of growth hormone (GH) and NPY secretion and exercise may alter leptin levels. We expect to find abnormal neuropeptidergic response in plasma and AT in patients with bulimia nervosa (BN). We hypothesize that Aci influences these peptides via a FFA-independent mechanism and that Aci inhibits lipolysis through a cyclic adenosine monophosphate (cAMP)-dependent pathway. Dysregulations of the AT-brain axis peptides might be involved in binge eating as is the case in BN.
The objective of this study was to determine the responses of plasma NPY, GH, leptin, FFA and glycerol levels to exercise in BN patients and healthy women (C) given the anti-lipolytic drug Aci or placebo. The secondary objective of this study was to compare the responses of extracellular glycerol levels and plasma glycerol levels to exercise alone or together with Aci administration in BN patients and C women. Extracellular glycerol was measured in vivo in subcutaneous (sc) abdominal AT using microdialysis. Eight BN and eight C women were recruited for this single-blind, randomized study. Aci or placebo was given 1 hour before the exercise (45 min, 2 W/kg of lean body mass [LBM]). NPY, GH, leptin, FFA, glycerol plasma and AT glycerol levels were measured using commercial kits.
The primary outcome of this study was that the exercise with Aci administration resulted in plasma NPY and GH increase (after a 45-minute exercise) and leptin (after a 90-minute post-exercise recovering phase) increased more in BN patients. The secondary outcomes of this study were that the exercise with Aci administration induced a higher decrease of extracellular glycerol in BN patients compared to the C group, while the exercise induced a higher increase of glycerol concentrations in sc abdominal AT of BN patients. Plasma glycerol levels decreased more in BN patients and plasma FFA levels were depressed in both groups after the exercise with Aci administration. The exercise induced similar increases in plasma NPY, GH, FFA and glycerol levels, and a similar decrease in the plasma leptin level in both groups.
We confirm the results of a single-blind, randomized, microdialysis study, i.e. that the Aci-induced elevation in plasma NPY and GH levels during the exercise is higher in BN patients and that Aci increased plasma leptin levels in the post-exercise recovering phase (90-minute) more in BN patients. The post-exercise rise (45-minute) in AT glycerol is much more attenuated by acute Aci treatment in BN patients. Simultaneously, we found facilitated turnover of plasma glycerol after the exercise together with Aci administration in BN. Our results support the hypotheses that Aci exerts an effect on the FFA-independent and cAMP-dependent mechanism.
Trial Registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000955910
PMCID: PMC3245450  PMID: 22093818
Neuropeptide Y; Growth hormone; Leptin; Bulimia nervosa; Acipimox; Exercise; Adipose tissue; Free fatty acids; Glycerol; Microdialysis
14.  Focal cerebral ischemia in the TNFalpha-transgenic rat 
To determine if chronic elevation of the inflammatory cytokine, tumor necrosis factor-α (TNFα), will affect infarct volume or cortical perfusion after focal cerebral ischemia.
Transgenic (TNFα-Tg) rats overexpressing the murine TNFα gene in brain were prepared by injection of mouse DNA into rat oocytes. Brain levels of TNFα mRNA and protein were measured and compared between TNFα-Tg and non-transgenic (non-Tg) littermates. Mean infarct volume was calculated 24 hours or 7 days after one hour of reversible middle cerebral artery occlusion (MCAO). Cortical perfusion was monitored by laser-Doppler flowmetry (LDF) during MCAO. Cortical vascular density was quantified by stereology. Post-ischemic cell death was assessed by immunohistochemistry and regional measurement of caspase-3 activity or DNA fragmentation. Unpaired t tests or analysis of variance with post hoc tests were used for comparison of group means.
In TNFα-Tg rat brain, the aggregate mouse and rat TNFα mRNA level was fourfold higher than in non-Tg littermates and the corresponding TNFα protein level was increased fivefold (p ≤ 0.01). Infarct volume was greater in TNFα-Tg rats than in non-Tg controls at 24 hours (p ≤ 0.05) and 7 days (p ≤ 0.01). Within the first 10 minutes of MCAO, cortical perfusion measured by LDF was reduced in TNFα-Tg rats (p ≤ 0.05). However, regional vascular density was equivalent between TNFα-Tg and non-Tg animals (p = NS). Neural cellular apoptosis was increased in transgenic animals as shown by elevated caspase-3 activity (p ≤ 0.05) and DNA fragmentation (p ≤ 0.001) at 24 hours.
Chronic elevation of TNFα protein in brain increases susceptibility to ischemic injury but has no effect on vascular density. TNFα-Tg animals are more susceptible to apoptotic cell death after MCAO than are non-Tg animals. We conclude that the TNFα-Tg rat is a valuable new tool for the study of cytokine-mediated ischemic brain injury.
PMCID: PMC2583993  PMID: 18947406
15.  Physical Exercise Reduces the Expression of RANTES and Its CCR5 Receptor in the Adipose Tissue of Obese Humans 
Mediators of Inflammation  2014;2014:627150.
RANTES and its CCR5 receptor trigger inflammation and its progression to insulin resistance in obese. In the present study, we investigated for the first time the effect of physical exercise on the expression of RANTES and CCR5 in obese humans. Fifty-seven adult nondiabetic subjects (17 lean and 40 obese) were enrolled in a 3-month supervised physical exercise. RANTES and CCR5 expressions were measured in PBMCs and subcutaneous adipose tissue before and after exercise. Circulating plasma levels of RANTES were also investigated. There was a significant increase in RANTES and CCR5 expression in the subcutaneous adipose tissue of obese compared to lean. In PBMCs, however, while the levels of RANTES mRNA and protein were comparable between both groups, CCR5 mRNA was downregulated in obese subjects (P < 0.05). Physical exercise significantly reduced the expression of both RANTES and CCR5 (P < 0.05) in the adipose tissue of obese individuals with a concomitant decrease in the levels of the inflammatory markers TNF-α, IL-6, and P-JNK. Circulating RANTES correlated negatively with anti-inflammatory IL-1ra (P = 0.001) and positively with proinflammatory IP-10 and TBARS levels (P < 0.05). Therefore, physical exercise may provide an effective approach for combating the deleterious effects associated with obesity through RANTES signaling in the adipose tissue.
PMCID: PMC4016945  PMID: 24895488
16.  The effect of minimal exercise on fitness in elderly women after hip surgery. 
The Ulster Medical Journal  1995;64(2):118-125.
To determine the effect of minimal exercise on functional fitness following total hip replacement in elderly women, 20 women (13 exercisers, 7 controls) who had undergone unilateral or bilateral hip replacement surgery for primary osteoarthritis were studied. An exercise treadmill test with respiratory gas and blood lactate analyses, and a field test of walking speed on a measured course, were administered before and after a twice weekly exercise programme of three months' duration. Markers of cardiorespiratory fitness, including peak achieved oxygen uptake (VO2) and ventilatory and lactate thresholds were measured. Maximum self-selected walking speed was also measured over a flat course. Peak VO2 increased in the exercise group when compared to baseline (P < 0.05) but did not differ from the control group. The exercise group significantly improved their walking speed by 10.1% compared with non-exercising controls (1.41 vs 1.20 m/sec, P < 0.05), and increased VO2 at lactate threshold. The improvements occurred despite the twice weekly exercise sessions being below the recommended frequency of exercise for improving cardiorespiratory fitness. Minimal exercise in elderly women after hip surgery can substantially improve submaximal exercise capacity, as well as walking speed.
PMCID: PMC2448534  PMID: 8533175
17.  Weight loss and exercise training effect on oxygen uptake and heart rate response to locomotion 
Effects of resistance and aerobic training on ease of physical activity during and following weight loss are unknown. Purpose of study is to determine what affect weight loss combined with either aerobic or resistance training has on ease of locomotion (netVO2 and heart rate). It is hypothesized that exercise training will result in increased ease, lower heart rate during locomotion. Seventy three overweight, premenopausal women were assigned to diet and aerobic training, diet and resistance training, or diet only. Subjects were evaluated while overweight, after diet induced weight loss (average 12.5 kg loss), and one year following weight loss (5.5 kg regain). Submaximal walking, grade walking, stair climbing, and bike oxygen uptake and heart rate were measured at all time points. Weight loss diet was 800 kcal/day. Exercisers trained 3 times/wk during weight loss and 2 times/wk during one year follow-up. Resistance training increased strength and aerobic training increased maximum oxygen uptake. Net submaximal oxygen uptake was not affected by weight loss or exercise training. However, heart rate during walking, stair climbing, and bicycling was reduced following weight loss. No significant differences in reduction in heart rate were observed between the 3 treatment groups for locomotion following weight loss. However, during one-year follow-up, exercise training resulted in maintenance of lower submaximal heart rate, while non exercisers increased heart rate during locomotion. Results, suggest that moderately intense exercise is helpful in improving ease of movement following weight loss. Exercise training may be helpful in increasing participation in free living physical activity.
PMCID: PMC3664274  PMID: 22344063
Aerobic training; Resistance training; calorie restriction
18.  Evaluation of immune response after moderate and overtraining exercise in wistar rat 
Objective(s): The effect of prolonged overtraining on cytokine kinetics was compared with moderate exercise in the present study.
Materials and Methods: Male Wistar rats were randomly divided into control sedentary (C), moderate trained (MT), (V=20 m/min, 30 min/day for 6 days a week, 8 weeks), overtrained (OT) (V=25 m/min, 60min/day for 6 days a week, 11 weeks) and recovered overtrained (OR) (OT plus 2 weeks recovery) groups, (n=6 for each group). Immediately, 24 hr and 2 weeks (in OR) after last bout of exercise blood samples were obtained. The plasma concentrations of TNFα, IL-6, IL-10, IL-4 and IFN were measured by ELISA method.
Results: Immediately after last bout of exercise the following findings were observed; IL-6, IL-10 and TNFα concentrations increased in OT and OR groups compared with control (P<0.05–P<0.001). Serum level of IL-4 decreased (P<0.01) but IFN increased (P<0.05) in MT group vs. control. In addition, circulatory levels of TNFα, IL-6, IL-10 and IL-4 were higher but the IFN concentrations were lower in OT and OR groups than MT group (P<0.05-P<0.01). The IFN-γ/IL4 ratio was significantly increased in MT (P<0.01) while it decreased in OT group. There were not statistical differences in TNFα, IL-6, and IFN levels between different time intervals after exercise in MT, OT and OR groups.
Conclusion: These data confirm a positive effect of moderate exercise on immune function and a decrease in susceptibility to viral infection by inducing Th1 cytokine profile shift. However, prolonged and overtraining exercise causes numerous changes in immunity that possibly reflects physiological stress and immune suppression.
PMCID: PMC3938879  PMID: 24592300
Immune system; Moderate exercise; Overtraining exercise; Rat; Th1; Th2
19.  The effects of treadmill exercise on expression of UCP-2 of brown adipose tissue and TNF-α of soleus muscle in obese Zucker rats 
Sorts of abnormal state, obesity and inflammation are involved in a number of serious disease occurring and both of them became important research topics among molecular biologists. UCP-2 and TNF-α respectively reflecting obese and inflammatory status have often been used to evaluate the effects of independent variable, such as exercise, on them. Because exercise has shown its potent control on obesity and inflammation, it is necessary to determine if exercise is working via same bioindices. The purpose of this study was to determine the effects of different treadmill exercise intensities on UCP-2 of brown adipose tissue and TNF-α of soleus muscle during 8 weeks in Zucker rat. Zucker rats were divided into four groups (n = 7 in each group): control group, low intensity exercise group, moderate intensity exercise group and high intensity exercise group. Zucker rats of the exercise groups were made to run on a motorized treadmill for 30 minutes once a day during 8 weeks. Rats were sacrificed 24 hours after the last bout of exercise. Blood glucose in Zucker rats were measured by Gluco-Card Ⅱ. Brown adipose tissue were extracted to analyze the level of UCP-2 and TNF-α, respectively. UCP-2 and TNF-α were analyzed using the Western Blotting technique. Statistical techniques for data analysis were repeated measure ANOVA and one way ANOVA to determine the difference between groups, and for post hoc test was Duncan' test. The 5% level of significance was utilized as the critical level for acceptance of hypotheses for the study. The following results were obtained from this study; UCP-2 protein expression of brown adipose tissue in Zucker rats were increased significantly following exercise of the low and moderate intensities compared to those of control group after 8 weeks. It was shown that TNF-α protein expression of soleus muscle in Zucker rats were decreased significantly following exercise of the low and moderate intensities compared to those of control group after 8 weeks. But no significant differences in levels of fasting glucose were shown between groups. The present data suggested that low and moderate intensities treadmill exercise may improve glycometabolism control and fat oxidation by up-regulating UCP-2 expression. In addition, we found low and moderate intensities reduce damages on skeletal muscle by down-regulation the TNF-α in Zucker rats. Thus, the low and moderate intensity exercise are appropriate for anti-obesity and inflammatory effects.
PMCID: PMC4241912  PMID: 25566431
Obese Zucker Rats; UCP-2; TNF-α
20.  Cryotherapy, Sensation, and Isometric-Force Variability 
Journal of Athletic Training  2003;38(2):113-119.
To determine the changes in sensation of pressure, 2-point discrimination, and submaximal isometric-force production variability due to cryotherapy.
Design and Setting:
Sensation was assessed using a 2 × 2 × 2 × 3 repeated-measures factorial design, with treatment (ice immersion or control), limb (right or left), digit (finger or thumb), and sensation test time (baseline, posttreatment, or postisometric-force trials) as independent variables. Dependent variables were changes in sensation of pressure and 2-point discrimination. Isometric-force variability was tested with a 2 × 2 × 3 repeated-measures factorial design. Treatment condition (ice immersion or control), limb (right or left), and percentage (10, 25, or 40) of maximal voluntary isometric contraction (MVIC) were the independent variables. The dependent variables were the precision or variability (the standard deviation of mean isometric force) and the accuracy or targeting error (the root mean square error) of the isometric force for each percentage of MVIC.
Fifteen volunteer college students (8 men, 7 women; age = 22 ± 3 years; mass = 72 ± 21.9 kg; height = 183.4 ± 11.6 cm).
We measured sensation in the distal palmar aspect of the index finger and thumb. Sensation of pressure and 2-point discrimination were measured before treatment (baseline), after treatment (15 minutes of ice immersion or control), and at the completion of isometric testing (final). Variability (standard deviation of mean isometric force) of the submaximal isometric finger forces was measured by having the subjects exert a pinching force with the thumb and index finger for 30 seconds. Subjects performed the pinching task at the 3 submaximal levels of MVIC (10%, 25%, and 40%), with the order of trials assigned randomly. The subjects were given a target representing the submaximal percentage of MVIC and visual feedback of the force produced as they pinched the testing device. The force exerted was measured using strain gauges mounted on an apparatus built to measure finger forces.
Sensation of pressure was less (ie, it took greater pressure to elicit a response) after ice immersion, thumbs were more affected than index fingers, and the decrease was greater in the right limb than the left. Two-point discrimination was not affected by cryotherapy but was higher in the finger than in the thumb under all conditions. Isometric-force variability (standard deviation of mean isometric force) was greater as percentage of force increased from 10% to 40% of MVIC. Targeting accuracy (root mean square error) was decreased at 40% of MVIC. Accuracy and force variability were not affected by cryotherapy.
The application of cryotherapy and reduced sensation of pressure appear to have little effect on motor control of the digits. These results support the hypothesis that the use of cold is not contraindicated for use as an analgesic before submaximal rehabilitative exercise focusing on restoring neuromuscular control to injured tissues.
PMCID: PMC164899  PMID: 12937521
root mean square error; accuracy; precision; sensation; maximal voluntary isometric contraction
21.  Responses of young girls to two modes of aerobic training. 
OBJECTIVES: To investigate the physiological effects of two different three times a week, eight week training programmes on the aerobic fitness of nine to ten year old girls. METHODS: Treadmill determined peak VO2, submaximal heart rates, and submaximal blood lactate were the criterion measures. Seventeen girls completed a programme of "aerobics" training where sessions lasted 20-25 minutes. Eighteen girls followed a cycle ergometer training programme which involved pedalling continuously for 20 minutes with the heart rate maintained between 160 and 170 beats/minute. A control group of 16 girls completed the criterion tests but did not train. In the cycle ergometer group and eight control subjects plasma total cholesterol and high density lipoprotein cholesterol were determined before and after training. RESULTS: Peak VO2 did not change significantly with training in either training group, neither were there any significant changes in submaximal heart rates. Blood lactate declined significantly at the two lowest submaximal exercise intensities in the cycle ergometer training group (from 2.3 (1.1) to 1.4 (0.06) mmol/l at stage 1 and from 2.1 (1.2) to 1.6 (0.06) mmol/l at stage 2; means (SD); P < 0.01). Total cholesterol and high density lipoprotein cholesterol remained unchanged with training. CONCLUSIONS: These findings suggest that an eight week structured exercise programme produces minimal changes in either the aerobic fitness or blood lipids of young girls. It may be more beneficial for long term health to promote enjoyment in activity and positive attitudes to exercise rather than attempting to enhance aerobic fitness through strenuous exercise programmes.
PMCID: PMC1332614  PMID: 9192129
22.  Acute exercise ameliorates differences in insulin resistance between physically active and sedentary overweight adults 
Although regular exercise is associated with reduced cardiometabolic disease risk among overweight adults, it remains unclear whether much of the health benefits of exercise are derived from the most recent session(s) of exercise or if they are the result of adaptations stemming from weeks, months, or even years of training. The purpose of this study was to compare the effects of habitual and acute exercise on key markers of cardiometabolic disease risk in overweight adults. We compared insulin sensitivity index (ISI) using an oral glucose tolerance test, blood pressure (BP), blood lipids, and systemic inflammatory cytokines in 12 overweight to mildly obese adults (BMI: 27–34 kg/m2) who exercise regularly (EX; >2.5 h exercise per week) with a well-matched cohort of 12 nonexercisers (Non-EX). Baseline measurements in EX were performed exactly 3 days after exercise, whereas Non-EX remained sedentary. We repeated these measurements the day after a session of exercise in both groups. At baseline, ISI was significantly greater in EX versus Non-EX (3.1 ± 0.2 vs. 2.3 ± 0.2; p = 0.02), but BP, blood lipids, and plasma concentration of the systemic inflammatory cytokines we measured were not different between groups. Acute exercise increased ISI the next morning in Non-EX (2.3 ± 0.2 vs. 2.8 ± 0.3; p = 0.03) but not EX. As a result, ISI was similar between groups the morning after exercise. In summary, exercising regularly was accompanied by a persistent improvement in insulin sensitivity that lasted at least 3 days after exercise in overweight adults, but just one session of exercise increased insulin sensitivity among sedentary overweight adults to levels equivalent to the regular exercisers.
PMCID: PMC4115061  PMID: 24773370
exercise training; physical activity; obesity; inflammation; cytokines
23.  Immunohistochemical profiling of the heat shock response in obese non-diabetic subjects revealed impaired expression of heat shock proteins in the adipose tissue 
Obesity is characterized by a chronic low-grade inflammation and altered stress responses in key metabolic tissues. Impairment of heat shock response (HSR) has been already linked to diabetes and insulin resistance as reflected by decrease in heat shock proteins (HSPs) expression. However, the status of HSR in non-diabetic human obese has not yet been elucidated. The aim of the current study was to investigate whether obesity triggers a change in the HSR pattern and the impact of physical exercise on this pattern at protein and mRNA levels.
Two groups of adult non-diabetic human subjects consisting of lean and obese (n = 47 for each group) were enrolled in this study. The expression pattern of HSP-27, DNAJB3/HSP-40, HSP-60, HSC-70, HSP72, HSP-90 and GRP-94 in the adipose tissue was primarily investigated by immunohistochemistry and then complemented by western blot and qRT-PCR in Peripheral blood mononuclear cells (PBMCs). HSPs expression levels were correlated with various physical, clinical and biochemical parameters. We have also explored the effect of a 3-month moderate physical exercise on the HSPs expression pattern in obese subjects.
Obese subjects displayed increased expression of HSP-60, HSC-70, HSP-72, HSP-90 and GRP-94 and lower expression of DNAJB3/HSP-40 (P < 0.05). No differential expression was observed for HSP-27 between the two groups. Higher levels of HSP-72 and GRP-94 proteins correlated positively with the indices of obesity (body mass index and percent body fat) and circulating levels of IFN-gamma-inducible protein 10 (IP-10) and RANTES chemokines. This expression pattern was concomitant with increased inflammatory response in the adipose tissue as monitored by increased levels of Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α), and RANTES (P < 0.05). Physical exercise reduced the expression of various HSPs in obese to normal levels observed in lean subjects with a parallel decrease in the endogenous levels of IL-6, TNF-α, and RANTES.
Taken together, these data indicate that obesity triggers differential regulation of various components of the HSR in non-diabetic subjects and a 3-month physical moderate exercise was sufficient to restore the normal expression of HSPs in the adipose tissue with concomitant attenuation in the inflammatory response.
PMCID: PMC4085713  PMID: 24986468
Heat shock protein; HSP; Exercise; ER stress; Obesity; Adipose tissue
24.  Metabolic inflexibility during submaximal aerobic exercise is associated with glucose intolerance in obese older adults 
Obesity (Silver Spring, Md.)  2013;22(2):451-457.
People with type 2 diabetes have reduced cardiorespiratory fitness and metabolic impairments that are linked to obesity and often occur prior to the development of type 2 diabetes. We hypothesized that obese, older adults with impaired glucose tolerance (IGT) have lower ability to shift from fat to carbohydrate oxidation when transitioning from rest to submaximal exercise than normal glucose tolerant (NGT) controls.
Design and Methods
Glucose tolerance, body composition, and substrate oxidation (measured by RER: respiratory exchange ratio) during submaximal exercise (50% and 60% VO2max) and insulin infusion (3-hour hyperinsulinemic-euglycemic clamp) were assessed in 23 sedentary, overweight-obese, older men and women.
Obese subjects with NGT (n=13) and IGT (n=10) had similar resting RER, but during submaximal exercise those with IGT had a lower RER and less transition to carbohydrate oxidation than the NGT group (P<0.05). The IGT group also oxidized less carbohydrate during insulin infusion than NGT (P<0.05). RER at each exercise intensity independently correlated with120-minute postprandial glucose (r= −0.54–−0.58, P<0.05), but not with body composition, VO2max, or RER during insulin infusion.
Obese, older adults have metabolic inflexibility during exercise that is associated with the degree of glucose intolerance independent of age and body composition.
PMCID: PMC3875833  PMID: 23983100
type 2 diabetes; metabolism; exercise physiology; substrate oxidation
25.  Inspiratory Muscle Fatigue Following Moderate-Intensity Exercise in the Heat 
Heavy exercise has been shown to elicit reductions in inspiratory muscle strength in healthy subjects. Our purpose was to determine the combined effects of moderate-intensity endurance exercise and a thermal load on inspiratory muscle strength in active subjects. Eight active, non heat-acclimatized female subjects (23.5 ± 1.4 yr; VO2max = 39.8 ± 2.4 randomly performed two 40 min endurance exercise bouts (60% VO2max) in either a thermo-neutral (22°C/21% RH) or hot (37°C/33% RH) environment on separate days. Maximal sustained inspiratory mouth pressure (PImax) was obtained pre and post exercise as an index of inspiratory muscle strength. Additional variables obtained every 10 min during the endurance exercise bouts included: rectal temperature (TRE), heart rate (HR), minute ventilation (VE), oxygen uptake (VO2), tidal volume (VT), breathing frequency (Fb), and ratings of perceived exertion and dyspnea (RPE/RPD). Data were analyzed with repeated measures ANOVA. PImax was significantly reduced (p < 0.05) after exercise in the hot environment when compared to baseline and when compared to post exercise values in the thermo-neutral environment. PImax was unchanged from baseline following exercise in the thermo-neutral environment. HR and TRE were significantly higher (p < 0.05) in the hot compared to the thermo-neutral environment. VE and VO2 were not significantly different between conditions. VT was unchanged between conditions whereas Fb was higher (p < 0.05) in the hot condition compared to thermo-neutral. RPE was not significantly different between conditions. RPD was significantly higher (p < 0.05) in the hot compared to the thermo-neutral environment. We conclude that moderate-intensity endurance exercise (60% VO2max) in a hot environment elicits significant reductions in inspiratory muscle strength in unfit females. This finding is novel in that previous studies conducted in a thermo-neutral environment have shown that an exercise intensity of >80% VO2max is required to elicit reductions in inspiratory muscle strength. In addition, dyspnea perception during exercise is greater in a hot environment, compared to thermo-neutral, at a similar level of VE and VO2.
Key PointsThe combined effects of a heat load and exercise on inspiratory muscle strength were investigated in untrained female subjects.Previous studies have shown that a very high exercise intensity (> 80% VO2max) is required to elicit reductions in inspiratory muscle strength.Prolonged submaximal exercise (40-min/60% VO2max) in a hot environment significantly reduced inspiratory muscle strength in untrained females whereas the same intensity in a thermo-neutral environment had no effect on inspiratory muscle function.These reductions in inspiratory muscle strength may be related to competition for blood flow among the locomotor, inspiratory, and cutaneous circulations.
PMCID: PMC3887326  PMID: 24453527
Control of breathing; endurance; respiratory function; thermal load

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