The protective effects and genetic pathways of thorn grape seeds oil against high glucose-induced apoptosis in pancreatic β-cells

Background

Chemicals of herbal products may cause unexpected toxicity or adverse effect by the potential for alteration of the activity of CYP450 when co-administered with other drugs. Eleutherococcus senticosus (ES), has been widely used as a traditional herbal medicine and popular herbal dietary supplements, and often co-administered with many other drugs. The main bioactive constituents of ES were considered to be eleutherosides including eleutheroside B (EB) and eleutheroside E (EE). This study was to investigate the effects of EB and EE on CYP2C9, CYP2D6, CYP2E1 and CYP3A4 in rat liver microsomes in vitro.

Method

Probe drugs of tolbutamide (TB), dextromethorphan (DM), chlorzoxazone (CLZ) and testosterone (TS) as well as eleutherosides of different concentrations were added to incubation systems of rat liver microsomes in vitro. After incubation, validated HPLC methods were used to quantify relevant metabolites.

Results

The results suggested that EB and EE exhibited weak inhibition against the activity of CYP2C9 and CYP2E1, but no effects on CYP2D6 and CYP3A4 activity. The IC₅₀ values for EB and EE were calculated to be 193.20 μM and 188.36 μM for CYP2E1, 595.66 μM and 261.82 μM for CYP2C9, respectively. Kinetic analysis showed that inhibitions of CYP2E1 by EB and EE were best fit to mixed-type with Ki value of 183.95 μM and 171.63 μM, respectively.

Conclusions

These results indicate that EB and EE may inhibit the metabolism of drugs metabolized via CYP2C9 and CYP2E1, and have the potential to increase the toxicity of the drugs.     

Sorbitol-modified hyaluronic acid reduces oxidative stress,apoptosis and mediators of inflammation and catabolism in human osteoarthritic chondrocytes

Objective and design

Our study was designed to elucidate the precise molecular mechanisms by which sorbitol-modified hyaluronic acid (HA/sorbitol) exerts beneficial effects in osteoarthritis (OA).

Methods

Human OA chondrocytes were treated with increasing doses of HA/sorbitol ± anti-CD44 antibody or with sorbitol alone and thereafter with or without interleukin-1beta (IL-1β) or hydrogen peroxide (H₂O₂). Signal transduction pathways and parameters related to oxidative stress, apoptosis, inflammation, and catabolism were investigated.

Results

HA/sorbitol prevented IL-1β-induced oxidative stress, as measured by reactive oxygen species, p47-NADPH oxidase phosphorylation, 4-hydroxynonenal (HNE) production and HNE-metabolizing glutathione-S-transferase A4-4 expression. Moreover, HA/sorbitol stifled IL-1β-induced metalloproteinase-13, nitric oxide (NO) and prostaglandin E2 release as well as inducible NO synthase expression. Study of the apoptosis process revealed that this gel significantly attenuated cell death, caspase-3 activation and DNA fragmentation elicited by exposure to a cytotoxic H₂O₂ dose. Examination of signaling pathway components disclosed that HA/sorbitol prevented IL-1β-induced p38 mitogen-activated protein kinase and nuclear factor-kappa B activation, but not that of extracellular signal-regulated kinases 1 and 2. Interestingly, the antioxidant as well as the anti-inflammatory and anti-catabolic effects of HA/sorbitol were attributed to sorbitol and HA, respectively.

Conclusions

Altogether, our findings support a beneficial effect of HA/sorbitol in OA through the restoration of redox status and reduction of apoptosis, inflammation and catabolism involved in cartilage damage.     

Involvement of histamine and histamine H<Subscript>2</Subscript> receptors in nicotinamide-induced differentiation of human amniotic epithelial cells into insulin-producing cells

Objective and design

Human amniotic epithelial cells (HAEC) resemble stem cells in their ability to differentiate into all three germ layers: endoderm, mesoderm, and ectoderm. Histamine receptors are expressed on HAEC. We examined the influence of histamine, and H₁ and H₂ antagonists on the generation of pancreatic islet beta-like cells from HAEC.

Materials and methods

HAEC were isolated after term pregnancies (N = 12) and cultured for 14 days with nicotinamide (10 mM) in normoxia. Altogether, 72 cultures were established. Histamine (100 μM) effects were investigated with mepyramine (10 μM) or cimetidine (10 μM). After 7 and 14 days, the mean concentration of C-peptide (MCCP) in the culture medium was measured immunoenzymatically as a marker of pancreatic differentiation.

Results

MCCP was approximately threefold higher on day 14, compared to day 7. Histamine significantly increased MCCP, and more evident differences were observed after 7 days of culture than after 14 days. The mean percent increase ±SEM in MCCP amounted to 142.19 ± 21.7 and 79.03 ± 12.35 compared to the controls on day 7 and 14, respectively. H₂ blockade significantly reduced histamine-related increase in MCCP, both on day 7 and 14 by 88.7 ± 14.3 and 39.2 ± 12.4%, respectively. H₁ receptor antagonist did not affect MCPP.

Conclusion

Nicotinamide-induced pancreatic differentiation of HAEC into beta-like cells may be augmented, probably at its earlier stage, by histamine acting via H₂ receptors.

     

Influence of thigh activation on the \dot{V}O2 slow component in boys and men

Purpose

During constant work rate exercise above the lactate threshold (LT), the initial rapid phase of pulmonary oxygen uptake ( \(\dot{V}\) O₂) kinetics is supplemented by an additional \(\dot{V}\) O₂ slow component ( \(\dot{V}\) O_2Sc) which reduces the efficiency of muscular work. The \(\dot{V}\) O_2Sc amplitude has been shown to increase with maturation but the mechanisms are poorly understood. We utilized the transverse relaxation time (T ₂) of muscle protons from magnetic resonance imaging (MRI) to test the hypothesis that a lower \(\dot{V}\) O₂ slow component ( \(\dot{V}\) O_2Sc) amplitude in children would be associated with a reduced muscle recruitment compared to adults.

Methods

Eight boys (mean age 11.4 ± 0.4) and eight men (mean age 25.3 ± 3.3 years) completed repeated step transitions of unloaded-to-very heavy-intensity (U → VH) exercise on a cycle ergometer. MRI scans of the thigh region were acquired at rest and after VH exercise up to the \(\dot{V}\) O_2Sc time delay (ScTD) and after 6 min. T ₂ for each of eight muscles was adjusted in relation to cross-sectional area and then summed to provide the area-weighted ΣT ₂ as an index of thigh recruitment.

Results

There were no child/adult differences in the relative \(\dot{V}\) O_2Sc amplitude [Boys 14 ± 7 vs. Men 18 ± 3 %, P = 0.15, effect size (ES) = 0.8] during which the change (?) in area-weighted ΣT ₂ between the ScTD and 6 min was not different between groups (Boys 1.6 ± 1.2 vs. Men 2.3 ± 1.1 ms, P = 0.27, ES = 0.6). A positive and strong correlation was found between the relative \(\dot{V}\) O_2Sc amplitude and the magnitude of the area-weighted ?ΣT ₂ in men (r = 0.92, P = 0.001) but not in boys (r = 0.09, P = 0.84).

Conclusions

This study provides evidence to show that progressive muscle recruitment (as inferred from T ₂ changes) contributes to the development of the \(\dot{V}\) O_2Sc during intense submaximal exercise independent of age.     

Cycloserine as an alternative urinary tract infection therapy: susceptibilities of 500 urinary pathogens to standard and alternative therapy antimicrobials

Purpose

Cycloserine has been used previously in some areas of the world for the treatment of urinary tract infections. The emergence of multi-resistant strains of Enterobacteriaceae and the lack of new agents in the development pipeline has prompted a need to review the activity of older agents. Susceptibility testing of cycloserine has traditionally been problematic owing to testing in standard media, containing competitive alanine, thus presenting falsely elevated minimum inhibitory concentrations (MICs). This study tests urinary coliforms against cycloserine in both standard and minimal media.

Methods

Susceptibilities were performed on 500 “wild type” UTI coliforms using Mueller–Hinton broth in the range 0.008–128 μg/ml in accordance with ISO guidelines. Cycloserine was also tested in Minimal Salts medium?+?2 % 1 M glucose?+?0.2 % 1 M magnesium sulphate. MICs were recorded after 18 h of incubation at 35 °C and interpreted with EUCAST breakpoints (where available).

Results

Cycloserine MIC₅₀ for the “wild type” coliforms was 32 μg/ml in Mueller–Hinton broth compared with 2 μg/ml in Minimal Salts. Eighty-seven per cent of “wild type” UTI coliforms show cycloserine MICs?<?=?8 μg/ml in Minimal Salts. The epidemiological cut-off values for cycloserine for E. coli in this study were 64 μg/ml using Mueller–Hinton broth and 8 μg/ml using Minimal Salts medium. Ninety-four per cent of trimethoprim-resistant and 82 % of third generation cephalosporin-resistant E. coli had MICs in Minimal Salts?≤?8 μg/ml.

Conclusion

Cycloserine is still licensed in some countries for the treatment of urinary infections and the data presented here suggest that it may play a role in the management of infections resistant to trimethoprim and third generation cephalosporins.     

Receptor mediation and nociceptin inhibition of bradykinin-induced plasma extravasation in the knee joint of the rat

Objective and design

The aim was to investigate the signaling mechanisms and regulation of bradykinin (BK)-induced inflammation in rat knee joint.

Materials and methods

Knee joints of anesthetized rats were perfused with BK (0.1–1.0 μM), and synovial plasma extravasation (PE) was evaluated by spectrophotometrical measurement of Evans Blue leakage. To examine the signaling pathway, B1 antagonist [des-Arg10]-HOE140 (0.1–1.0 μM) and B2 antagonist HOE140 (0.05–1.0 μM), calcitonin gene-related peptide (CGRP) antagonist CGRP8-37 (0.5–1.0 μM), prostaglandin E2 antagonist AH-6809 (0.1–1.0 μM), and histamine H1 antagonist mepyramine (0.1–1.0 μM) were used. Nociceptin (0.0001–1.0 μM) and antagonist J-113397 were tested for modulation of BK-induced PE. The analyses were compared side-by-side with 5-hydroxytryptamine-induced PE.

Results

BK perfusion dose-dependently induced PE, which was blocked by HOE140, CGRP8-37, AH-6809, and mepyramine. It was also inhibited by nociceptin, which could be reversed by antagonist J-113397. In contrast, 5-hydroxytryptamine-induced PE was biphasically regulated by nociceptin and was not antagonized by CGRP8-37.

Conclusions

BK-induced PE is mediated by B2 receptors and may involve CGRP, prostaglandin, and histamine pathways. BK-induced PE is inhibited by nociceptin through the activation of ORL1 receptors. There are differences between BK- and 5-hydroxytryptamine-induced inflammation in signaling and modulation.     

Central and peripheral adjustments during high-intensity exercise following cold water immersion

Purpose

We investigated the acute effects of cold water immersion (CWI) or passive recovery (PAS) on physiological responses during high-intensity interval training (HIIT).

Methods

In a crossover design, 14 cyclists completed 2 HIIT sessions (HIIT1 and HIIT2) separated by 30 min. Between HIIT sessions, they stood in cold water (10 °C) up to their umbilicus, or at room temperature (27 °C) for 5 min. The natural logarithm of square-root of mean squared differences of successive R–R intervals (ln rMSSD) was assessed pre- and post-HIIT1 and HIIT2. Stroke volume (SV), cardiac output ( $ \dot{Q} $ ), O₂ uptake ( $ \dot{V} $ O₂), total muscle hemoglobin (t _Hb) and oxygenation of the vastus lateralis were recorded (using near infrared spectroscopy); heart rate, $ \dot{Q} $ , and $ \dot{V} $ O₂ on-kinetics (i.e., mean response time, MRT), muscle de-oxygenation rate, and anaerobic contribution to exercise were calculated for HIIT1 and HIIT2.

Results

ln rMSSD was likely higher [between-trial difference (90 % confidence interval) [+13.2 % (3.3; 24.0)] after CWI compared with PAS. CWI also likely increased SV [+5.9 % (?0.1; 12.1)], possibly increased $ \dot{Q} $ [+4.4 % (?1.0; 10.3)], possibly slowed $ \dot{Q} $ MRT [+18.3 % (?4.1; 46.0)], very likely slowed $ \dot{V} $ O₂ MRT [+16.5 % (5.8; 28.4)], and likely increased the anaerobic contribution to exercise [+9.7 % (?1.7; 22.5)].

Conclusion

CWI between HIIT slowed $ \dot{V} $ O₂ on-kinetics, leading to increased anaerobic contribution during HIIT2. This detrimental effect of CWI was likely related to peripheral adjustments, because the slowing of $ \dot{V} $ O₂ on-kinetics was twofold greater than that of central delivery of O₂ (i.e., $ \dot{Q} $ ). CWI has detrimental effects on high-intensity aerobic exercise performance that persist for ≥45 min.     

Short-term high-intensity interval and continuous moderate-intensity training improve maximal aerobic power and diastolic filling during exercise

Purpose

This study examined the effects of short-term high-intensity interval training (HIT) and continuous moderate-intensity training (CMT) on cardiac function in young, healthy men.

Methods

Sixteen previously untrained men (mean age of 25.1 ± 4.1 years) were randomly assigned to HIT and CMT (n = 8 each) and assessed before and after six sessions over a 12-day training period. HIT consisted of 8–12 intervals of cycling for 60 s at 95–100 % of pre-training maximal aerobic power ( $\dot{V}$ O_2max), interspersed by 75 s of cycling at 10 % $\dot{V}$ O_2max. CMT involved 90–120 min of cycling at 65 % pre-training $\dot{V}$ O_2max. Left ventricular (LV) function was determined at rest and during submaximal exercise (heart rate ~105 bpm) using two-dimensional and Doppler echocardiography.

Results

Training resulted in increased calculated plasma volume (PV) in both groups, accompanied by improved $\dot{V}$ O_2max in HIT (HIT: from 39.5 ± 7.1 to 43.9 ± 5.5 mL kg^?1 min^?1; CMT: from 39.9 ± 5.9 to 41.7 ± 5.3 mL kg^?1 min^?1; P < 0.001). Resting LV function was not altered. However, increased exercise stroke volume (P = 0.02) and cardiac output (P = 0.02) were observed, secondary to increases in end-diastolic volume (P < 0.001). Numerous Doppler and speckle tracking indices of diastolic function were similarly enhanced during exercise in both training groups and were related to changes in PV.

Conclusion

Short-term HIT and CMT elicit rapid improvements in $\dot{V}$ O_2max and LV filling without global changes in cardiac performance at rest.     

The validity of the Moxus Modular metabolic system during incremental exercise tests: impacts on detection of small changes in oxygen consumption

Purpose

We investigated the accuracy of the Moxus Modular Metabolic System (MOXUS) against the Douglas Bag Method (DBM) during high-intensity exercise, and whether the two methods agreed when detecting small changes in $\dot{V}{\text{O}}_{2}$ between two consecutive workloads ( $\Delta {\dot{{V}}\text{O}}_{ 2}$ ).

Methods

Twelve trained male runners performed two maximal incremental running tests while gas exchange was analyzed simultaneously by the two systems using a serial setup for four consecutive intervals of 30 s on each test. Comparisons between methods were performed for $\dot{V}{\text{O}}_{2}$ , ${\dot{{V}}}_{\text{E}}$ , fractions of expired O₂ (FeO₂) and CO₂ (FeCO₂) and $\Delta {\dot{{V}}\text{O}}_{ 2}$ .

Results

The MOXUS produced significant higher (mean ± SD, n = 54) readings for $\dot{V}{\text{O}}_{2}$ (80 ± 200 mL min^?1, p = 0.005) and ${\dot{{V}}}_{\text{E}}$ (2.9 ± 4.2 L min^?1, p < 0.0001), but not FeO₂ (?0.01 ± 0.09). Log-transformed 95 % limits of agreement for readings between methods were 94–110 % for $\dot{V}{\text{O}}_{2}$ , 97–108 % for $\dot{V}_{\text{E}}$ and 99–101 % for FeO₂. $\Delta \dot{V}{\text{O}}_{2}$ for two consecutive measurements was not different between systems (120 ± 110 vs. 90 ± 190 mL min^?1 for MOXUS and DBM, respectively, p = 0.26), but agreement between methods was very low (r = 0.25, p = 0.12).

Discussion

Although it was tested during high-intensity exercise and short sampling intervals, the MOXUS performed within the acceptable range of accuracy reported for automated analyzers. Most of the differences between equipments were due to differences in $\dot{V}_{\text{E}}$ . Detecting small changes in $\dot{V}{\text{O}}_{2}$ during an incremental test with small changes in workload, however, might be beyond the equipment’s accuracy.     

A Randomized, Controlled Dose-Finding Phase II Study of the M72/AS01 Candidate Tuberculosis Vaccine in Healthy PPD-Positive Adults

Purpose

In this dose-finding Phase II study (NCT00621322), we evaluated the safety and immunogenicity of different formulations of the candidate tuberculosis vaccine containing the M72 antigen (10/20/40 μg doses) and the liposome-based AS01 Adjuvant System. We aimed to select the lowest-dose combination of M72 and AS01 that was clinically well tolerated with immunogenicity comparable to that of the previously tested M72/AS01_B (40 μg) candidate vaccine.

Methods

Healthy PPD-positive (induration 3–10 mm) adults (18–45 years) in The Philippines were randomized (4:4:4:4:1:1) to receive 2 injections, 1 month apart, of M72/AS01_B (40 μg), M72/AS01_E (10 μg), M72/AS01_E (20 μg), M72/AS02_D (10 μg), M72/Saline (40 μg) or AS01_B alone, and were followed up for 6 months. AS01_E and AS02_D contain half the quantities of the immunostimulants present in AS01_B. AS02_D is an oil-in-water emulsion. Vaccine selection was based on the CD4⁺ T-cell responses at 1 month post vaccination.

Results

All formulations had a clinically acceptable safety profile with no vaccine-related serious adverse events reported. Two vaccinations of each adjuvanted M72 vaccine induced M72-specific CD4⁺ T-cell and humoral responses persisting at 6 months post vaccination. No responses were observed with AS01_B alone. One month post second vaccination, CD4⁺ T-cell responses induced by each of the three M72/AS01 vaccine formulations were of comparable magnitudes, and all were significantly higher than those induced by M72/AS02_D (10 μg) and M72/Saline.

Conclusions

The formulation with the lowest antigen and adjuvant dose, M72/AS01_E (10 μg), fulfilled our pre-defined selection criteria and has been selected for further clinical development.     

Urinary trypsin inhibitor suppresses excessive generation of superoxide anion radical, systemic inflammation, oxidative stress, and endothelial injury in endotoxemic rats

Objective and design

The protective effects of ulinastatin, a human urinary trypsin inhibitor (UTI), against superoxide radical (O ₂ ^?· ) generation, systemic inflammation, lipid peroxidation, and endothelial injury were investigated in endotoxemic rats.

Materials and treatment

Twenty-one Wistar rats were allocated to a control group, a UTI group, and a sham group. A bolus of lipopolysaccharide (LPS; 3 μg/g) was administered intravenously to the control group, a bolus of LPS and UTI (5 U/g) to the UTI group, and a bolus of saline to the sham group.

Methods

The O ₂ ^?· generated was measured as the current in the right atrium using an electrochemical O ₂ ^?· sensor. Plasma nitrite, high mobility group box 1 (HMGB1), tumor necrosis factor (TNF)-α, inteleukin (IL)-6, malondialdehyde, and soluble intercellular adhesion molecule-1 (sICAM-1) were measured 360 min after LPS administration.

Results

The O ₂ ^?· current increased in the control group and was significantly attenuated in the UTI group after 55 min (P < 0.05 at 55–60 min, P < 0.01 at 65–360 min). Plasma nitrite, HMGB1, TNF-α, IL-6, malondialdehyde, and sICAM-1 were attenuated in the UTI group.

Conclusions

UTI suppressed excessive O ₂ ^?· generation, systemic inflammation, lipid peroxidation, and endothelial injury in endotoxemic rats.     

The effects of breathing a helium–oxygen gas mixture on maximal pulmonary ventilation and maximal oxygen consumption during exercise in acute moderate hypobaric hypoxia

To test the hypothesis that maximal exercise pulmonary ventilation ( $ \dot{V}{\text{E}}_{ \max } $ ) is a limiting factor affecting maximal oxygen uptake ( $ \dot{V}{\text{O}}_{{ 2 {\text{max}}}} $ ) in moderate hypobaric hypoxia (H), we examined the effect of breathing a helium–oxygen gas mixture (He–O₂; 20.9% O₂), which would reduce air density and would be expected to increase $ \dot{V}{\text{E}}_{ \max } $ . Fourteen healthy young male subjects performed incremental treadmill running tests to exhaustion in normobaric normoxia (N; sea level) and in H (atmospheric pressure equivalent to 2,500 m above sea level). These exercise tests were carried out under three conditions [H with He–O₂, H with normal air and N] in random order. $ \dot{V}{\text{O}}_{{ 2 {\text{max}}}} $ and arterial oxy-hemoglobin saturation (SaO₂) were, respectively, 15.2, 7.5 and 4.0% higher (all p < 0.05) with He–O₂ than with normal air ( $ \dot{V}{\text{E}}_{ \max } $ _, 171.9 ± 16.1 vs. 150.1 ± 16.9 L/min; $ \dot{V}{\text{O}}_{{ 2 {\text{max}}}} $ , 52.50 ± 9.13 vs. 48.72 ± 5.35 mL/kg/min; arterial oxyhemoglobin saturation (SaO₂), 79 ± 3 vs. 76 ± 3%). There was a linear relationship between the increment in $ \dot{V}{\text{E}}_{ \max } $ and the increment in $ \dot{V}{\text{O}}_{{ 2 {\text{max}}}} $ in H (r = 0.77; p < 0.05). When subjects were divided into two groups based on their $ \dot{V}{\text{O}}_{{ 2 {\text{max}}}} $ , both groups showed increased $ \dot{V}{\text{E}}_{ \max } $ and SaO₂ in H with He–O₂, but $ \dot{V}{\text{O}}_{{ 2 {\text{max}}}} $ was increased only in the high $ \dot{V}{\text{O}}_{{ 2 {\text{max}}}} $ group. These findings suggest that in acute moderate hypobaric hypoxia, air-flow resistance can be a limiting factor affecting $ \dot{V}{\text{E}}_{ \max } $ ; consequently, $ \dot{V}{\text{O}}_{{ 2 {\text{max}}}} $ is limited in part by $ \dot{V}{\text{E}}_{ \max } $ , especially in subjects with high $ \dot{V}{\text{O}}_{{ 2 {\text{max}}}} $ .     

Faster \dot{V}{\text{O}}_{ 2} kinetics after eccentric contractions is explained by better matching of O2 delivery to O2 utilization

Purpose

This study examined the impact of eccentric exercise-induced muscle damage on the rate of adjustment in muscle deoxygenation and pulmonary O₂ uptake ( \(\dot{V}{\text{O}}_{{2{\text{p}}}}\) ) kinetics during moderate exercise.

Methods

Fourteen males (25 ± 3 year; mean ± SD) completed three step transitions to 90 % θ_L before (Pre), 24 h (Post24) and 48 h after (Post48) eccentric exercise (100 eccentric leg-press repetitions with a load corresponding to 110 % of the participant’s concentric 1RM). Participants were separated into two groups: phase II \(\dot{V}{\text{O}}_{{2{\text{p}}}}\) time constant (τ \(\dot{V}{\text{O}}_{{2{\text{p}}}}\) ) ≤ 25 s (fast group; n = 7) or τ \(\dot{V}{\text{O}}_{{2{\text{p}}}}\)  > 25 s (slow group; n = 7). \(\dot{V}{\text{O}}_{{2{\text{p}}}}\) and [HHb] responses were modeled as a mono-exponential.

Results

In both groups, isometric peak torque (0°/s) at Post24 was decreased compared to Pre (p < 0.05) and remained depressed at Post48 (p < 0.05). τ \(\dot{V}{\text{O}}_{{2{\text{p}}}}\) was designed to be different (p < 0.05) at Pre between the Fast (τ \(\dot{V}{\text{O}}_{{2{\text{p}}}}\) ; 19 ± 4 s) and Slow (32 ± 6 s) groups. There were no differences among time points (τ \(\dot{V}{\text{O}}_{{2{\text{p}}}}\) : Pre, 19 ± 4 s; Post24, 22 ± 3 s; Post48, 20 ± 4 s) in the Fast group. In Slow, there was a speeding (p < 0.05) from the Pre (32 ± 6 s) to the Post24 (25 ± 6) but not Post48 (31 ± 6), resulting in no difference (p > 0.05) between groups at Post24. This reduction of τ \(\dot{V}{\text{O}}_{{2{\text{p}}}} \,\) was concomitant with the abolishment (p < 0.05) of an overshoot in the [HHb]/ \(\dot{V}{\text{O}}_{{2{\text{p}}}}\) ratio.

Conclusion

We propose that the sped \(\dot{V}{\text{O}}_{{2{\text{p}}}}\) kinetics observed in the Slow group coupled with an improved [HHb]/ \(\dot{V}{\text{O}}_{{2{\text{p}}}}\) ratio suggest a better matching of local muscle O₂ delivery to O₂ utilization following eccentric contractions.     

Low-volume,high-intensity,aerobic interval exercise for sedentary adults: \dot{V}O2max,cardiac mass,and heart rate recovery

Purpose

The aim of this study was to compare the effects of low-volume, high-intensity aerobic interval training (HAIT) on maximal oxygen consumption ( \(\dot{V}\) O_2max), left ventricular (LV) mass, and heart rate recovery (HRR) with high-volume, moderate-intensity continuous aerobic training (CAT) in sedentary adults.

Methods

Twenty-four healthy but sedentary male adults (aged 29.2 ± 7.2 years) participated in an 8-week, 3-day a week, supervised exercise intervention. They were randomly assigned to either HAIT (18 min, 180 kcal per exercise session) or CAT (45 min, 360 kcal). \(\dot{V}\) O_2max, LV mass (3T-MRI), and HRR at 1 min (HRR-1) and 2 min (HRR-2) after maximal exercise were measured pre- and post-intervention.

Results

Changes in \(\dot{V}\) O_2max during the 8-week intervention were significant (P < 0.01) in both groups (HAIT, 8.7 ± 3.2 ml kg^?1 min^?1, 22.4 ± 8.9 %; CAT, 5.5 ± 2.8 ml kg^?1 min^?1, 14.7 ± 9.5 %), while the \(\dot{V}\) O_2max improvement in HAIT was greater (P = 0.02) than in CAT. LV mass in HAIT increased (5.1 ± 8.4 g, 5.7 ± 9.1 %, P = 0.05), but not in CAT (0.9 ± 7.8 g, 1.1 ± 8.4 %, P = 0.71). While changes in HRR-1 were not significant in either group, change in HRR-2 for HAIT (9.5 ± 6.4 bpm, 19.0 ± 16.0 %, P < 0.01) was greater (P = 0.03) than for CAT (1.6 ± 10.9 bpm, 3.9 ± 16.2 %, P = 0.42).

Conclusions

This study suggests that HAIT has potential as a time-efficient training mode to improve cardiorespiratory capacity and autonomic nervous system function in sedentary adults.     

Hypoxia and CO alter O2 extraction but not peripheral diffusing capacity during maximal aerobic exercise

Purpose

To determine if and how hypoxia combined with elevated carboxyhaemoglobin fraction (F _HbCO) affects peripheral diffusing capacity and O₂ extraction in animals exercising at their maximal aerobic capacity ( $ \dot{V}{\text{O}}_{ 2\hbox{max} } $ ).

Methods

Six goats ran on a treadmill at speeds eliciting $ \dot{V}{\text{O}}_{ 2\hbox{max} } $ while breathing inspired O₂ fractions (F _IO₂) of 0.21 or 0.12 with F _HbCO 0.02 or 0.30. We measured O₂ consumption and arterial and mixed-venous blood variables to assess how hypoxia and elevated F _HbCO individually, and in combination, alter O₂ transport and utilisation.

Results

Peripheral diffusing capacity did not differ among the four gas combinations (P = 0.867), whereas O₂ extraction fraction increased with hypoxia [0.920 ± 0.018 (SD)] and decreased with elevated F _HbCO (0.792 ± 0.038) compared to control (0.897 ± 0.032). Oxygen extraction increases with hypoxia due to the sigmoid relationship between O₂ saturation (SO₂) and O₂ partial pressures (PO₂) affecting low (hypoxia) and high (normoxia) PO₂ differently. Oxygen extraction decreases with elevated F _HbCO because elevated F _HbCO increases haemoglobin (Hb) affinity for O₂ and raises SO₂, especially at very low (mixed-venous) PO₂. Pulmonary gas exchange was impaired only with combined hypoxia and elevated F _HbCO due to hypoxia decreasing alveolar PO₂ and O₂ flux coupled with elevated F _HbCO increasing Hb affinity for O₂ and decreasing the rate of PO₂ increase for a given rise in SO₂.

Conclusion

This study quantifies the mechanisms by which O₂ delivery and peripheral diffusion interact to limit $ \dot{V}{\text{O}}_{ 2\hbox{max} } $ when O₂ delivery is reduced due to breathing hypoxic gas with elevated F _HbCO.     

Posttreatment with propofol attenuates lipopolysaccharide-induced up-regulation of inflammatory molecules in primary microglia

Background

Activation of microglia is involved in a broad range of neuroinflammatory diseases. Suppression of microglial activation may, therefore, contribute to alleviate the progression of neuroinflammatory diseases. It has been reported that propofol has a potent anti-inflammatory property. In the present study, we investigated the effects of posttreatment with propofol on the production of inflammatory molecules in lipopolysaccharide (LPS)-stimulated microglia.

Materials and methods

Microglia were exposed to various concentrations (25, 50, 100, 250 μM) of propofol for 1 h after LPS stimulation for 24 h. The levels of proinflammatory mediators inducible nitric oxide synthase (iNOS)/nitric oxide (NO), cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured.

Results

Propofol at a concentration of 25 μM did not affect the production of proinflammatory mediators, which was enhanced by LPS. At the concentrations of 50, 100, and 250 μM, propofol significantly inhibited LPS-mediated production of NO, PGE2, TNF-α, and IL-1β and the expression of iNOSmRNA, COX-2mRNA, TNF-α mRNA, and IL-1β mRNA.

Conclusions

These results suggest that propofol, at clinically relevant concentrations, can reduce inflammatory responses in LPS-induced inflammation in activated microglia and might be an intravenous anesthetic of choice when patients with neuroinflammatory diseases require sedation and/or general anesthesia.     

Anti-nociceptive and anti-edematogenic effects of glibenclamide in a model of acute gouty attack in rats

Objective and design

We investigated the effect of glibenclamide on inflammatory parameters in a model of acute gouty attack in rats.

Treatment

Intra-articular injection of 50 μl of monosodium urate (MSU) crystals (1.25 mg/site) was used to induce gout-related inflammation. The effects of glibenclamide (1–10 mg/kg, s.c.) or dexamethasone (8 mg/kg, s.c., positive control) were assessed on several inflammation parameters.

Methods

Spontaneous nociception assessment, edema measurement, total and differential leucocyte counts, interleukin (IL)-1β release, prostaglandin E₂ production and determination of blood glucose levels were analyzed. Peritoneal macrophages were incubated with MSU and levels of IL-1β were measured. Statistical significance was assessed by one- or two-way analysis of variance.

Results

Glibenclamide (3 mg/kg) or dexamethasone (8 mg/kg) prevented nociception and edema induced by MSU injection in rats. Glibenclamide did not affect leukocyte infiltration, IL-1β release and PGE₂ production, but only reduced IL-1β production by MSU-stimulated macrophages at very high concentration (200 μM). Dexamethasone significantly reduced leukocyte infiltration, IL-1β release and PGE₂ production. Glibenclamide reduced whereas dexamethasone increased blood glucose levels of MSU-injected rats.

Conclusions

Glibenclamide reduced nociception and edema, but not leukocyte infiltration, IL-1β release and PGE₂ production. However, its substantial effect on nociception and edema suggests that glibenclamide can be an interesting option as an adjuvant treatment for pain induced by acute attacks of gout.     

Prediction of peak oxygen uptake from differentiated ratings of perceived exertion during wheelchair propulsion in trained wheelchair sportspersons

Purpose

To assess the validity of predicting peak oxygen uptake ( $ {\dot{\text{V}}}{\text{O}}_{{\text{2peak}}}$ ) from differentiated ratings of perceived exertion (RPE) obtained during submaximal wheelchair propulsion.

Methods

Three subgroups of elite male wheelchair athletes [nine tetraplegics (TETRA), nine paraplegics (PARA), eight athletes without spinal cord injury (NON-SCI)] performed an incremental speed exercise test followed by graded exercise to exhaustion ( $ {\dot{\text{V}}}{\text{O}}_{{\text{2peak}}}$ test). Oxygen uptake ( $ {\dot{\text{V}}}{\text{O}}_2$ ), heart rate (HR) and differentiated RPE (Central RPE_C, Peripheral RPE_P and Overall RPE_O) were obtained for each stage. The regression lines for the perceptual ranges 9–15 on the Borg 6–20 scale ratings were performed to predict $ {\dot{\text{V}}}{\text{O}}_{{\text{2peak}}}$ .

Results

There were no significant within-group mean differences between measured $ {\dot{\text{V}}}{\text{O}}_{{\text{2peak}}}$ (mean 1.50 ± 0.39, 2.74 ± 0.48, 3.75 ± 0.33 L min^?1 for TETRA, PARA and NON-SCI, respectively) and predicted $ {\dot{\text{V}}}{\text{O}}_{{\text{2peak}}}$ determined using HR or differentiated RPEs for any group (P > 0.05). However, the coefficients of variation (CV %) between measured and predicted $ {\dot{\text{V}}}{\text{O}}_{{\text{2peak}}}$ using HR showed high variability for all groups (14.3, 15.9 and 9.7 %, respectively). The typical error ranged from 0.14 to 0.68 L min^?1 and the CV % between measured and predicted $ {\dot{\text{V}}}{\text{O}}_{{\text{2peak}}}$ using differentiated RPE was ≤11.1 % for TETRA, ≤7.5 % for PARA and ≤20.2 % for NON-SCI.

Conclusions

Results suggest that differentiated RPE may be used cautiously for TETRA and PARA athletes when predicting $ {\dot{\text{V}}}{\text{O}}_{{\text{2peak}}}$ across the perceptual range of 9–15. However, predicting $ {\dot{\text{V}}}{\text{O}}_{{\text{2peak}}}$ is not recommended for the NON-SCI athletes due to the large CV %s (16.8, 20.2 and 18.0 %; RPE_C, RPE_P and RPE_O, respectively).     

Increases in \dot{V} O2max with “live high–train low” altitude training: role of ventilatory acclimatization

The purpose of this study was to estimate the percentage of the increase in whole body maximal oxygen consumption ( $ \dot{V} $ O_2max) that is accounted for by increased respiratory muscle oxygen uptake after altitude training. Six elite male distance runners ( $ \dot{V} $ O_2max = 70.6 ± 4.5 ml kg^?1 min^?1) and one elite female distance runner ( $ \dot{V} $ O_2max = 64.7 ml kg^?1 min^?1) completed a 28-day “live high–train low” training intervention (living elevation, 2,150 m). Before and after altitude training, subjects ran at three submaximal speeds, and during a separate session, performed a graded exercise test to exhaustion. A regression equation derived from published data was used to estimate respiratory muscle $ \dot{V} $ O₂ ( $ \dot{V} $ O_2RM) using our ventilation ( $ \dot{V} $ _E) values. $ \dot{V} $ O_2RM was also estimated retrospectively from a larger group of distance runners (n = 22). $ \dot{V} $ O_2max significantly (p < 0.05) increased from pre- to post-altitude (196 ± 59 ml min^?1), while $ \dot{V} $ _E at $ \dot{V} $ O_2max also significantly (p < 0.05) increased (13.3 ± 5.3 l min^?1). The estimated $ \dot{V} $ O_2RM contributed 37 % of Δ $ \dot{V} $ O_2max. The retrospective group also saw a significant increase in $ \dot{V} $ O_2max from pre- to post-altitude (201 ± 36 ml min^?1), along with a 10.8 ± 2.1 l min^?1 increase in $ \dot{V} $ _E, thus requiring an estimated 27 % of Δ $ \dot{V} $ O_2max. Our data suggest that a substantial portion of the improvement in $ \dot{V} $ O_2max with chronic altitude training goes to fuel the respiratory muscles as opposed to the musculature which directly contributes to locomotion. Consequently, the time-course of decay in ventilatory acclimatization following return to sea-level may have an impact on competitive performance.     

Tetramethylpyrazine decreases hypothalamic glutamate, hydroxyl radicals and prostaglandin-E2 and has antipyretic effects

Objective

We studied the effects of tetramethylpyrazine (TMP) on the fever, increased plasma levels of tumor necrosis factor-α (TNF-α) and increased hypothalamic levels of glutamate, hydroxyl radicals and prostaglandin-E₂ (PGE₂) induced by lipopolysaccharide (LPS).

Materials and methods

The microdialysis probes were stereotaxically and chronically implanted into the hypothalamus of rabbit brain for determining extracellular levels of glutamate, hydroxyl radials, and PGE₂. In addition, both the body core temperature and plasma levels of TNF-α were measured.

Results

All the body core temperature, plasma levels of TNF-α, and hypothalamic levels of glutamate, hydroxyl radicals, and PGE₂ were up-graded by an intravenous dose of LPS (2 μg/kg). Pretreatment with intravenous TMP (10–40 mg/kg) or intracerebroventricular TMP (130 μg in 20 μl per animal) 1 h before LPS administration significantly attenuated the LPS-induced fever as well as the increased hypothalamic levels of glutamate, hydroxyl radicals, and PGE₂. LPS-induced fever could also be attenuated by intravenous or intracerebroventricular TMP 1 h after LPS injection.

Conclusion

TMP preconditioning may cause its antipyretic action by reducing plasma levels of TNF-α as well as hypothalamic levels of glutamate, hydroxyl radicals, and PGE₂ in rabbits.