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Purpose: The purpose of this study was twofold: (i) determine if well-trained athletes can achieve similar peak oxygen uptake (V˙O2peak) in downhill running (DR) versus level running (LR) or uphill running (UR) and (ii) investigate if lower limb extensor muscle strength is related to the velocity at V˙O2peak (vV˙O2peak) in DR, LR, and UR., Methods: Eight athletes (V˙O2max = 68 ± 2 mL·min·kg) completed maximal incremental tests in LR, DR (-15% slope), and UR (+15% slope) on a treadmill (+1, +1.5, and +0.5 km·h every 2 min, respectively) while cardiorespiratory responses and spatiotemporal running parameters were continuously measured. They were also tested for maximal voluntary isometric strength of hip and knee extensors and plantar flexors., Results: Oxygen uptake at maximal effort was approximately 16% to 18% lower in DR versus LR and UR (~57 ± 2 mL·min·kg, 68 ± 2 mL·min·kg, and 70 ± 3 mL·min·kg, respectively) despite much greater vV˙O2peak (22.7 ± 0.6 km·h vs 18.7 ± 0.5 km·h and 9.3 ± 0.3 km·h, respectively). At vV˙O2peak, longer stride length and shorter contact time occurred in DR versus LR and UR (+12%, +119%, -38%, and -61%, respectively). Contrary to knee extensor and plantar flexor, hip extensor isometric strength correlated to vV˙O2peak in DR, LR, and UR (r = -0.86 to -0.96, P < 0.05). At similar V˙O2, higher heart rate and ventilation emerged in DR versus LR and UR, associated with a more superficial ventilation pattern., Conclusions: This study demonstrates that well-trained endurance athletes, accustomed to DR, achieved lower V˙O2peak despite higher vV˙O2peak during DR versus LR or UR maximal incremental tests. The specific heart rate and ventilation responses in DR might originate from altered running gait and increased lower-limb musculotendinous mechanical loading, furthering our understanding of the particular physiology of DR, ultimately contributing to optimize trail race running performance.

Objective: To refine the predictive significance of muscle granuloma in patients with myositis., Methods: A group of 23 patients with myositis and granuloma on muscle biopsy (granuloma-myositis) from 8 French and Belgian centers was analyzed and compared with (1) a group of 23 patients with myositis without identified granuloma (control-myositis) randomly sampled in each center and (2) a group of 20 patients with sporadic inclusion body myositis (sIBM) without identified granuloma (control-sIBM)., Results: All but 2 patients with granuloma-myositis had extramuscular involvement, including signs common in sarcoidosis that were systematically absent in the control-myositis and the control-sIBM groups. Almost half of patients with granuloma-myositis matched the diagnostic criteria for sIBM. In these patients, other than the granuloma, the characteristics of the myopathy and its nonresponse to treatment were similar to the control-sIBM patients. Aside from 1 patient with myositis overlapping with systemic sclerosis, the remaining patients with granuloma-myositis did not match the criteria for a well-defined myositis subtype, suggesting pure sarcoidosis. Matching criteria for sIBM was the sole feature independently associated with nonresponse to myopathy treatment in patients with granuloma-myositis., Conclusion: Patients with granuloma-myositis should be carefully screened for sIBM associated with sarcoidosis in order to best tailor their care., (© 2019 American Academy of Neurology.)

Introduction: In septic shock patients, postseptic immunosuppression state after the systemic inflammatory response syndrome is responsible for nosocomial infections, with subsequent increased mortality. The aim of the present study was to assess the underlying cellular mechanisms of the postseptic immunosuppression state, by investigating mitochondrial functions of peripheral blood mononuclear cells (PBMCs) from septic shock patients over 7 days., Materials and Methods: Eighteen patients admitted to a French intensive care unit for septic shock were included. At days 1 and 7, PBMCs were isolated by Ficoll density gradient centrifugation. Mitochondrial respiration of intact septic PBMCs was assessed versus control group PBMCs, by measuring O2 consumption in plasma, using high-resolution respirometry. Mitochondrial respiration was then compared between septic plasmas and control plasmas for control PBMCs, septic PBMCs, and lymphoid cell-line (CEM). To investigate the role of plasma, we measured several plasma cytokines, among them High-Mobility Group Box 1 (HMGB1), by enzyme-linked immunosorbent assays., Results: Basal O2 consumption of septic shock PBMCs was of 8.27 ± 3.39 and 10.48 ± 3.99 pmol/s/10 cells at days 1 and 7, respectively, significantly higher than in control PBMCs (5.37 ± 1.46 pmol/s/10 cells, P < 0.05). Septic patient PBMCs showed a lower response to oligomycin, suggesting a reduced ATP-synthase activity, as well as an increased response to carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) suggesting an increased mitochondrial respiratory capacity. At 6 h, septic plasmas showed a decreased O2 consumption of CEM (4.73 ± 1.46 vs. 6.58 ± 1.53, P < 0.05) as well as in control group PBMCs (1.76 ± 0.36 vs. 2.70 ± 0.42, P < 0.05), and triggered a decreased ATP-synthase activity but an increased response to FCCP. These differences are not explained by different cell survival. High HMGB1 levels were significantly associated with reduced PBMCs mitochondrial respiration., Conclusions: Septic plasma impairs mitochondrial respiration in immune cells, with a possible role of the proinflammatory protein HMGB1, leading to a subsequent compensation, probably by enzymatic activation. This compensation result is an improvement of global mitochondrial respiratory capacity, but without restoring ATP-synthase activity.

Background: After lung transplantation (LT), early prediction of grade 3 pulmonary graft dysfunction (PGD) remains a research gap for clinicians. We hypothesized that it could be improved using extravascular lung water (EVLWi) and plasma biomarkers of acute lung injury., Methods: After institutional review board approval and informed consent, consecutive LT recipients were included. Transpulmonary thermodilution-based EVLWi, plasma concentrations of epithelial (soluble receptor for advanced glycation endproducts [sRAGE]) and endothelial biomarkers (soluble intercellular adhesion molecule-1 and endocan [full-length and cleaved p14 fragment]) were obtained before and after LT (0 [H0], 6, 12, 24, 48 and 72 hours after pulmonary artery unclamping). Grade 3 PGD was defined according to the International Society for Lung and Heart Transplantation definition, combining arterial oxygen partial pressure (PaO2)/inspired fraction of oxygen (FiO2) ratio and chest X-rays. Association of clinical risk factors, EVLWi and biomarkers with grade 3 PGD was analyzed under the Bayesian paradigm, using logistic model and areas under the receiver operating characteristic curves (AUCs)., Results: In 47 LT recipients, 10 developed grade 3 PGD, which was obvious at H6 in 8 cases. Clinical risk factors, soluble intercellular adhesion molecule-1 and endocan (both forms) were not associated with grade 3 PGD. Significant predictors of grade 3 PGD included (1) EVLWi (optimal cutoff, 13.7 mL/kg; AUC, 0.74; 95% confidence interval [CI], 0.48-0.99), (2) PaO2/FiO2 ratio (optimal cutoff, 236; AUC, 0.68; 95% CI, 0.52-0.84), and (3) sRAGE (optimal cutoff, 11 760 pg/mL; AUC, 0.66; 95% CI, 0.41-0.91) measured at H0., Conclusions: Immediate postreperfusion increases in EVLWi and sRAGE along with impaired PaO2/FiO2 ratios were early predictors of grade 3 PGD at or beyond 6 hours and may trigger early therapeutic interventions.

Anticitrullinated peptide/protein antibodies (ACPA), which are highly specific for rheumatoid arthritis (RA), may be found in some patients with other systemic autoimmune diseases. The clinical significance of ACPA in patients with antisynthetase syndrome (ASS), a systemic disease characterized by the association of myositis, interstitial lung disease, polyarthralgia, and/or polyarthritis, has not yet been evaluated with regard to phenotype, prognosis, and response to treatment. ACPA-positive ASS patients were first identified among a French multicenter registry of patients with ASS. Additionally, all French rheumatology and internal medicine practitioners registered on the Club Rhumatismes et Inflammation web site were asked to report their observations of ASS patients with ACPA. The 17 collected patients were retrospectively studied using a standardized questionnaire and compared with 34 unselected ACPA-negative ASS patients in a case-control study. All ACPA-positive ASS patients suffered from arthritis versus 41% in the control group (P < 0.0001). The number of swollen joints was significantly higher (7.0 ± 5.0 vs 2.9 ± 3.9, P < 0.005), with a distribution resembling that of RA. Radiographic damages were also more frequent in ACPA-positive ASS patients (87% vs 11%, P < 0.0001). Aside from a significantly higher transfer factor for carbon monoxide in ACPA-ASS patients, lung, muscle, and skin involvements had similar incidences, patterns, and severity in both groups. Although Nonbiologic treatments were similarly used in both groups, ACPA-positive patients received biologics more frequently (59% vs 12%, P < 0.0008), mostly due to refractory arthritis (n = 9). Eight patients received anti-Cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) with good efficacy and tolerance, whereas 2 of the 5 patients treated with antitumor necrosis factor drugs had worsened myositis and/or interstitial lung disease. After a >7-year mean follow-up, extra-articular outcomes and survival were not different. ACPA-positive ASS patients showed an overlapping RA-ASS syndrome, were at high risk of refractory erosive arthritis, and might experience ASS flare when treated with antitumor necrosis factor drugs. In contrast, other biologics such as anti-CD20 mAb were effective in this context, without worsening systemic involvements.

Objective: Our aim was to evaluate a fluorescence-based enhanced-reality system to assess intestinal viability in a laparoscopic mesenteric ischemia model., Materials and Methods: A small bowel loop was exposed, and 3 to 4 mesenteric vessels were clipped in 6 pigs. Indocyanine green (ICG) was administered intravenously 15 minutes later. The bowel was illuminated with an incoherent light source laparoscope (D-light-P, KarlStorz). The ICG fluorescence signal was analyzed with Ad Hoc imaging software (VR-RENDER), which provides a digital perfusion cartography that was superimposed to the intraoperative laparoscopic image [augmented reality (AR) synthesis]. Five regions of interest (ROIs) were marked under AR guidance (1, 2a-2b, 3a-3b corresponding to the ischemic, marginal, and vascularized zones, respectively). One hour later, capillary blood samples were obtained by puncturing the bowel serosa at the identified ROIs and lactates were measured using the EDGE analyzer. A surgical biopsy of each intestinal ROI was sent for mitochondrial respiratory rate assessment and for metabolites quantification., Results: Mean capillary lactate levels were 3.98 (SD = 1.91) versus 1.05 (SD = 0.46) versus 0.74 (SD = 0.34) mmol/L at ROI 1 versus 2a-2b (P = 0.0001) versus 3a-3b (P = 0.0001), respectively. Mean maximal mitochondrial respiratory rate was 104.4 (±21.58) pmolO2/second/mg at the ROI 1 versus 191.1 ± 14.48 (2b, P = 0.03) versus 180.4 ± 16.71 (3a, P = 0.02) versus 199.2 ± 25.21 (3b, P = 0.02). Alanine, choline, ethanolamine, glucose, lactate, myoinositol, phosphocholine, sylloinositol, and valine showed statistically significant different concentrations between ischemic and nonischemic segments., Conclusions: Fluorescence-based AR may effectively detect the boundary between the ischemic and the vascularized zones in this experimental model.

Purpose: The objective of this study was to investigate the time course of the endurance training-induced adaptations in two major mitochondrial functions., Methods: Forty rats were divided into four groups: a control group and three training groups--a 1-d training group, a 5-d training group, and a 10-d training group. The training protocol consisted of 30 min of running on a motorized treadmill (26 m·min(-1), 15% grade). Nuclear respiratory factor-1; transcription factor A, mitochondrial; superoxide dismutase-2; glutathione peroxidase-4; and citrate synthase (CS) messenger RNA levels were measured by qPCR. Mitochondrial respiration and H2O2 release were assessed using permeabilized fibers of white gastrocnemius in situ. Calculation of free radical leak was performed in two conditions where substrates were identical in both measurements. CS activity was assessed spectrophotometrically., Results: An early time-dependent modulation in messenger RNA levels was observed with training: nuclear respiratory factor-1 and superoxide dismutase-2 levels increased after acute exercise, transcription factor A, mitochondrial and CS levels improved after 5 d, and glutathione peroxidase-4 levels increased after 10 d. CS activity improved by 29% ± 8% (P < 0.01) after 5 d together with a 50% ± 7% reduction in the free radical leak (P < 0.05). Finally, 10 d of endurance training did not significantly alter mitochondrial H2O2 release but increased mitochondrial respiration rates in situ (P < 0.05)., Conclusions: Our results demonstrate that mitochondrial adaptations follow a sequential program in which mitochondrial respiration and free radical leak adaptations occur according to a different timing. Collectively, these results suggest early mitochondrial qualitative adaptations in response to endurance training.

Background: Lung and liver dysfunction is involved in gut ischemia-reperfusion (IR)-induced multiple organ failure. We compared the effects of ketamine and isoflurane on liver and lung mitochondrial oxidative capacity after gut IR., Methods: Adult male Wistar rats were randomized into 4 groups (controls and gut IR receiving either intraperitoneal ketamine or inhaled isoflurane). Maximal oxygen consumption and the activity of respiratory chain complexes were measured on isolated liver and lung mitochondria., Results: Gut IR significantly impaired liver and lung mitochondrial oxidative capacity when using ketamine but not isoflurane., Conclusions: Isoflurane preserved liver and lung mitochondrial oxidative capacity after gut IR.

Background: Evidence is emerging to support the concept that the failing heart is "energy depleted" and that defects in energy metabolism are important determinants in the development and the progression of the disease. We have shown previously that depressed mitochondrial function in cardiac and skeletal muscles in chronic heart failure is linked to decreased expression of the gene encoding transcriptional proliferator-activated receptor-gamma coactivator-1alpha, the inducible regulator of mitochondrial biogenesis and its transcription cascade, leading to altered expression of mitochondrial proteins. However, oxidative capacity of the myocardium of patients treated for chronic heart failure and pathophysiological mechanisms of mitochondrial dysfunction are still largely unknown., Methods and Results: In patients with chronic heart failure treated with angiotensin-converting enzyme inhibition, cardiac oxidative capacity, measured in saponin-permeabilized fibers, was 25% lower, and proliferator-activated receptor-gamma coactivator-1alpha protein content was 34% lower compared with nonfailing controls. In a rat model of myocardial infarction, angiotensin-converting enzyme inhibition therapy was only partially able to protect cardiac mitochondrial function and transcription cascade. Expression of proliferator-activated receptor-gamma coactivator-1alpha and its transcription cascade were evaluated after a 48-hour exposure of cultured adult rat ventricular myocytes to endothelin-1, angiotensin II, aldosterone, phenylephrine, or isoprenaline. Endothelin-1 (-30%) and, to a lesser degree, angiotensin II (-20%) decreased proliferator-activated receptor-gamma coactivator-1alpha mRNA content, whereas other hormones had no effect (phenylephrine) or even increased it (aldosterone, isoprenaline)., Conclusions: Taken together, these results show that, despite angiotensin-converting enzyme inhibition treatment, oxidative capacity is reduced in human and experimental heart failure and that endothelin-1 and angiotensin II could be involved in the downregulation of the mitochondrial transcription cascade.

Background: Intraperitoneal local anesthetic administration has been reported to provide perioperative analgesia during laparoscopic procedures. The aim of this in vitro study was to assess the efficiency of commercially available humidification devices to deliver ropivacaine and to determine the effects of modifying the device's position between the insufflator and the Veress needle on the amount of ropivacaine delivered., Methods: In the first experiment, four humidification devices filled with ropivacaine (0.20% and 0.75%) were placed at the outlet of a laparoscopic insufflation system delivering a constant carbon dioxide flow. A catheter was connected to the humidifier's outlet and the other end submerged in a calibrated vial containing 25 mL of 50% methanol in water. The concentration of ropivacaine collected in the methanol-water solution was measured using high performance liquid chromatography. In the second experiment, the clinical situation was imitated by placing 3 m of silicone tubing between the humidifier and the collection vial to evaluate its influence on the amount of ropivacaine delivered. Only one humidifier was tested in the second experiment because the other three tested humidification devices did not efficiently deliver ropivacaine., Results: The evaporation-based humidifiers delivered very small or nonmeasurable quantities of ropivacaine. In contrast, the microvibration-based aerosol humidification device delivered significant amounts (89.1%-94.3%) of the drug. The insertion of silicone tubing between the humidifier and the collecting vial reduced the amount of delivered ropivacaine to 62.3%., Conclusions: The microvibration-based aerosol humidification device may be used to deliver local anesthetics during laparoscopic procedures. Further research is necessary to confirm these results in clinical practice and to provide effective humidification that does not blur the surgeon's view.

Unlabelled: Nitrous oxide (N2O) accumulates in the CO2 pneumoperitoneum during laparoscopy when N2O is used as an adjuvant for inhaled anesthesia. This may worsen the consequences of gas embolism and introduce a fire risk. In this study, we quantified the pneumoperitoneal gas venting necessary to prevent significant contamination by inhaled N2O. Four domestic pigs (26-30 kg) were anesthetized and ventilated with 66% N2O in oxygen. A CO2 pneumoperitoneum was insufflated and maintained at a pressure of 12 mm Hg. Each animal underwent three experimental conditions, in random sequence, for 70 min each: 1) no pneumoperitoneal leak, 2) leak of 2 L every 10 min (12 L/h), and 3) leak of 4 L every 10 min (24 L/h). Every 10 min, pneumoperitoneal gas samples were analyzed for fractions (FPn) of N2O and CO2. Without leaks, FPnN2O increased continually and reached 29.58% +/- 3.15% at 70 min. With leaks of 2 and 4 L every 10 min (12 and 24 L/h), FPnN2O reached a plateau of <10% after 30 min. We conclude that calibrated pneumoperitoneal venting of 12 or 24 L/h is enough to prevent the constitution of potentially dangerous pneumoperitoneal gas mixtures if venting is constant., Implications: External venting calibrated at four or eight initial pneumoperitoneal volumes per hour with compensation by fresh CO2 is sufficient to prevent nitrous oxide buildup of more than 10% in the pneumoperitoneum during laparoscopy with inhaled general anesthesia if venting is constant.

Background: Contrast echocardiography is a useful tool for assessing repeatedly patients with coronary artery disease. Nevertheless, elevated pulmonary artery and systemic blood pressures likely to be associated with cardiac ischemia may limit the left ventricular opacification (LVO) because of the microspheres' sensitivity to pressure., Objective: To determine the effects of systemic and pulmonary artery blood pressures on LVO., Methods: We performed 55 intravenous injections (0.08 and 0.22 ml/kg) of a new transpulmonary contrast agent (Albunex), during two separated exposures, into 20 cardiac ischemic patients while monitoring invasively their cardiac indexes, and intracardiac, systemic, and pulmonary artery blood pressures. LVO was graded qualitatively from faint to full., Results: A logistic model with the grade of LVO as the dependent variable and a selection from among the dose, exposure, right and left atrial blood pressures, systolic systemic and pulmonary artery blood pressures (ranges 94-208 and 14-45 mmHg, respectively), cardiac index, stroke index, and pulmonary and systemic vascular resistances as the explanatory variables demonstrated that increasing the dose gives an increasing probability of LVO (P = 0.02) and that increasing the pulmonary artery pressure reduces that probability (P = 0.006). A decreased cardiac index tended also to be associated with decreased LVO. The systemic blood pressure and the pulmonary and systemic vascular resistances had no statistically significant effect on the grade of LVO., Conclusions: LVO after intravenous administration of Albunex is dose-dependent and limited by an elevated pulmonary artery pressure. These data suggest that one should use higher doses for cardiac ischemic patients with elevated pulmonary artery pressures and that use of Albunex has the potential to detect pulmonary hypertension in patients.