We investigated the role of somatosensory feedback on cardioventilatory responses to rhythmic exercise in five men. In a double-blind, placebo-controlled design, subjects performed the same leg ...cycling exercise (50/100/150/325 ± 19 W, 3 min each) under placebo conditions (interspinous saline, L(3)-L(4)) and with lumbar intrathecal fentanyl impairing central projection of spinal opioid receptor-sensitive muscle afferents. Quadriceps strength was similar before and after fentanyl administration. To evaluate whether a cephalad migration of fentanyl affected cardioventilatory control centers in the brain stem, we compared resting ventilatory responses to hypercapnia (HCVR) and cardioventilatory responses to arm vs. leg cycling exercise after each injection. Similar HCVR and minor effects of fentanyl on cardioventilatory responses to arm exercise excluded direct medullary effects of fentanyl. Central command during leg exercise was estimated via quadriceps electromyogram. No differences between conditions were found in resting heart rate (HR), ventilation minute ventilation (VE), or mean arterial pressure (MAP). Quadriceps electromyogram, O(2) consumption (VO(2)), and plasma lactate were similar in both conditions at the four steady-state workloads. Compared with placebo, a substantial hypoventilation during fentanyl exercise was indicated by the 8-17% reduction in VE/CO(2) production (VCO(2)) secondary to a reduced breathing frequency, leading to average increases of 4-7 Torr in end-tidal PCO(2) (P < 0.001) and a reduced hemoglobin saturation (-3 ± 1%; P < 0.05) at the heaviest workload (∼90% maximal VO(2)) with fentanyl. HR was reduced 2-8%, MAP 8-13%, and ratings of perceived exertion by 13% during fentanyl vs. placebo exercise (P < 0.05). These findings demonstrate the essential contribution of muscle afferent feedback to the ventilatory, cardiovascular, and perceptual responses to rhythmic exercise in humans, even in the presence of unaltered contributions from other major inputs to cardioventilatory control.
Non‐Technical Summary We investigated the influence of group III/IV muscle afferents on central motor drive, the development of peripheral locomotor muscle fatigue, and endurance performance time ...during high‐intensity constant‐load cycling exercise to exhaustion. Our findings suggest that, on the one hand, afferent feedback ensures adequate circulatory and ventilatory responses to exercise which optimizes muscle O2 transport and thereby facilitates exercise performance by preventing premature peripheral fatigue. On the other hand, afferent feedback inhibits central motor drive, which is reflected in the restriction of the neural excitation of the locomotor musculature and the reduced tolerance for peripheral muscle fatigue, and thereby limits exercise performance. Taken together, the current investigation revealed the net effects of sensory afferent feedback on time to exhaustion during high‐intensity constant‐load cycling exercise and showed that intact group III/IV muscle afferent feedback is a vital component in achieving optimal endurance performance.
We investigated the influence of group III/IV muscle afferents on peripheral fatigue, central motor drive (CMD) and endurance capacity during high‐intensity leg‐cycling. In a double‐blind, placebo‐controlled design, seven males performed constant‐load cycling exercise (318 ± 9 W; 80% of peak power output (Wpeak)) to exhaustion under placebo conditions and with lumbar intrathecal fentanyl impairing spinal μ‐opioid receptor‐sensitive group III/IV muscle afferents. Peripheral fatigue was assessed via changes in pre‐ vs. post‐exercise quadriceps force in response to supramaximal magnetic femoral nerve stimulation (ΔQtw,pot). CMD was estimated via quadriceps electromyogram. To rule out a direct central effect of fentanyl, we documented unchanged resting cardioventilatory responses. Compared to placebo, significant hypoventilation during the fentanyl trial was indicated by the 9% lower /, causing a 5 mmHg increase in end‐tidal and a 3% lower haemoglobin saturation. Arterial pressure and heart rate averaged 8 and 10% lower, respectively, during the fentanyl trial and these differences progressively diminished towards end‐exercise. Although initially similar, the percent change in CMD was 9 ± 3% higher at end‐exercise with fentanyl vs. placebo (P < 0.05). Time to exhaustion was shorter (6.8 ± 0.3 min vs. 8.7 ± 0.3 min) and end‐exercise ΔQtw,pot was about one‐third greater (–44 ± 2%vs.–34 ± 2%) following fentanyl vs. placebo. The rate of peripheral fatigue development was 67 ± 10% greater during the fentanyl trial (P < 0.01). Our findings suggest that feedback from group III/IV muscle afferents limits CMD but also minimizes locomotor muscle fatigue development by stimulating adequate ventilatory and circulatory responses to exercise. In the face of blocked group III/IV muscle afferents, CMD is less inhibited but O2 transport compromised and locomotor muscle fatigability is exacerbated with a combined net effect of a reduced endurance performance.
We investigated the role of somatosensory feedback from locomotor muscles on central motor drive (CMD) and the development
of peripheral fatigue during high-intensity endurance exercise. In a ...double-blind, placebo-controlled design, eight cyclists
randomly performed three 5 km time trials: control, interspinous ligament injection of saline (5K Plac , L3âL4) or intrathecal fentanyl (5K Fent , L3âL4) to impair cortical projection of opioid-mediated muscle afferents. Peripheral quadriceps fatigue was assessed via
changes in force output pre- versus postexercise in response to supramaximal magnetic femoral nerve stimulation (ÎQ tw ). The CMD during the time trials was estimated via quadriceps electromyogram (iEMG). Fentanyl had no effect on quadriceps
strength. Impairment of neural feedback from the locomotor muscles increased iEMG during the first 2.5 km of 5K Fent versus 5K Plac by 12 ± 3% ( P < 0.05); during the second 2.5 km, iEMG was similar between trials. Power output was also 6 ± 2% higher during the first
and 11 ± 2% lower during the second 2.5 km of 5K Fent versus 5K Plac (both P < 0.05). Capillary blood lactate was higher (16.3 ± 0.5 versus 12.6 ± 1.0%) and arterial haemoglobin O 2 saturation was lower (89 ± 1 versus 94 ± 1%) during 5K Fent versus 5K Plac . Exercise-induced ÎQ tw was greater following 5K Fent versus 5K Plac (â46 ± 2 versus
â33 ± 2%, P < 0.001). Our results emphasize the critical role of somatosensory feedback from working muscles on the centrally mediated
determination of CMD. Attenuated afferent feedback from exercising locomotor muscles results in an overshoot in CMD and power
output normally chosen by the athlete, thereby causing a greater rate of accumulation of muscle metabolites and excessive
development of peripheral muscle fatigue.
Meningioma is the most common brain tumor in adults. Surgical resection remains the primary treatment. No chemotherapy exists. However, gene mutations now could explain ~ 80% of meningioma and ...targeted therapies based on these are being investigated. Furthermore, with the recent discovery of PD-L1 in malignant meningioma, clinical trials using immunotherapy have commenced. Here, we report for the first time the expression profiles of immune checkpoint proteins PD-L2, B7-H3 and CTLA-4 in meningioma and their association to common gene mutations. PD-L2 and B7-H3 expression was significantly greater than all immune checkpoint proteins studied, and particularly elevated in patients with gene mutations affecting the PI3K/AKT/mTOR pathway. CTLA-4 expressing CD3+ lymphocytes were observed in atypical and malignant meningioma and tumors harboring a
or
mutation. These results identify novel targets for immunotherapy irrespective of grade and distinguish potential patient populations based on genetic classification for stratification into checkpoint inhibitor clinical trials.
Background
Multiple training modalities for laparoscopy have different advantages, but little research has been conducted on the benefit of a training program that includes multiple different ...training methods compared to one method only. This study aimed to evaluate benefits of a combined multi-modality training program for surgical residents.
Methods
Laparoscopic cholecystectomy (LC) was performed on a porcine liver as the pre-test. Randomization was stratified for experience to the multi-modality Training group (12 h of training on Virtual Reality (VR) and box trainer) or Control group (no training). The post-test consisted of a VR LC and porcine LC. Performance was rated with the Global Operative Assessment of Laparoscopic Skills (GOALS) score by blinded experts.
Results
Training (
n
= 33) and Control (
n
= 31) were similar in the pre-test (GOALS: 13.7 ± 3.4 vs. 14.7 ± 2.6;
p
= 0.198; operation time 57.0 ± 18.1 vs. 63.4 ± 17.5 min;
p
= 0.191). In the post-test porcine LC, Training had improved GOALS scores (+ 2.84 ± 2.85 points,
p
< 0.001), while Control did not (+ 0.55 ± 2.34 points,
p
= 0.154). Operation time in the post-test was shorter for Training vs. Control (40.0 ± 17.0 vs. 55.0 ± 22.2 min;
p
= 0.012). Junior residents improved GOALS scores to the level of senior residents (pre-test: 13.7 ± 2.7 vs. 18.3 ± 2.9;
p
= 0.010; post-test: 15.5 ± 3.4 vs. 18.8 ± 3.8;
p
= 0.120) but senior residents remained faster (50.1 ± 20.6 vs. 25.0 ± 1.9 min;
p
< 0.001). No differences were found between groups on the post-test VR trainer.
Conclusions
Structured multi-modality training is beneficial for novices to improve basics and overcome the initial learning curve in laparoscopy as well as to decrease operation time for LCs in different stages of experience. Future studies should evaluate multi-modality training in comparison with single modalities.
Trial registration: German Clinical Trials Register DRKS00011040
Abstract
Background
The value of virtual reality (VR) simulators for robot-assisted surgery (RAS) for skill assessment and training of surgeons has not been established. This systematic review and ...meta-analysis aimed to identify evidence on transferability of surgical skills acquired on robotic VR simulators to the operating room and the predictive value of robotic VR simulator performance for intraoperative performance.
Methods
MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science were searched systematically. Risk of bias was assessed using the Medical Education Research Study Quality Instrument and the Newcastle–Ottawa Scale for Education. Correlation coefficients were chosen as effect measure and pooled using the inverse-variance weighting approach. A random-effects model was applied to estimate the summary effect.
Results
A total of 14 131 potential articles were identified; there were eight studies eligible for qualitative and three for quantitative analysis. Three of four studies demonstrated transfer of surgical skills from robotic VR simulators to the operating room measured by time and technical surgical performance. Two of three studies found significant positive correlations between robotic VR simulator performance and intraoperative technical surgical performance; quantitative analysis revealed a positive combined correlation (r = 0.67, 95 per cent c.i. 0.22 to 0.88).
Conclusion
Technical surgical skills acquired through robotic VR simulator training can be transferred to the operating room, and operating room performance seems to be predictable by robotic VR simulator performance. VR training can therefore be justified before operating on patients.
Graphical Abstract
Graphical Abstract
This systematic review and meta-analysis presents current evidence on transferability of surgical skills acquired on robotic VR simulators to the real operating room, and on the predictability of intraoperative performance by robotic VR simulator performances. The limited data currently available support the use of robotic VR simulators for surgical skill acquisition and assessment.
This systematic review and meta-analysis presents current evidence on transferability of surgical skills acquired on robotic VR simulators to the real operating room, and on the predictability of intraoperative performance by robotic VR simulator performances. The limited data currently available support the use of robotic VR simulators for surgical skill acquisition and assessment.
Human amyloid beta peptide (Aβ) is a brain catabolite that at nanomolar concentrations can form neurotoxic oligomers (AβOs), which are known to accumulate in Alzheimer's disease. Because a ...predisposition to form neurotoxins seems surprising, we have investigated whether circumstances might exist where AβO accumulation may in fact be beneficial. Our investigation focused on the embryonic chick retina, which expresses the same Aβ as humans. Using conformation-selective antibodies, immunoblots, mass spectrometry, and fluorescence microscopy, we discovered that AβOs are indeed present in the developing retina, where multiple proteoforms are expressed in a highly regulated cell-specific manner. The expression of the AβO proteoforms was selectively associated with transiently expressed phosphorylated Tau (pTau) proteoforms that, like AβOs, are linked to Alzheimer's disease (AD). To test whether the AβOs were functional in development, embryos were cultured ex ovo and then injected intravitreally with either a beta-site APP-cleaving enzyme 1 (BACE-1) inhibitor or an AβO-selective antibody to prematurely lower the levels of AβOs. The consequence was disrupted histogenesis resulting in dysplasia resembling that seen in various retina pathologies. We suggest the hypothesis that embryonic AβOs are a new type of short-lived peptidergic hormone with a role in neural development. Such a role could help explain why a peptide that manifests deleterious gain-of-function activity when it oligomerizes in the aging brain has been evolutionarily conserved.
1 John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin-Madison Medical School, Madison, Wisconsin; 2 University of Zürich, Institute of Physiology, and ETH Zürich, Exercise ...Physiology, Zürich, Switzerland; and 3 Department of Anesthesiology, University of Wisconsin-Madison Medical School, Madison, Wisconsin
Submitted 27 March 2008
; accepted in final form 4 September 2008
We investigated whether somatosensory feedback from contracting limb muscles exerts an inhibitory influence on the determination of central command during closed-loop cycling exercise in which the subject voluntarily determines his second-by-second central motor drive. Eight trained cyclists performed two 5-km time trials either without (5K Ctrl ) or with lumbar epidural anesthesia (5K Epi ; 24 ml of 0.5% lidocaine, vertebral interspace L 3 –L 4 ). Percent voluntary quadriceps muscle activation was determined at rest using a superimposed twitch technique. Epidural lidocaine reduced pretime trial maximal voluntary quadriceps strength (553 ± 45 N) by 22 ± 3%. Percent voluntary quadriceps activation was also reduced from 97 ± 1% to 81 ± 3% via epidural lidocaine, and this was unchanged following the 5K Epi , indicating the presence of a sustained level of neural impairment throughout the trial. Power output was reduced by 9 ± 2% throughout the race ( P < 0.05). We found three types of significant effects of epidural lidocaine that supported a substantial role for somatosensory feedback from the exercising limbs as a determinant of central command throughout high-intensity closed-loop cycling exercise: 1 ) significantly increased relative integrated EMG of the vastus lateralis; 2 ) similar pedal forces despite the reduced number of fast-twitch muscle fibers available for activation; 3 ) and increased ventilation out of proportion to a reduced carbon dioxide production and heart rate and increased blood pressure out of proportion to power output and oxygen consumption. These findings demonstrate the inhibitory influence of somatosensory feedback from contracting locomotor muscles on the conscious and/or subconscious determination of the magnitude of central motor drive during high intensity closed-loop endurance exercise.
nociception; control of breathing; exercise hyperpnea; cardiorespiratory response; muscle metaboreflex; ascending sensory pathway
Address for reprint requests and other correspondence: M. Amann, Institute of Physiology, Univ. of Zürich, and Institute for Exercise Physiology, ETH Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland (e-mail: markus.amann{at}physiol.biol.ethz.ch )
Meningioma, a most common brain tumor, has a high rate of recurrence. Tumor-associated macrophages (TAMs) are the most abundant immune cell type in meningioma. TAMs display functional phenotypic ...diversity and may establish either an inflammatory and anti-tumoral or an immunosuppressive and pro-tumoral microenvironment. TAM subtypes present in meningioma and potential contribution to growth and recurrence is unknown.
Immunofluorescence staining was used to quantify M1 and M2 TAM populations in tissues obtained from 30 meningioma patients. Associations between M1 and M2 cells, M1:M2 cell ratio to tumor characteristics, WHO grade, recurrence, size, location, peri-tumoral edema, and patient demographics such as age and sex were examined.
TAM cells accounted for ~18% of all cells in meningioma tissues. More than 80% of infiltrating TAMs were found to be of pro-tumoral M2 phenotype and correlated to tumor size (
= .0409). M1:M2 cell ratio was significantly decreased in WHO grade II, compared to grade I tumors (
= .009). Furthermore, a 2.3-fold difference in M1:M2 ratio between primary (0.14) and recurrent (0.06) tumors was observed (
= 18 and 12 respectively,
= .044).
This study is the first to confirm existence of pro-tumoral M2 TAMs in the meningioma microenvironment, emphasizing its potential role in tumor growth and recurrence.
The random-anisotropy Heisenberg model is numerically studied on lattices containing over ten million spins. The study is focused on hysteresis and metastability due to topological defects, and is ...relevant to magnetic properties of amorphous and sintered magnets. We are interested in the limit when ferromagnetic correlations extend beyond the size of the grain inside which the magnetic anisotropy axes are correlated. In that limit the coercive field computed numerically roughly scales as the fourth power of the random anisotropy strength and as the sixth power of the grain size. Theoretical arguments are presented that provide an explanation of numerical results. Our findings should be helpful for designing amorphous and nanosintered materials with desired magnetic properties.
•We study the random-anisotropy model on lattices containing up to ten million spins.•Irreversible behavior due to topological defects (hedgehogs) is elucidated.•Hysteresis loop area scales as the fourth power of the random anisotropy strength.•In nanosintered magnets the coercivity scales as the six power of the grain size.
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