Six weeks of high-load resistance and low-load blood flow restricted training increase Na/K-ATPase sub-units α2 and ß1 equally, but does not alter ClC-1 abundance in untrained human skeletal muscle.

Contractile function of skeletal muscle relies on the ability of muscle fibers to trigger and propagate action potentials (APs). These electrical signals are created by transmembrane ion transport through ion channels and membrane transporter systems. In this regard, the Cl- ion channel 1 (ClC-1) and the Na+/K--ATPase (NKA) are central for maintaining ion homeostasis across the sarcolemma during intense contractile activity. Therefore, this randomized controlled trial aimed to investigate the changes in ClC-1 and specific NKA subunit isoform expression in response to six weeks (18 training sessions) of high-load resistance exercise (HLRE) and low-load blood flow restricted resistance exercise (BFRRE), respectively. HLRE was conducted as 4 sets of 12 repetitions of knee extensions performed at 70% of 1 repetition maximum (RM), while BFRRE was conducted as 4 sets of knee extensions at 30% of 1RM performed to volitional fatigue. Furthermore, the potential associations between protein expression and contractile performance were investigated. We show that muscle ClC-1 abundance was not affected by either exercise modality, whereas NKA subunit isoforms [Formula: see text]2 and [Formula: see text]1 increased equally by appx. 80-90% with BFRRE (p < 0.05) and 70-80% with HLRE (p < 0.05). No differential impact between exercise modalities was observed. At baseline, ClC-1 protein expression correlated inversely with dynamic knee extensor strength (r=-0.365, p = 0.04), whereas no correlation was observed between NKA subunit content and contractile performance at baseline. However, training-induced changes in NKA [Formula: see text]2 subunit (r = 0.603, p < 0.01) and [Formula: see text]1 subunit (r = 0.453, p < 0.05) correlated with exercise-induced changes in maximal voluntary contraction. These results suggest that the initial adaptation to resistance-based exercise does not involve changes in ClC-1 abundance in untrained skeletal muscle, and that increased content of NKA subunits may facilitate increases in maximal force production.

Prolonged loss of force and power following fatiguing contractions in rat soleus muscles. Is low-frequency fatigue an issue during dynamic contractions?

Low-frequency fatigue (LFF) is defined by a relatively larger deficit in isometric force elicited by low-frequency electrical stimulation compared with high-frequency stimulation. However, the effects of LFF on power during dynamic contractions elicited at low and high frequencies have not been thoroughly characterized. In the current study, rat soleus muscles underwent fatiguing either concentric, eccentric, or isometric contractions. Before and 1 h after the fatiguing contractions, a series of brief isometric and dynamic contractions elicited at 20 and 80 Hz stimulation to establish force-velocity relationships. Maximal force (Fmax), velocity (Vmax), and power (Pmax) were assessed for each frequency. Sarcoplasmic reticulum (SR) Ca2+ release and reuptake rates were assessed pre- and postfatigue. Prolonged fatigue was observed as a loss of Fmax and Pmax in muscles fatigued by concentric or eccentric, but not by isometric contractions. When quantified as a decrease in the ratio between 20 Hz and 80 Hz contractile output, LFF was more pronounced for isometric force than for power (-21% vs. -16% for concentrically fatigued muscles, P = 0.003; 29 vs. 13% for eccentrically fatigued muscles, P < 0.001). No changes in SR Ca2+ release or reuptake rates were observed. We conclude that LFF is less pronounced when expressed in terms of power deficits than when expressed in terms of force deficits, and that LFF, therefore, likely affects performance to a lesser degree during fast concentric contractions than during static or slow contractions.

Protein signalling in response to ex vivo dynamic contractions is independent of training status in rat skeletal muscle.

NEW FINDINGS: What is the central question of this study? Are myofibre protein signalling responses to ex vivo dynamic contractions altered by accustomization to voluntary endurance training in rats? What is the main finding and its importance? In response to ex vivo dynamic muscle contractions, canonical myofibre protein signalling pertaining to metabolic transcriptional regulation, as well as translation initiation and elongation, was not influenced by prior accustomization to voluntary endurance training in rats. Accordingly, intrinsic myofibre protein signalling responses to standardized contractile activity may be independent of prior exercise training in rat skeletal muscle. ABSTRACT: Skeletal muscle training status may influence myofibre regulatory protein signalling in response to contractile activity. The current study employed a purpose-designed ex vivo dynamic contractile protocol to evaluate the effect of exercise-accustomization on canonical myofibre protein signalling for metabolic gene expression and for translation initiation and elongation. To this end, rats completed 8 weeks of in vivo voluntary running training versus no running control intervention, whereupon an ex vivo endurance-type dynamic contraction stimulus was conducted in isolated soleus muscle preparations from both intervention groups. Protein signalling response by phosphorylation was evaluated by immunoblotting at 0 and 3 h following ex vivo stimulation. Phosphorylation of AMP-activated protein kinase α-isoforms and its downstream target, acetyl-CoA carboxylase, as well as phosphorylation of eukaryotic elongation factor 2 (eEF2) was increased immediately following the dynamic contraction protocol (at 0 h). Signalling for translation initiation and elongation was evident at 3 h after dynamic contractile activity, as evidenced by increased phosphorylation of p70 S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1, as well as a decrease in phosphorylation of eEF2 back to resting control levels. However, prior exercise training did not alter phosphorylation responses of the investigated signalling proteins. Accordingly, protein signalling responses to standardized endurance-type contractions may be independent of training status in rat muscle during ex vivo conditions. The present findings add to our current understanding of molecular regulatory events responsible for skeletal muscle plasticity.

The Role of Plasma Extracellular Vesicles in Remote Ischemic Conditioning and Exercise-Induced Ischemic Tolerance.

Ischemic conditioning and exercise have been suggested for protecting against brain ischemia-reperfusion injury. However, the endogenous protective mechanisms stimulated by these interventions remain unclear. Here, in a comprehensive translational study, we investigated the protective role of extracellular vesicles (EVs) released after remote ischemic conditioning (RIC), blood flow restricted resistance exercise (BFRRE), or high-load resistance exercise (HLRE). Blood samples were collected from human participants before and at serial time points after intervention. RIC and BFRRE plasma EVs released early after stimulation improved viability of endothelial cells subjected to oxygen-glucose deprivation. Furthermore, post-RIC EVs accumulated in the ischemic area of a stroke mouse model, and a mean decrease in infarct volume was observed for post-RIC EVs, although not reaching statistical significance. Thus, circulating EVs induced by RIC and BFRRE can mediate protection, but the in vivo and translational effects of conditioned EVs require further experimental verification.

Isolation and characterization of muscle stem cells, fibro-adipogenic progenitors, and macrophages from human skeletal muscle biopsies.

Animal models clearly illustrate that the maintenance of skeletal muscle mass depends on the function and interaction of a heterogeneous population of resident and infiltrating mononuclear cells. Several lines of evidence suggest that mononuclear cells also play a role in muscle wasting in humans, and targeting these cells may open new treatment options for intervention or prevention in sarcopenia. Methodological and ethical constraints have perturbed exploration of the cellular characteristics and function of mononuclear cells in human skeletal muscle. Thus, investigations of cellular phenotypes often depend on immunohistochemical analysis of small tissue samples obtained by needle biopsies, which do not match the deep phenotyping of mononuclear cells obtained from animal models. Here, we have developed a protocol for fluorescence-activated cell sorting (FACS), based on single-cell RNA-sequencing data, for quantifying and characterizing mononuclear cell populations in human skeletal muscle. Muscle stem cells, fibro-adipogenic progenitors, and two subsets of macrophages (CD11c+/-) are present in needle biopsies in comparable quantities per milligram tissue to open surgical biopsies. We find that direct cell isolation is preferable due to a substantial shift in transcriptome when using preculture before the FACS procedure. Finally, in vitro validation of the cellular phenotype of muscle stem cells, fibro-adipogenic progenitors, and macrophages confirms population-specific traits. This study demonstrates that mononuclear cell populations can be quantified and subsequently analyzed from needle biopsy material and opens the perspective for future clinical studies of cellular mechanisms in muscle wasting.

Utilization of biomarkers as predictors of skeletal muscle mitochondrial content after physiological intervention and in clinical settings.

The measurement of mitochondrial content is essential for bioenergetic research, as it provides a tool to evaluate whether changes in mitochondrial function are strictly due to changes in content or other mechanisms that influence function. In this perspective, we argue that commonly used biomarkers of mitochondrial content may possess limited utility for capturing changes in content with physiological intervention. Moreover, we argue that they may not provide reliable estimates of content in certain pathological situations. Finally, we discuss potential solutions to overcome issues related to the utilization of biomarkers of mitochondrial content. Shedding light on this important issue will hopefully aid conclusions about the mitochondrial structure-function relationship.

Chloride Channels Take Center Stage in Acute Regulation of Excitability in Skeletal Muscle: Implications for Fatigue.

Initiation and propagation of action potentials in muscle fibers is a key element in the transmission of activating motor input from the central nervous system to their contractile apparatus, and maintenance of excitability is therefore paramount for their endurance during work. Here, we review current knowledge about the acute regulation of ClC-1 channels in active muscles and its importance for muscle excitability, function, and fatigue.

The anti-convulsants lacosamide, lamotrigine, and rufinamide reduce myotonia in isolated human and rat skeletal muscle.

INTRODUCTION: In myotonia congenita, loss of ClC-1 Cl- channel function results in skeletal muscle hyperexcitability and myotonia. Anti-myotonic treatment has typically targeted the voltage-gated sodium channel in skeletal muscle (Nav1.4). In this study we explored whether 3 sodium channel-modulating anti-epileptics can reduce myotonia in isolated rat and human muscle. METHODS: Dissected muscles were rendered myotonic by ClC-1 channel inhibition. The ability of the drugs to suppress myotonia was then assessed from subclinical to maximal clinical concentrations. Drug synergy was determined using isobole plots. RESULTS: All drugs were capable of abolishing myotonia in both rat and human muscles. Lamotrigine and rufinamide completely suppressed myotonia at submaximal clinical concentrations, whereas lacosamide had to be raised above the maximal clinical concentration to suppress myotonia completely. A synergistic effect of lamotrigine and rufinamide was observed. CONCLUSION: These findings suggest that lamotrigine and rufinamide could be considered for anti-myotonic treatment in myotonia congenita. Muscle Nerve 56: 136-142, 2017.

Protein kinase C-dependent regulation of ClC-1 channels in active human muscle and its effect on fast and slow gating.

KEY POINTS: Regulation of ion channel function during repeated firing of action potentials is commonly observed in excitable cells. Recently it was shown that muscle activity is associated with rapid, protein kinase C (PKC)-dependent ClC-1 Cl(-) channel inhibition in rodent muscle. While this PKC-dependent ClC-1 inhibition during muscle activity was shown to be important for the maintenance of contractile endurance in rat muscle it is unknown whether a similar regulation exists in human muscle. Also, the molecular mechanisms underlying the observed PKC-dependent ClC-1 inhibition are unclear. Here we present the first demonstration of ClC-1 inhibition in active human muscle fibres, and we determine the changes in ClC-1 gating that underlie the PKC-dependent ClC-1 inhibition in active muscle using human ClC-1 expressed in Xenopus oocytes. This activity-induced ClC-1 inhibition is suggested to represent a mechanism by which human muscle fibres maintain their excitability during sustained activity. ABSTRACT: Repeated firing of action potentials (APs) is known to trigger rapid, protein kinase C (PKC)-dependent inhibition of ClC-1 Cl(-) ion channels in rodent muscle and this inhibition is important for contractile endurance. It is currently unknown whether similar regulation exists in human muscle, and the molecular mechanisms underlying PKC-dependent ClC-1 inhibition are unclear. This study first determined whether PKC-dependent ClC-1 inhibition exists in active human muscle, and second, it clarified how PKC alters the gating of human ClC-1 expressed in Xenopus oocytes. In human abdominal and intercostal muscles, repeated AP firing was associated with 30-60% reduction of ClC-1 function, which could be completely prevented by PKC inhibition (1 µm GF109203X). The role of the PKC-dependent ClC-1 inhibition was evaluated from rheobase currents before and after firing 1000 APs: while rheobase current was well maintained after activity under control conditions it rose dramatically if PKC-dependent ClC-1 inhibition had been prevented with the inhibitor. This demonstrates that the ClC-1 inhibition is important for maintenance of excitability in active human muscle fibres. Oocyte experiments showed that PKC activation lowered the overall open probability of ClC-1 in the voltage range relevant for AP initiation in muscle fibres. More detailed analysis of this reduction showed that PKC mostly affected the slow gate of ClC-1. Indeed, there was no effect of PKC activation in C277S mutated ClC-1 in which the slow gate is effectively locked open. It is concluded that regulation of excitability of active human muscle fibres relies on PKC-dependent ClC-1 inhibition via a gating mechanism.

No differential effects of divergent isocaloric supplements on signaling for muscle protein turnover during recovery from muscle-damaging eccentric exercise.

Unaccustomed high-intensity eccentric exercise (ECC) can provoke muscle damage including several days of muscle force loss. Post-exercise dietary supplementation may provide a strategy to accelerate rate of force regain by affecting mechanisms related to muscle protein turnover. The aim of the current study was to investigate if protein signaling mechanisms involved in muscle protein turnover would be differentially affected by supplementation with either whey protein hydrolysate and carbohydrate (WPH+CHO) versus isocaloric carbohydrate (CHO) after muscle-damaging ECC. Twenty-four young healthy participants received either WPH+CHO (n = 12) or CHO supplements (n = 12) during post-exercise recovery from 150 maximal unilateral eccentric contractions. Prior to, at 3 h and at 24, 48, 96 and/or 168 h post-exercise, muscle strength, muscle soreness, and Akt-mTOR and FOXO signaling proteins, were measured in an ECC exercising leg and in the contralateral non-exercise control leg (CON). After ECC, muscle force decreased by 23-27 % at 24 h post-exercise, which was followed by gradual, although not full recovery at 168 h post-exercise, with no differences between supplement groups. Phosphorylation of mTOR, p70S6K and rpS6 increased and phosphorylation of FOXO1 and FOXO3 decreased in the ECC leg, with no differences between supplement groups. Phosphorylation changes were also observed for rpS6, FOXO1 and FOXO3a in the CON leg, suggesting occurrence of remote tissue effects. In conclusion, divergent dietary supplementation types did not produce differences in signaling for muscle turnover during recovery from muscle-damaging exercise.

Extracellular magnesium and calcium reduce myotonia in isolated ClC-1 chloride channel-inhibited human muscle.

INTRODUCTION: Experimental myotonia induced in rat muscle by ClC-1 chloride channel-inhibited has been shown to be related inversely to extracellular concentrations of Mg(2+) and Ca(2+) ([Mg(2+) ]o and [Ca(2+) ]o) within physiological ranges. Because this implicates a role for [Mg(2+)]o and [Ca(2+)]o in the variability of symptoms among myotonia congenita patients, we searched for similar effects of [Mg(2+)]o and [Ca(2+)]o on myotonia in human muscle. METHODS: Bundles of muscle fibers were isolated from abdominal rectus in patients undergoing abdominal surgery. Myotonia was induced by ClC-1 inhibition using 9-anthracene carboxylic acid (9-AC) and was assessed from integrals of force induced by 5-Hz stimulation for 2 seconds. RESULTS: Myotonia disappeared gradually when [Mg(2+)]o or [Ca(2+)]o were elevated throughout their physiological ranges. These effects of [Mg(2+)]o and [Ca(2+)]o were additive and interchangeable. CONCLUSIONS: These findings suggest that variations in symptoms in myotonia congenita patients may arise from physiological variations in serum Mg(2+) and Ca(2+).

Whey protein supplementation accelerates satellite cell proliferation during recovery from eccentric exercise.

Human skeletal muscle satellite cells (SCs) are essential for muscle regeneration and remodeling processes in healthy and clinical conditions involving muscle breakdown. However, the potential influence of protein supplementation on post-exercise SC regulation in human skeletal muscle has not been well investigated. In a comparative human study, we investigated the effect of hydrolyzed whey protein supplementation following eccentric exercise on fiber type-specific SC accumulation. Twenty-four young healthy subjects received either hydrolyzed whey protein + carbohydrate (whey, n = 12) or iso-caloric carbohydrate (placebo, n = 12) during post-exercise recovery from 150 maximal unilateral eccentric contractions. Prior to and 24, 48 and 168 h post-exercise, muscle biopsies were obtained from the exercise leg and analyzed for fiber type-specific SC content. Maximal voluntary contraction (MVC) and serum creatine kinase (CK) were evaluated as indices of recovery from muscle damage. In type II fiber-associated SCs, the whey group increased SCs/fiber from 0.05 [0.02; 0.07] to 0.09 [0.06; 0.12] (p < 0.05) and 0.11 [0.06; 0.16] (p < 0.001) at 24 and 48 h, respectively, and exhibited a difference from the placebo group (p < 0.05) at 48 h. The whey group increased SCs/myonuclei from 4 % [2; 5] to 10 % [4; 16] (p < 0.05) at 48 h, whereas the placebo group increased from 5 % [2; 7] to 9 % [3; 16] (p < 0.01) at 168 h. MVC decreased (p < 0.001) and muscle soreness and CK increased (p < 0.001), irrespective of supplementation. In conclusion, whey protein supplementation may accelerate SC proliferation as part of the regeneration or remodeling process after high-intensity eccentric exercise.

Slipping rib syndrome.

Slipping rib syndrome (SRS) is a possibly lesser known but not rare condition associated with severe pain in the lower part of the thorax and/or upper abdomen. SRS is caused by an anatomical variant where typical costa 9 collides with costa 8 resulting in neuralgic pain. Surgery with reconstruction of the rib curvature has few recurrences. The diagnosis and treatment of SRS patients are presented, but our primary aim is to raise awareness about a painful and largely overlooked condition as a differential diagnosis in patients with unexplained chronic pain in the lower thorax.

Complication rates rise with age and Haller index in minimally invasive correction of pectus excavatum: A high-volume, single-center retrospective cohort study.

OBJECTIVES: The study objectives were to describe the compounded complication rate of minimally invasive repair of pectus excavatum, identify predisposing risk factors, and evaluate the optimal timing of correction. Minimally invasive repair of pectus excavatum is the standard treatment for pectus excavatum and consists of 2 invasive procedures, for example, correction with bar insertion followed by bar removal after 2 to 3 years. METHODS: A retrospective cohort study identifying children, adolescents, and adults of both genders corrected for pectus excavatum with minimally invasive repair of pectus excavatum between 2001 and 2022. Information on complications related to bar insertion and removal procedures for each individual patient was compiled into a compounded complication rate. Complication severities were categorized according to the Clavien-Dindo classification. RESULTS: A total of 2013 patients were corrected by minimally invasive repair of pectus excavatum with a median age (interquartile range) for correction of 16.6 (5) years. Overall compounded complication rate occurred at a frequency of 16.4%, of which 9.3% required invasive reinterventions (Clavien-Dindo classification ≥IIIa). The complication rate related to bar insertion was 2.6-fold higher compared with bar removal (11.8% vs 4.5%, respectively). Multivariable analysis revealed age (adjusted odds ratio, 1.05; P < .001), precorrection Haller Index (adjusted odds ratio, 1.10; P < .033), and early-phase institutional experience (adjusted odds ratio, 1.59; P < .002) as independent predisposing risk factors. The optimal age of correction was 12 years, and the compounded complication rate correlated exponentially with age with a doubling time of 7.2 years. Complications increased 2.2-fold when the Haller index increased to 5 or more units. CONCLUSIONS: Minimally invasive repair of pectus excavatum is associated with a high compounded complication rate that increases exponentially with age and high Haller Index. Consequently, we recommend repair during late childhood and early adolescence, and emphasize the importance of informing patients and relatives about the significant risks of adult correction as well as the need of 2 consecutive procedures taking the complication profile into account before planning surgery.

Relationship between membrane Cl- conductance and contractile endurance in isolated rat muscles.

Resting skeletal muscle fibres have a large membrane Cl(-) conductance (G(Cl)) that dampens their excitability. Recently, however, muscle activity was shown to induce PKC-mediated reduction in G(Cl) in rat muscles of 40-90%. To examine the physiological significance of this PKC-mediated G(Cl) reduction for the function of muscles, this study explored effects of G(Cl) reductions on contractile endurance in isolated rat muscles. Contractile endurance was assessed from the ability of muscle to maintain force during prolonged stimulation under conditions when G(Cl) was manipulated by: (i) inhibition of PKC, (ii) reduction of solution Cl(-) or (iii) inhibition of ClC-1 Cl(-) channels using 9-anthracene-carboxylic acid (9-AC). Experiments showed that contractile endurance was optimally preserved by reductions in G(Cl) similar to what occurs in active muscle. Contrastingly, further G(Cl) reductions compromised the endurance. The experiments thus show a biphasic relationship between G(Cl) and contractile endurance in which partial G(Cl) reduction improves endurance while further G(Cl) reduction compromises endurance. Intracellular recordings of trains of action potentials suggest that this biphasic dependency of contractile endurance on G(Cl) reflects that lowering G(Cl) enhances muscle excitability but low G(Cl) also increases the depolarisation of muscle fibres during excitation and reduces their ability to re-accumulate K(+) lost during excitation. If G(Cl) becomes very low, the latter actions dominate causing reduced endurance. It is concluded that the PKC-mediated ClC-1 channel inhibition in active muscle reduces G(Cl) to a level that optimises contractile endurance during intense exercise.

Low-load blood flow-restricted resistance exercise produces fiber type-independent hypertrophy and improves muscle functional capacity in older individuals.

Low-load blood flow-restricted resistance exercise (BFRRE) constitutes an effective means to produce skeletal muscle hypertrophy. Nonetheless, its applicability to counteract the age-related skeletal muscle decay at a cellular level, is not clear. Therefore, we investigated the effect of BFRRE on muscle fiber morphology, integrated muscle protein synthesis, muscle stem cells (MuSCs), myonuclear content, and muscle functional capacity in healthy older individuals. Twenty-three participants with a mean age of 66 yr (56-75 yr) were randomized to 6 wk of supervised BFRRE (3 sessions per week) or non-exercise control (CON). Biopsies were collected from the vastus lateralis before and after the intervention. Immunofluorescent microscopy was utilized to assess muscle fiber type-specific cross-sectional area (CSA) as well as MuSC and myonuclear content. Deuterium oxide was orally administered throughout the intervention period, enabling assessment of integrated myofibrillar and connective tissue protein fractional synthesis rate (FSR). BFRRE produced uniform ∼20% increases in the fiber CSA of both type I and type II fibers (P < 0.05). This occurred concomitantly with improvements in both maximal muscle strength and strength-endurance capacity but in the absence of increased MuSC content and myonuclear addition. The observed muscle fiber hypertrophy was not mirrored by increases in either myofibrillar or connective tissue FSR. In conclusion, BFRRE proved effective in stimulating skeletal muscle growth and increased muscle function in older individuals, which advocates for the use of BFRRE as a countermeasure of age-related deterioration of skeletal muscle mass and function.NEW & NOTEWORTHY We provide novel insight, that as little as 6 wk of low-load blood flow-restricted resistance exercise (BFRRE) produces pronounced fiber type-independent hypertrophy, alongside improvements across a broad range of muscle functional capacity in older individuals. Notably, since these results were obtained with a modest exercise volume and in a very time-efficient manner, BFRRE may represent a potent exercise strategy to counteract age-related muscle decay.

Individualised perioperative blood pressure and fluid therapy in oesophagectomy ­ study protocol for a randomised clinical trial

INTRODUCTION: Oesophagectomy is the mainstay of curative treatment for oesophageal cancer, but it is associated with a high risk of major complications. Goal-directed fluid therapy and individualised blood pressure management may prevent complications after surgery. Extending goal-directed fluid therapy after surgery and applying an individual blood pressure target may have substantial benefit in oesophagectomy. This is a protocol for a clinical trial implementing a novel haemodynamic protocol from the start of anaesthesia to the next day with the patient's own night-time blood pressure as the lower threshold. METHODS: This is a single-centre, single-blind, randomised, clinical trial. Oesophagectomy patients are randomised 1:1 for either perioperative haemodynamic management according to a goal-directed fluid therapy protocol with an individual target blood pressure or for standard care. The primary endpoint is the total burden of morbidity and mortality assessed by the Comprehensive Complication Index 30 days after surgery. Secondary endpoints are complications, reoperations, fluid and vasopressor dosage and quality of life at 90 days after surgery. CONCLUSIONS: The results from this trial provide an objective and easy-to-follow algorithm for fluid administration, which may improve patient-centred outcomes in oesophagectomy patients. FUNDING: The trial is supported by Aarhus University (1,293,400 DKK) and the Novo Nordisk Foundation (625,200 DKK). TRIAL REGISTRATION: EudraCT number: 2021-002816-30.

Epidural analgesia and abnormal coagulation in patients undergoing minimal invasive repair of pectus excavatum.

Background: Epidural analgesia (EA) is effective in patients undergoing minimal invasive repair of pectus excavatum (MIRPE) but is associated with major complications such as epidural hematomas. It is recommended to assess coagulation status in patients receiving anticoagulant therapy prior to EA, although no consensus exists in patients without a history of bleeding tendency or anticoagulant therapy. Thus, the aim of this paper was to assess 1) the prevalence of abnormal routine coagulation parameters, i.e., international normalized ratio (INR) and platelet count, and 2) the safety of EA in patients undergoing MIRPE. Methods: In this retrospective study, we identified 1,973 patients undergoing MIRPE at our center between 2001 and 2019. Complications related to EA were registered for all patients. Information on coagulation parameters was present in 929 patients. Patients with spontaneously elevated INR ≥1.5 were referred for assessment of coagulation factor VII in order to assess the cause of the elevated INR. Results: Of 929 patients with coagulation information available, 18 patients had spontaneously elevated INR ≥1.5 (1.9%). In patients with INR ≥1.5, 12 patients underwent further assessment of factor VII, with all patients having a slightly reduced factor VII close to the lower reference range. The majority of the 1,973 patients undergoing MIRPE received EA (99.6%) with very low complication rates (0.2%) and no incidence of epidural hematomas. Conclusion: In patients undergoing MIRPE, coagulation screening prior to EA should not be mandatory as it revealed no clinically relevant consequences. EA is safe with very low complication rates.

Skeletal muscle phenotype signaling with ex vivo endurance-type dynamic contractions in rat muscle.

Skeletal muscle phenotype may influence the response sensitivity of myocellular regulatory mechanisms to contractile activity. To examine this, we employed an ex vivo endurance-type dynamic contraction model to evaluate skeletal muscle phenotype-specific protein signaling responses in rat skeletal muscle. Preparations of slow-twitch soleus and fast-twitch extensor digitorum longus skeletal muscle from 4-wk-old female Wistar rats were exposed to an identical ex vivo dynamic endurance-type contraction paradigm consisting of 40 min of stretch-shortening contractions under simultaneous low-frequency electrostimulation delivered in an intermittent pattern. Phosphorylation of proteins involved in metabolic signaling and signaling for translation initiation was evaluated at 0, 1, and 4 h after stimulation by immunoblotting. For both muscle phenotypes, signaling related to metabolic events was upregulated immediately after stimulation, with concomitant absence of signaling for translation-initiation. Signaling for translation-initiation was then activated in both muscle phenotypes at 1-4 h after stimulation, coinciding with attenuated metabolic signaling. The recognizable pattern of signaling responses support how our ex vivo dynamic muscle contraction model can be utilized to infer a stretch-shortening contraction pattern resembling stretch-shortening contraction of in vivo endurance exercise. Moreover, using this model, we observed that some specific signaling proteins adhering to metabolic events or to translation-initiation exhibited phosphorylation changes in a phenotype-dependent manner, whereas other signaling proteins exhibited phenotype-independent changes. These findings may aid the interpretation of myocellular signaling outcomes adhering to mixed muscle samples collected during human experimental trials.NEW & NOTEWORTHY The application of cyclic ex vivo dynamic muscle contractions delivered in an intermittent pattern may be suitable for the exploration of skeletal muscle regulatory responses to endurance-type contractile activity. In the present study, it is demonstrated that the response to such stimulus of some nodal myocellular signaling proteins related to either metabolic or anabolic signaling events may be influenced by muscle phenotype, whereas the response of others appears to be independent of phenotype.

Incidence and severity of surgical complications after pectus excavatum bar removal.

OBJECTIVES: Pectus bar removal is the final step of minimally invasive repair of pectus excavatum. Complication rates related to bar removal have been reported in 2-15% of patients and severe, near-fatal and fatal complications have been reported. No systematic assessment of complication severity or risk factors associated with bar removal has been reported in large study populations. The aim of this paper is to investigate the safety of the bar removal procedure with regard to complication rates and severities as well as assessment of risk factors. METHODS: Between 2003 and 2019, 1574 patients underwent the bar removal procedure. Medical records were assessed retrospectively and complications registered. Complications were categorized in infections, bleedings and other complications. The severity of the surgical complications was systematically classified using the validated Clavien-Dindo classification. Furthermore, risk factors associated with complications were assessed. RESULTS: The overall complication rate was 4.1% (Clavien-Dindo classification I-IV), mainly consisting of bleedings (1.3%) and infections (1.5%). Five cases of severe bleedings were registered (0.3%, Clavien-Dindo classification IV). Risk factors associated with complications during bar removal were greater age and removal of more than one bar. CONCLUSIONS: The bar removal procedure is a safe and effective procedure. Both age and number of bars inserted should be considered prior to surgical correction of pectus excavatum as these factors predict complications related to bar removal.