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What is the central question of this study? Skeletal muscle extracellular vesicles likely act as pro-angiogenic signalling factors: does overexpression of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) alter skeletal muscle myotube extracellular vesicle release, contents and angiogenic potential? What is the main finding and its importance? Overexpression of PGC-1α results in secretion of extracellular vesicles that elevate measures of angiogenesis and protect against acute oxidative stress in vitro. Skeletal muscle with high levels of PGC-1α expression, commonly associated with exercise induced angiogenesis and high basal capillarization, may secrete extracellular vesicles that support capillary growth and maintenance.Skeletal muscle capillarization is proportional to muscle fibre mitochondrial content and oxidative capacity. Skeletal muscle cells secrete many factors that regulate neighbouring capillary endothelial cells (ECs), including extracellular vesicles (SkM-EVs). Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) regulates mitochondrial biogenesis and the oxidative phenotype in skeletal muscle. Skeletal muscle PGC-1α also regulates secretion of multiple angiogenic factors, but it is unknown whether PGC-1α regulates SkM-EV release, contents and angiogenic signalling potential. PGC-1α was overexpressed via adenovirus in primary human myotubes. EVs were collected from PGC-1α-overexpressing myotubes (PGC-EVs) as well as from green fluorescent protein-overexpressing myotubes (GFP-EVs), and from untreated myotubes. EV release and select mRNA contents were measured from EVs. Additionally, ECs were treated with EVs to measure angiogenic potential of EVs in normal conditions and following an oxidative stress challenge. PGC-1α overexpression did not impact EV release but did elevate EV content of mRNAs for several antioxidant proteins (nuclear factor erythroid 2-related factor 2, superoxide dismutase 2, glutathione peroxidase). PGC-EV treatment of cultured human umbilical vein endothelial cells (HUVECs) increased their proliferation (+36.6%), tube formation (length: +28.1%; number: +25.7%) and cellular viability (+52.9%), and reduced reactive oxygen species levels (-41%) compared to GFP-EVs. Additionally, PGC-EV treatment protected against tube formation impairments and induction of cellular senescence following acute oxidative stress. Overexpression of PGC-1α in human myotubes increases the angiogenic potential of SkM-EVs. These angiogenic benefits coincided with increased anti-oxidative capacity of recipient HUVECs. High PGC-1α expression in skeletal muscle may prompt the release of SkM-EVs that support vascular redox homeostasis and angiogenesis.

The size of the satellite cell pool is reduced in estradiol (E2)-deficient female mice and humans. Here, we use a combination of in vivo and in vitro approaches to identify mechanisms, whereby E2 deficiency impairs satellite cell maintenance. By measuring satellite cell numbers in mice at several early time points postovariectomy (Ovx), we determine that satellite cell numbers decline by 33% between 10 and 14 days post-Ovx in tibialis anterior and gastrocnemius muscles. At 14 days post-Ovx, we demonstrate that satellite cells have a reduced propensity to transition from G0/G1 to S and G2/M phases, compared with cells from ovary-intact mice, associated with changes in two key satellite cell cycle regulators, ccna2 and p16INK4a. Further, freshly isolated satellite cells treated with E2 in vitro have 62% greater cell proliferation and require less time to complete the first division. Using clonal and differentiation assays, we measured 69% larger satellite cell colonies and enhanced satellite cell-derived myoblast differentiation with E2 treatment compared with vehicle-treated cells. Together, these results identify a novel mechanism for preservation of the satellite cell pool by E2 via promotion of satellite cell cycling.

What is the central question of this study? Is 1 week of exercise training sufficient to reduce local and systemic inflammation? Do obesity and short-term concurrent aerobic and resistance exercise training alter skeletal muscle extracellular vesicle (EV) contents? What is the main finding and its importance? Obesity alters skeletal muscle small EV microRNAs targeting inflammatory and growth pathways. Exercise training alters skeletal muscle small EV microRNAs targeting inflammatory pathways, indicative of reduced inflammation. Our findings provide support for the hypotheses that EVs play a vital role in intercellular communication during health and disease and that EVs mediate many of the beneficial effects of exercise.Obesity is associated with chronic inflammation characterized by increased levels of inflammatory cytokines, whereas exercise training reduces inflammation. Small extracellular vesicles (EVs; 30-150 nm) participate in cell-to-cell communication in part through microRNA (miRNA) post-transcriptional regulation of mRNA. We examined whether obesity and concurrent aerobic and resistance exercise training alter skeletal muscle EV miRNA content and inflammatory signalling. Vastus lateralis biopsies were obtained from sedentary individuals with (OB) and without obesity (LN). Before and after 7 days of concurrent aerobic and resistance training, muscle-derived small EV miRNAs and whole-muscle mRNAs were measured. Pathway analysis revealed that obesity alters small EV miRNAs that target inflammatory (SERPINF1, death receptor and Gα

Obesity is associated with numerous changes in skeletal muscle including greater muscle mass and muscle fiber cross sectional area (FCSA), yet fasted muscle protein synthesis is lower. Activation of the IGF-1/Akt/mTOR pathway is critical for muscle mass maintenance, muscle hypertrophy, and muscle protein regulation. Resistance exercise (RE) increases muscle mass, FCSA, and IGF-1. Persons with obesity have greater skeletal muscle mass and larger skeletal muscle fiber cross sectional area. The IGF-1/Akt/mTOR pathway is critical for the regulation of skeletal muscle mass. Our study found men and women with obesity have lower skeletal muscle IGF-1 mRNA and protein and higher expression of miR-206 an epigenetic regulator of IGF-1, at rest and following an acute bout of resistance exercise. Despite this, Akt mediated signaling was maintained and maintenance of phosphorylation does not appear to be accounted for by compensatory pathways. Our findings suggest a possible negative feedback mechanism via increased miR-206 and in turn decreased IGF-1 to limit further skeletal muscle hypertrophy in persons with obesity. The current work investigated if: (1) obesity dysregulates basal skeletal muscle IGF-1 pathways; and (2) obesity augments the muscle IGF-1 pathway responses to acute RE. Eight sedentary (no self-reported physical activity), lean (LN) and eight sedentary subjects with obesity (OB) had vastus lateralis biopsies taken at rest, and 15 min and 3 h post-acute RE for the measurement of the IGF-1 pathway and muscle FCSA. Type II FCSA was larger in OB vs. LN. Skeletal muscle IGF-1 mRNA and IGF-1 protein were lower in OB vs. LN at rest and post-exercise. Acute RE increased IGF-1 protein similarly in both groups. The expression of miR-206, a post-transcriptional inhibitor of IGF-1 expression, was higher in OB vs. LN and linked with lower IGF-1 mRNA (r = – 0.54). In spite of greater muscle FCSA, muscle IGF-1 expression was lower in obesity suggesting negative feedback may be limiting muscle mass expansion in obesity.

What is the central question of this study? Do obesity and acute resistance exercise alter the regulation of muscle intercellular communication pathways consistent with inadequate compensatory angiogenesis in response to muscle loading present in individuals with obesity? What is the main finding and its importance? Obesity is associated with differences in both pro- and anti-angiogenic signalling consistent with lower muscle capillarization. Acute resistance exercise increases the release of skeletal muscle small extracellular vesicles independent of body mass. These results identify new cellular factors associated with impaired angiogenesis in obesity and the positive effects of acute resistance exercise in lean and obese skeletal muscle.Obesity (OB) impairs cell-to-cell communication signalling. Small extracellular vesicles (EVs), which include exosomes, are released by skeletal muscle and participate in cell-to-cell communication, including the regulation of angiogenesis. Resistance exercise (REx) increases muscle fibre size and capillarization. Although obesity increases muscle fibre size, there is an inadequate increase in capillarization such that capillary density is reduced. It was hypothesized that REx-induced angiogenic signalling and EV biogenesis would be lower with obesity. Sedentary lean (LN) and OB subjects (n = 8 per group) performed three sets of single-leg knee-extension REx at 80% of maximum. Muscle biopsies were obtained at rest, 15 min and 3 h postexercise and analysed for angiogenic and EV biogenesis mRNA and protein. In OB subjects, muscle fibre size was ∼20% greater and capillary density with type II fibres ∼25% lower compared with LN subjects (P 0.001). In response to REx, the increase in VEGF mRNA (pro-angiogenic) was similar (3-fold) between groups, while thrombospondin-1 (TSP-1) mRNA (anti-angiogenic) increased ∼2.5-fold in OB subjects only (P = 0.010). miR-130a (pro-angiogenic) was ∼1.4-fold (P = 0.011) and miR-503 (anti-angiogenic) ∼1.8-fold (P = 0.017) greater in OB compared with LN subjects at all time points. In both groups, acute REx decreased the EV surface protein Alix by ∼50%, consistent with the release of exosomes (P = 0.016). Acute REx appears to induce the release of skeletal muscle small EVs independent of body mass. However, with obesity there is predominantly impaired angiogenic signalling, consistent with inadequate angiogenesis in response to basal muscle hypertrophy.

OBJECTIVE: Burnout is prevalent among vascular surgery trainees. Here we aim to identify modifiable risk factors for burnout in vascular surgery training, to facilitate the development of programs to enhance and sustain trainee well-being. METHODS: The Association of Program Directors in Vascular Surgery issued the Annual Training survey in the fall of 2018 to all trainees. The survey contained items to assess frequency of burnout, as well as mentorship, training environment, and stress coping mechanisms using an abbreviated COPE (Coping Orientation to Problems Experienced) inventory. RESULTS: Of 628 surveys issued, the response rate was 30% (n = 188). Respondents indicated that the majority of programs offer mentorship opportunities (n = 150 [83%]) that are longitudinal throughout the duration of training (n = 140 [77%]). Fifty-eight percent (n = 109) indicated there was an appropriate balance between learning and productivity in their program, with more respondents leaning toward too much clinical productivity (n = 57) and fewer toward too much learning (n = 19). Forty-five percent of respondents indicated feeling burnout at least weekly (n = 81). The burnout group was less likely to report an appropriate balance between clinical productivity and learning (49.4% vs 67.7%; P < .001), as well as a lower frequency of mentorship opportunities (72.1% vs 92.7%; P < .001). Certain coping skills were used more frequently in the burnout group, including self-distraction, disengagement, humor, self-blame, and substance use. In multivariate analysis, frequent use of self-blame conferred a 9.847-fold increased risk (95% confidence interval, 2.114–45.871) of burnout (P = .003), while feeling appropriately challenged by the faculty was significantly protective (odds ratio for burnout, 0.158; 95% confidence interval, 0.031–0.820; P = .03). CONCLUSIONS: The protective effect against vascular surgery trainee burnout conferred by the availability of mentorship suggests that an expansion and emphasis on mentorship in training may help to mitigate trainee burnout. Mentorship may also be a suitable channel to assess for an appropriate level of challenge, as well as for an appropriate balance between clinical productivity and learning that, when present, are also protective against burnout. Furthermore, the correlation between the frequent use of certain coping skills and burnout highlight this as an area for intervention, potentially through a combination of mentor modeling and formal training on healthy stress-related coping strategies.

AIM: Interventions that decrease atrophy during disuse are desperately needed to maintain muscle mass. We recently found that massage as a mechanotherapy can improve muscle regrowth following disuse atrophy. Therefore, we aimed to determine if massage has similar anabolic effects when applied during normal weight bearing conditions (WB) or during atrophy induced by hindlimb suspension (HS) in adult rats. METHODS: Adult (10 month) male Fischer344-Brown Norway rats underwent either hindlimb suspension (HS, n=8) or normal weight bearing (WB, n=8) for 7 days. Massage was applied using cyclic compressive loading (CCL) in WB (WBM, n=9) or HS rats (HSM, n=9) and included four 30-minute bouts of CCL applied to gastrocnemius muscle every other day. RESULTS: Massage had no effect on any anabolic parameter measured under WB conditions (WBM). In contrast, massage during HS (HSM) stimulated protein turnover, but did not mitigate muscle atrophy. Atrophy from HS was caused by both lowered protein synthesis and higher degradation. HS and HSM had lowered total RNA compared with WB and this was the result of significantly higher ribosome degradation in HS that was attenuated in HSM, without differences in ribosomal biogenesis. Also, massage increased protein turnover in the non-massaged contralateral limb during HS. Finally, we determined that total RNA degradation primarily dictates loss of muscle ribosomal content during disuse atrophy. CONCLUSION: We conclude that massage is an effective mechanotherapy to impact protein turnover during muscle disuse in both the massaged and non-massaged contralateral muscle, but it does not attenuate the loss of muscle mass.

Congenital abdominal wall defects are common anomalies which include gastroschisis, omphalocele and umbilical cord hernia. Recent reports indicate that gastroschisis is increasing in prevalence, whereas omphalocele has remained steady, suggesting that environmental factors may play a part in their pathogenesis. The aim of this study is to review animal teratogen studies resulting in abdominal wall defects to investigate their possible causes. Each report was examined not only for the teratogens causing the defects, but also to carefully identify the defect occurring and its correlation with the known clinical anomalies. We found many discrepancies between the nomenclature used by animal teratology investigators and that used by clinicians. We were able to confirm the induction of gastroschisis by 22 teratogens, omphalocele by 9 teratogens and umbilical cord hernia by 8. There is no doubt that environmental factors may be responsible, at least in part, for all three of the clinical abdominal wall defects. Future studies should take care to appreciate the differences between these anomalies and describe them in detail, so that accurate and meaningful conclusions can be obtained.

No abstract available.

Background The literature directly comparing the utility of clinical examination (CE) to that of CT in detecting recurrence of squamous cell carcinoma (SCC) for primary site recurrences is lacking. Methods Patients who received both CT scans and CEs after primary treatment for SCC of the upper aerodigestive tract (oropharynx, hypopharynx, and larynx) were identified. Individual CT scans and CEs were evaluated for their ability to detect recurrence status. Results One hundred thirty-one patients underwent a total of 886 CEs and 346 CT scans during the follow-up period. The sensitivity for CE and CT was 84.0% and 66.7%, respectively; for specificity, 98.7% and 90.7%, respectively; for positive predictive value, 65.6% and 31.8%, respectively; and for negative predictive value the values were 99.5% and 97.7%, respectively. Conclusion Due to the low sensitivity and positive predictive value of CT scans compared to physical examination in evaluating primary site tumor recurrences, the utility of CT for surveillance may be limited. © 2010 Wiley Periodicals, Inc. Head Neck, 2011

The role of a super-Alfv\'enic plasmoid instability in the onset of fast reconnection is studied by means of the largest Hall magnetohydrodynamics simulations to date, with system sizes up to $10^{4}$ ion skin depths ($d_{i}$). It is demonstrated that the plasmoid instability can facilitate the onset of rapid Hall reconnection, in a regime where the onset would otherwise be inaccessible because the Sweet-Parker width is significantly above $d_{i}$. However, the topology of Hall reconnection is not inevitably a single stable X-point. There exists an intermediate regime where the single X-point topology itself exhibits instability, causing the system to alternate between a single X-point geometry and an extended current sheet with multiple X-points produced by the plasmoid instability. Through a series of simulations with various system sizes relative to $d_{i}$, it is shown that system size affects the accessibility of the intermediate regime. The larger the system size is, the easier it is to realize the intermediate regime. Although our Hall MHD model lacks many important physical effects included in fully kinetic models, the fact that a single X-point geometry is not inevitable raises the interesting possibility for the first time that Hall MHD simulations may have the potential to realize reconnection with geometrical features similar to those seen in fully kinetic simulations, namely, extended current sheets and plasmoid formation., Comment: Accepted for publication in Physics of Plasmas

Object The vertebral artery (VA) and its branches may be encountered during various neurosurgical procedures such as far lateral suboccipital approaches to the skull base and spinal operations. Therefore, a working knowledge of the distribution and significance of such VA branches may be advantageous to the surgeon. To date, quantitation of these branches is lacking in the literature. Methods The authors evaluated the branches of 20 VAs from 10 adult cadavers and assessed the distribution and surgical significance of the branches from the V2 and V3 segments. Results In terms of target tissues, the VA branches encountered at the C1–2 level were most likely to be muscular, branches at C2–3 osseous, and those at C3–6 radicular. No radicular or medullary branches were identified arising from any V3 segment of the VA or C1–2 level of the V2 segment. The greatest concentration of branches per level was found arising from the V2 segment at C2–3. Posterior branches of the VA tended to be radicular or muscular, whereas anterior branches tended to be radicular or osseous. Lateral branches were most commonly radicular and medial branches tended to be osseous or muscular in nature. The largest branches of the VA originated from its V3 segment or the C2–3 part of its V2 segment. Rarely, branches to the extracranial glossopharyngeal and spinal accessory nerves were identified originating from the V3 and V2 segments of the VA, respectively. Conclusions Although seemingly diverse in their distribution, the branches of the V2 and V3 segments of the VA may follow a certain consistent arrangement. The potential for injury to neural branches of the VA is minimal at its V3 segment and the C1–2 portion of its V2 segment. Such knowledge may be of use to the neurosurgeon who operates in the neck and at the craniocervical junction.

Purpose Raman spectroscopy has distinguished malignant from normal tissues in several types of cancer. This is the first report of applying Raman spectroscopy to the diagnosis of Wilms' tumor. Methods Specimens of normal kidney, Wilms' tumor, xanthogranuloma, nephrogenic rests, and rhabdoid tumor were collected fresh from the operating room. Specimens of Wilms' tumor, normal kidney, and congenital mesoblastic nephroma were retrieved from the cryobank and thawed to room temperature. At least 12 Raman spectra were collected from each tissue sample. Histologic slides of each specimen were reviewed by pediatric pathologists. A computer algorithm based on discriminant function analysis (DFA) classified the Raman spectra of Wilms' tumor and the normal sample. Results Four hundred sixty-seven spectra were collected from 41 specimens. Using DFA, Raman spectroscopy differentiated Wilms' tumor from normal with 100% sensitivity and specificity and treated from untreated Wilms' tumor with 100% sensitivity and specificity. Using a DFA model built from cryopreserved specimens but applied to fresh Wilms' and normal samples, the sensitivity and specificity were 93.3% and 90.9%, respectively. Conclusion Raman spectroscopy is an accurate technique for differentiating Wilms' tumor from normal kidney and treated from untreated Wilms' tumor. It has potential to diagnose in minutes what currently takes several hours to days.

Recently testimony has been put forth in wrongful death cases as to the "value of life." Witnesses offering such testimony base their estimates of life’s value on various risk-tradeoff studies. However, the assumptions underlying the risktradeoff studies are open to question and also seem to be inconsistent with the requisites of standard jury instructions in wrongful death cases. The problems with such studies are made apparent by an examination of the assumptions, the overall study precision, the precision of the risk coefficient and a comparison to standard jury instruction.

Controversy has been raised regarding the cause of hysteresis, or bistability, of solutions to the equations that govern the geometry of the reconnection region in Hall magnetohydrodynamic (MHD) systems. This brief communication presents a comparison of the frameworks within which this controversy has arisen and illustrates that the Hall MHD hysteresis originally discovered numerically by Cassak et al. [Phys. Rev. Lett. 95, 235002 (2005)] is a different phenomenon from that recently reported by Zocco et al. [Phys. Plasmas 16, 110703 (2009)] on the basis of analysis and simulations in electron MHD with finite electron inertia. We demonstrate that the analytic prediction of hysteresis in EMHD does not describe or explain the hysteresis originally reported in Hall MHD, which is shown to persist even in the absence of electron inertia.

This paper presents linear analytical and numerical studies of plasmoid instabilities in the presence of shear flow in high-Lundquist-number plasmas. Analysis demonstrates that the stability problem becomes essentially two dimensional as the stabilizing effects of shear flow become more prominent. Scaling results are presented for the two-dimensional instabilities. An approximate criterion is given for the critical aspect ratio of thin current sheets at which the plasmoid instability is triggered.

This paper presents Sweet–Parker type scaling arguments in the context of hyper-resistive Hall magnetohydrodynamics. Numerical experiments suggest that both cusplike and modestly more extended geometries are realizable. However, the length of the electron dissipation region, which is taken as a parameter by several recent studies, is found to depend explicitly on the level of hyper-resistivity. Furthermore, although hyper-resistivity can produce more extended electron dissipation regions, the length of the region remains smaller than one ion skin depth for the largest values of hyper-resistivity considered here, significantly shorter than current sheets seen in many recent kinetic studies. The length of the electron dissipation region is found to depend on electron inertia as well, scaling like (me/mi)3/8. However, the thickness of the region appears to scale similarly, so that the aspect ratio is at most very weakly dependent on (me/mi).

This note is a Reply to Dr. Gilbert who criticizes our assertion that in value-of-life studies the proper measure of on-the-job death risk is by occupation, and that the failure of researchers to find evidence that death risk tabulated by occupation is an important determinant of wages implies that the value-of-life studies using death risk by industry are flawed. Dr. Gilbert challenges us to support empirically our assertion that prospective employees would focus more on death risk by occupation rather than death risk by industry. Our reply is based upon a review of data categorizing on-the-job deaths from the 1996 Census of Fatal Occupational Injuries. This data shows that deaths on the job are more likely to be associated with "what you do" rather than "where you do it".

This paper presents two-fluid simulations of forced magnetic reconnection with finite electron inertia in a collisionless three-dimensional (3D) cube with periodic boundaries in all three directions. Comparisons are made to analogous two-dimensional (2D) simulations. Reconnection in this system is driven by a spatially localized forcing function that is added to the ion momentum equation inside the computational domain. Consistent with previous results in similar, but larger forced 2D simulations [B. Sullivan, B. N. Rogers, and M. A. Shay, Phys. Plasmas 12, 122312 (2005)], for sufficiently strong forcing the reconnection process is found to become Alfvenic in both 2D and 3D, i.e., the inflow velocity scales roughly like some fraction of the Alfven speed based on the upstream reconnecting magnetic field, and the system takes on a stable configuration with a dissipation region aspect ratio on the order of 0.15.

Three mutant brome mosaic virus (BMV) RNA-2 transcripts bearing two alterations in the pseudoknot region and one in arm C of the 3′ tRNA region, previously characterized as being deficient in tRNA-like functions, have been assayed for their ability to infect and replicate (in the presence of wild-type RNAs-1 and -3) in Chenopodium hybridum plants. Although the introduced mutations have been shown to incapacitate the replication of RNA-2 in barley protoplasts, C. hybridum plants inoculated with these mutants developed local lesions indistinguishable in appearance and morphology from control inoculations containing wild-type RNA-2. Sequence analysis of progeny RNA-2 from two single lesion isolates for each mutant inoculum revealed that the input mutations were restored to functional sequences by homologous recombination within the 3′ tRNA-like region. These results, which reflect the ease with which progeny RNA can be characterized from single lesions, exemplify the value of C. hybridum for studying recombination among viral RNAs.

This paper presents two-fluid simulations of forced magnetic reconnection with finite electron inertia in a collisionless three-dimensional (3D) cube with periodic boundaries in all three directions. Comparisons are made to analogous two-dimensional (2D) simulations. Reconnection in this system is driven by a spatially localized forcing function that is added to the ion momentum equation inside the computational domain. Consistent with previous results in similar, but larger forced 2D simulations [B. Sullivan, B. N. Rogers, and M. A. Shay, Phys. Plasmas 12, 122312 (2005)], for sufficiently strong forcing the reconnection process is found to become Alfvenic in both 2D and 3D, i.e., the inflow velocity scales roughly like some fraction of the Alfven speed based on the upstream reconnecting magnetic field, and the system takes on a stable configuration with a dissipation region aspect ratio on the order of 0.15.

No abstract available.