Influence of muscle-belly and tendon gearing on the energy cost of human walking

This study combines metabolic and kinematic measurements at the whole-body level, with EMG and ultrasound measurements to investigate the influence of muscle-tendon mechanical behavior on the energy cost (Cnet) of walking (from 2 to 8 km·h−1). Belly gearing (Gb = Δmuscle-belly length/Δfascicles length) and tendon gearing (Gt = ∆muscle-tendon unit length/∆muscle-belly length) of vastus lateralis (VL) and gastrocnemius medialis (GM) were calculated based on ultrasound data. Pendular energy recovery (%R) was calculated based on kinematic data, whereas the cumulative activity per distance travelled (CMAPD) was calculated for the VL, GM, tibialis anterior, and biceps femoris as the ratio between their EMG activity and walking speed. Finally, total CAMPD (CMAPDTOT) was calculated as the sum of the CMAPD of all the investigate muscles. Cnet and CMAPDTOT showed a U-shaped behavior with a minimum at 4.2 and 4.1 km·h−1, respectively; while %R, VL, and GM belly gearing showed an opposite trend, reaching a maximum (60% ± 5%, 1.1 ± 0.1 and 1.5 ± 0.1, respectively), between 4.7 and 5 km·h−1. Gt was unaffected by speed in GM (3.5 ± 0.1) and decreased as a function of it in VL. A multiple stepwise linear regression indicated that %R has the greatest influence on Cnet, followed by CMAPDTOT and GM belly gearing. The role of Gb on Cnet could be attributed to its role in determining muscle work: when Gb increases, fascicles shortening decreases compared with that of the muscle-belly, thereby reducing the energy cost of contraction

Treatment of locally advanced and metastatic basosquamous carcinoma, navigating among sonic hedgehog pathway inhibitors, immune checkpoint inhibitors, chemotherapy, and radiotherapy: A case series and literature review

Locally advanced (laBSCs) and metastatic basosquamous carcinomas (mBSCs) represent a therapeutic challenge. By definition, these forms are not amenable to surgery or radiotherapy, but according to literature reports, sonic hedgehog pathway inhibitors (HHIs), anti-programmed death 1 receptor antibodies (anti-PD-1), and other treatment approaches involving chemotherapy, surgery, and radiotherapy have been used. This work features 5 real-life cases of advanced BSCs, treated at the Dermato-Oncology Unit of Trieste (Maggiore Hospital, University of Trieste). In addition, a review of the current treatment options reported in the literature for laBSC and mBSC is provided, collecting a total of 17 patients. According to these preliminary data, HHIs such as sonidegib and vismodegib could represent a safe and effective first line of treatment, while the anti-PD-1 cemiplimab may be useful as a second-line option. Chemotherapy and combined approaches involving surgery and radiotherapy have been also reported to be suitable in some patients

Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome

: The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species

Sled towing: the optimal overload for peak power production

Purpose: The effects of different loads on kinematic and kinetic variables during sled towing were investigated with the aim to identify the optimal overload for this specific sprint training. Methods: Thirteen male sprinters (100-m personal best: 10.91 \ub1 0.14 s) performed 5 maximal trials over a 20-m distance in the following conditions: unloaded and with loads from 15% to 40% of the athlete\u2019s body mass (BM). In these calculations the sled mass and friction were taken into account. Contact and flight times, stride length, horizontal hip velocity (vh), and relative angles of hip, knee, and ankle (at touchdown and takeoff) were measured step by step. In addition, the horizontal force (Fh) and power (Ph) and maximal force (Fh0) and power (Ph0) were calculated. Results: vh, flight time, and step length decreased while contact time increased with increasing load (P 30%BM joint angles tended to decrease. Conclusion: The 20%BM condition represents the optimal overload for peak power production at this load sprinters reach their highest power without significant changes in their running technique (eg, joint angles)

Mechanical advantage and joint function of the lower limb during hopping at different frequencies

Mechanical output at a joint level could be influenced by its leverage characteristics and by its functional behaviour and both could change to accommodate the demands of a given locomotor task. In this study, the mechanical power generated at the knee and ankle joints and their functional indexes (i.e. damper, strut, spring and motor like-function) were calculated by using 3D kinematic and kinetic data during hopping at 2, 2.5, 3 and 3.5 Hz. The effective mechanical advantage (i.e. the ratio between internal and external moment arm) of the knee (EMAK) and ankle (EMAA) and joint stiffness were calculated as well. Joint stiffness increased with frequency whereas positive and negative joint power decreased with it, the ankle power values being always larger (20-50%) than those at the knee. EMAA reached its highest value (0.4) during the propulsive phase at 3 Hz whereas no significant changes in EMAK were observed as a function of frequency in both the absorption and propulsive phases. Knee joint-functional index shifted from a spring to a strut-like function with increasing frequency (from 56 to 8% and from 4 to 51%, respectively) while the ankle operated mainly as a spring (from 90 to 53%), its damper and motor-like indexes being negligible at all frequencies (<5%). Therefore, in hopping, the knee works to dissipate mechanical energy (the combination of its damper and strut indexes increase from 23 to 72% at these frequencies) and the primary source of mechanical power is attributable to the elastic function of the ankle

Sprint running: how changes in step frequency affect running mechanics and leg spring behaviour at maximal speed

The purpose of this study was to investigate the changes in selected biomechanical variables in 80-m maximal sprint runs while imposing changes in step frequency (SF) and to investigate if these adaptations differ based on gender and training level. A total of 40 athletes (10 elite men and 10 women, 10 intermediate men and 10 women) participated in this study; they were requested to perform 5 trials at maximal running speed (RS): at the self-selected frequency (SFs) and at SF \ub115% and \ub130%SFs. Contact time (CT) and flight time (FT) as well as step length (SL) decreased with increasing SF, while kvert increased with it. At SFs, kleg was the lowest (a 20% decrease at \ub130%SFs), while RS was the largest (a 12% decrease at \ub130%SFs). Only small changes (1.5%) in maximal vertical force (Fmax) were observed as a function of SF, but maximum leg spring compression (\u394L) was largest at SFs and decreased by about 25% at \ub130%SFs. Significant differences in Fmax, \u394y, kleg and kvert were observed as a function of skill and gender (P\ua0<\ua00.001). Our results indicate that RS is optimised at SFs and that, while kvert follows the changes in SF, kleg is lowest at SFs

Achilles tendon mechanical properties during walking and running are underestimated when its curvature is not accounted for

Achilles tendon (AT) mechanical properties can be estimated using an inverse dynamic approach, taking into account the tendon internal moment arm (IMA) and its kinematic behavior. Although AT presents a curvilinear line of action, a straight-line function to estimate IMA and AT length is often utilized in the literature. In this study, we combined kinetic, kinematic and ultrasound data to understand the impact of two different approaches (straight-line vs. curvilinear) in determining AT mechanical properties in vivo (during walking and running at the self-selected speed). AT force and power were calculated based on data of AT IMA and AT length derived by both respective methods. All investigated parameters were significantly affected by the method utilized (paired t-test; p&nbsp;&lt;&nbsp;0.05): when using the curvilinear method IMA was about 5% lower and AT length about 1.2% higher, whereas peak and mean values of AT force and power were 5% higher when compared to the straight-line method (both in walking and running). Statistic-parametric mapping (SMP) analysis revealed significant differences in IMA during the early and the late stance phase of walking and during the late stance phase of running (p&nbsp;&lt;&nbsp;0.01); SPM revealed significant differences also in AT length during the entire stance phase in both locomotion modes (p&nbsp;&lt;&nbsp;0.01). These results confirm and extend previous findings to human locomotion: neglecting the AT curvature might be a source of error, resulting in underestimates not only of internal moment arm and tendon length, but also of tendon force and power

The influence of in-vivo mechanical behaviour of the Achilles tendon on the mechanics, energetics and apparent efficiency of bouncing gaits

In this study, we used kinematic, kinetic, metabolic and ultrasound analysis to investigate the role of elastic energy utilisation on the mechanical and physiological demands of a movement task that primarily involves the plantar-flexors muscles (hopping) to determine the contribution of tendon work to total mechanical work and its relationship with apparent efficiency (AE) in bouncing gaits. Metabolic power (PMET) and (positive) mechanical power at the whole-body level (PMEC) were measured during hopping at different frequencies (2, 2.5, 3 and 3.5 Hz). The (positive) mechanical power produced during the Achilles tendon recoil phase (PTEN) was obtained by integrating ultrasound data with an inverse dynamic approach. As a function of hopping frequency, PMEC decreased steadily and PMET exhibited a U-shape behaviour, with a minimum at about 3 Hz. AE (PMEC/PMET) showed an opposite trend and was maximal (about 0.50) at the same frequency when also PTEN was the highest. Positive correlations were observed: i) between PTEN and AE (AE=0.22+0.15.PTEN, R2=0.67, P&lt;0.001) and the intercept of this relationship indicates the value of AE that should be expected when tendon work is nil; ii) between AE and tendon gearing (Gt=DMTU length/Dmuscle belly length) (R2=0.50, P&lt;0.001), a high Gt indicates that the muscle is contracting more isometrically thus allowing the movement to be more economical (and efficient); iii) between Gt and PTEN (R2=0.73, P&lt;0.001) and this indicates that Gt could play an important role in the tendon's capability to store and release mechanical power

Muscle shape changes in Parkinson's disease impair function during rapid contractions

Aim: Parkinson's disease (PD) is a progressive neuro-degenerative disorder characterized, among the others, by muscle weakness: PD patients reach lower values of peak torque during maximal voluntary contractions but also slower rates of torque development (RTD) during explosive contractions. The aim of this study was to better understand how an impairment in structural/mechanical (peripheral) factors could explain the difficulty of PD patients to raise torque rapidly. Methods: Participants (PD patients and healthy matched controls) performed maximum voluntary explosive fixed-end contraction of the knee extensor muscles during which dynamic muscle shape changes (in muscle thickness, pennation angle and belly gearing: the ratio between muscle belly velocity and fascicle velocity), muscle-tendon unit (MTU) stiffness and EMG activity of the vastus lateralis (VL) were investigated. Both the affected (PDA) and less affected limb (PDNA) were investigated in patients. Results: Control participants reached higher values of peak torque and showed a better capacity to express force rapidly compared to patients (PDA and PDNA). EMG activity was observed to differ between patients (PDA) and controls but not between controls and PDNA: this suggests a specific neural/nervous effect on the most affected side. On the contrary, MTU stiffness and dynamic muscle shape changes were found to differ between controls and patients but not between PDA and PDNA: both sides are thus similarly affected by the pathology. Conclusion: The higher MTU stiffness in PD patients is likely responsible for the impaired muscle capability to change in shape which, in turn, negatively affect the torque rise