Neuromuscular Impairment Research Articles

Extensor digitorum brevis bulk and associations with fibular motor nerve conduction amplitude.

Prior work demonstrates that fibular compound motor action potential (CMAP) amplitude <4.0 mV predicts impairment of ankle proprioceptive precision and increased fall risk. Extensor digitorum brevis (EDB) inspection may present a simple clinical surrogate for CMAP amplitude. (1) To estimate the inter-rater reliability of assessment of EDB bulk. (2) To determine whether inspection of EDB bulk is associated with fibular CMAP amplitude. Prospective inter-rater reliability study. Academic center outpatient Physical Medicine & Rehabilitation electromyography (EMG) clinics. Fifty-two adult participants (102 feet). (1) Inter-rater reliability of assessment of EDB bulk. (2) Mean fibular CMAP amplitude. (3) A binary measure of fibular CMAP amplitude at/above or below a 4.0mV threshold. Inter-rater reliability of EDB bulk grading was moderate (kappa: 0.65 [95% confidence interval (CI) 0.48-0.82]). The mean CMAP value was 5.9 ± 2.2mV when bulk was normal, 3.4 ± 2.1mV when diminished, and 0.6 ± 0.9mV when atrophied. A multivariable analysis demonstrated that EDB bulk, distal symmetric polyneuropathy (DSP), and lumbar radiculopathy were all associated with CMAP amplitude. The sensitivity and specificity of grading muscle bulk as normal versus abnormal in detecting CMAP amplitude above or below 4.0mV were 0.86 (95% CI 0.78-0.94) and 0.71 (95% CI 0.54-0.88), respectively. An atrophied EDB was a highly specific indicator that CMAP amplitude was abnormal (<4.0mV) in 100% of cases (8/8). EDB bulk was associated with fibular CMAP amplitude. Atrophy was a highly specific indicator for CMAP amplitude below 4.0mV. Evaluation of EDB bulk may represent a quick and easy clinical surrogate marker for CMAP amplitude and distal neuromuscular impairment.

Stability threshold during seated balancing is sensitive to low back pain and safe to assess

Challenging trunk neuromuscular control maximally using a seated balancing task is useful for unmasking impairments that may go unnoticed with traditional postural sway measures and appears to be safe to assess in healthy individuals. This study investigates whether the stability threshold, reflecting the upper limits in trunk neuromuscular control, is sensitive to pain and disability and is safe to assess in low back pain (LBP) patients. Seventy-nine subjects with non-specific LBP balanced on a robotic seat while rotational stiffness was gradually reduced. The critical rotational stiffness, KCrit, that marked the transition between stable and unstable balance was used to quantify the individual’s stability threshold. The effects of current pain, 7-day average pain, and disability on KCrit were assessed, while controlling for age, sex, height, and weight. Adverse events (AEs) recorded at the end of the testing session were used to assess safety. Current pain and 7-day average pain were strongly associated with KCrit (current pain p < 0.001, 7-day pain p = 0.023), reflecting that people experiencing more pain have poorer trunk neuromuscular control. There was no evidence that disability was associated with KCrit, although the limited range in disability scores in subjects may have impacted the analysis. AEs were reported in 13 out of 79 total sessions (AE Severity: 12 mild, 1 moderate; AE Relatedness: 1 possibly, 11 probably, 1 definitely-related to the study). Stability threshold is sensitive to pain and appears safe to assess in people with LBP, suggesting it could be useful for identifying trunk neuromuscular impairments and guiding rehabilitation.

Lumbopelvic Stability and Trunk Muscle Contractility of Individuals with Chronic Ankle Instability.

BackgroundChronic ankle instability (CAI) results in hip neuromuscular impairments that can perpetuate dysfunction through reduced lumbopelvic stability and subsequent malpositioning of the lower body during functional movement. Lumbopelvic stability might be further impaired through changes in trunk muscular contractility. However, lumbopelvic stability and trunk muscle morphology have not been compared between individuals with and without CAI.PurposeTo compare lumbopelvic stability and trunk muscle contractility between individuals with and without chronic ankle instability (CAI) and determine if lumbopelvic stability and trunk muscle contractility are associated with self-reported function.Study DesignCase-control study.MethodsTen individuals with CAI, 10 ankle sprain copers (COP), and 10 healthy controls (CON) participated. Diagnostic ultrasound imaging was used to assess transversus abdominis (TrA) and lumbar multifidus (LM) muscle contractility. A percent change in contraction thickness from rested to contracted conditions was calculated for each muscle. Lumbopelvic stability was assessed using unilateral hip bridge, trunk flexion endurance, Biering-Sorensen, and side plank tests. Self-reported function was measured with the Foot and Ankle Ability Measure Activity of Daily Living (FAAM-ADL) and Sport (FAAM-S) subscales. One-way ANOVAs and Cohen’s d effect sizes compared scores on clinician and patient-reported outcomes between groups. Pearson product moment correlations analyzed associations between self-reported function and trunk muscle contractility and lumbopelvic stability. Significance was set a priori at P<0.05ResultsCOP had significantly greater TrA contractility than CAI (P<0.01, d=2.65[1.45,3.85]) and CON (P=0.03, d=1.05[0.08,1.94]). Although not statistically significant, a large effect size suggest that CAI had lower TrA contractility than CON (P=0.12, d=0.92[-0.03,1.80]). No differences existed for LM contractility or lumbopelvic stability tests. A moderate direct correlation (r=0.65, P=0.04) existed between CON’s TrA contractility and FAAM-ADL scores.ConclusionDeficits in TrA contractility are a novel finding among individuals with CAI. While LM contractility and lumbopelvic stability did not differ between groups, future research should continue to examine their relevance to CAI.Level of Evidence3b

Reliability and Validity of the Functional Movement Screen™ with a Modified Scoring System for Young Adults with Low Back Pain.

BackgroundLow back pain (LBP) is one of the most common complaints in individuals who seek medical care and is a leading cause of movement impairments. The Functional Movement Screen (FMS™) was developed to evaluate neuromuscular impairments during movement. However, the reliability and validity of the FMS™ have not yet been established for the LBP population because of a limitation of its original scoring system.PurposeThe purposes of this study were to determine the reliability and validity of the FMS™ with a modified scoring system in young adults with and without LBP. The FMS™ scores were modified by assigning a zero score only when there was an increase in LBP during the FMS™, not simply for the presence of pain, as in the original FMS™ scoring system.Study DesignReliability and validity study.MethodsTwenty-two participants with LBP (8 males and 14 females, 26.7 ± 4.68 years old) and 22 age- and gender-matched participants without LBP (26.64 ± 4.20 years old) completed the study. Each participant performed the FMS™ once while being scored simultaneously and independently by two investigators. In addition, each participant’s FMS™ performance was video-recorded and then was scored by another two investigators separately. The video-recorded performance also was scored twice six weeks apart by the same investigator to determine intra-rater reliability.ResultsThe results showed excellent inter-rater and intra-rater reliability of the FMS™ composite score with intraclass correlation coefficients ranging from 0.93 to 0.99 for both groups. In addition, the LBP group scored significantly lower than the group without LBP (p = 0.008).ConclusionsThe results indicate that the FMS™ is able to distinguish between individuals with and without LBP, and that it could be a useful test for clinicians to quantify movement quality and to assess movement restrictions in individuals with LBP.Levels of Evidence2b.

Limber tail syndrome in a Labrador Retriever with confirmed hypothyroidism

AbstractA 4‐year‐old, female, neutered Labrador Retriever was referred with tail flaccidity of acute onset after an extensive period of swimming. There were no other neuromuscular clinical signs on physical examination and no pain of tail palpation. Comorbidity was reported, with previous diagnosis of hypothyroidism (9 months before), but the disease was considered controlled since levothyroxine supplementation. Despite the impossibility to confirm nonrelated neuromuscular impairment associated with hypothyroidism, the fast resolution of clinical signs without intervention was more likely to confirm a limber tail syndrome rather than an endocrine neuromyopathy, but, to the authors' knowledge, this is the first report of its kind, and further investigations are required.

Effect of an inverted seated position with upper arm blood flow restriction on measures of elbow flexors neuromuscular performance.

PurposeThe objective of the investigation was to determine the concomitant effects of upper arm blood flow restriction (BFR) and inversion on elbow flexors neuromuscular responses.MethodsRandomly allocated, 13 volunteers performed four conditions in a within-subject design: rest (control, 1-min upright position without BFR), control (1-min upright with BFR), 1-min inverted (without BFR), and 1-min inverted with BFR. Evoked and voluntary contractile properties, before, during and after a 30-s maximum voluntary contraction (MVC) exercise intervention were examined as well as pain scale.ResultsInversion induced significant pre-exercise intervention decreases in elbow flexors MVC (21.1%, = 0.48, p = 0.02) and resting evoked twitch forces (29.4%, = 0.34, p = 0.03). The 30-s MVC induced significantly greater pre- to post-test decreases in potentiated twitch force ( = 0.61, p = 0.0009) during inversion (↓75%) than upright (↓65.3%) conditions. Overall, BFR decreased MVC force 4.8% ( = 0.37, p = 0.05). For upright position, BFR induced 21.0% reductions in M-wave amplitude ( = 0.44, p = 0.04). There were no significant differences for electromyographic activity or voluntary activation as measured with the interpolated twitch technique. For all conditions, there was a significant increase in pain scale between the 40–60 s intervals and post-30-s MVC (upright<inversion, and without BFR<BFR).ConclusionThe concomitant application of inversion with elbow flexors BFR only amplified neuromuscular performance impairments to a small degree. Individuals who execute forceful contractions when inverted or with BFR should be cognizant that force output may be impaired.

A reappraisal of the strength-duration test to assess neuromuscular impairment of critically ill patients

IntroductionNeuromuscular impairment (NMI) affects almost half of critically ill patients. The purpose was to investigate the role of neuromuscular electrical stimulation (NMES) to gain more insight into the nature of the NMI associated with ICU admission. To this aim, we analyzed the strength-duration (S-D) curves of the rectus femoris muscles of ICU patients compared to healthy volunteers. MethodsS-D curves were recorded from 44 healthy volunteers and 29 ICU patients. Three electrophysiological parameters were used to classify the neuromuscular function, from grade 0 (normal function), to grade 3 (no evocable muscle contraction). ICU patients underwent electroneurographic peroneal nerve testing (PENT) to analyze NMI by electroneurography (ENG). ResultsThree patients were classified as Grade 0; nine as mild NMI (Grade 1), 13 as Grade 2, and four showed unexcitable muscles (Grade 3). Mean CMAP amplitudes were 6.1, 3.4, 2.9 and 0.81 mV from Grade 0 to Grade 3, respectively. CMAP was inversely correlated to NMI grade (−1.7 mV, R2 = 0.946, p < 0.05). ConclusionsThe normative parameters of the S-D curves obtained by NMES in healthy volunteers allowed identification of NMI in ICU patients. NMES was an affordable tool to evaluate NMI in ICU patients, providing additional information to that obtained by ENG.

Towards an ankle-foot orthosis powered by a dielectric elastomer actuator

Foot drop is the inability to dorsiflex the ankle (raise the toes) due to neuromuscular impairment, and this common condition can cause trips and falls. Current treatments for chronic foot drop provide dorsiflexion support, but they either impede ankle push off or are not suitable for all patients. Powered ankle-foot orthosis (AFO) can counteract foot drop without these drawbacks, but they are heavy and bulky and have short battery life. To counteract foot drop without the drawbacks of current treatments or powered AFO, we designed and built an AFO powered by dielectric elastomer actuators (DEAs), a type of artificial muscle technology. This paper presents our design and the results of benchtop testing. We found that the DEA AFO can provide 49% of the dorsiflexion support necessary to raise the foot. Further, charging the DEAs reduced the effort that would be required for plantarflexion compared to that with passive DEA behavior, and this operation could be powered for 7000 steps or more in actual operation. DEAs are a promising approach for building an AFO that counteracts foot drop without impeding plantarflexion, and they may prove useful for other powered prosthesis and orthosis designs.

Time course of ventilatory failure in a novel rat model of Pompe Disease

Pompe disease (PD) is caused by mutations in the gene encoding the enzyme acid-α-glucosidase (GAA). Since GAA acts to degrade lysosomal glycogen, reduced or loss of enzyme activity leads to glycogen accumulation and neuromuscular impairments. Respiratory dysfunction and ventilator-dependence is common in both early- and late-onset PD. Our group has created a rat model of PD using Zinc Finger Nuclease (ZFN) technology. The goal of the current study was to characterize ventilation and metabolism in unrestrained ZFN Pompe rats using whole body plethysmography. Data were collected during a normoxic baseline period, acute exposures to hypoxia (FiO2=10.5%), hypercapnia (FiCO2=7%), and combined hypercapnic-hypoxic challenge intended to produce a maximal ventilatory drive. ZFN Pompe rats and age-matched, wild type (WT) controls were studied at age 3, 6, and 10-11 months to assess ventilation throughout disease progression. Both male and female 3 month old ZFN Pompe rats hyperventilated (greater VE/VCO2) due to greater tidal volume compared to WT rats. However, as the ZFN Pompe rats aged, the ventilatory phenotype changed such that by 10-11 months they showed significant hypoventilation as well as a blunted ability to increase ventilation in response to respiratory challenge relative to WT controls. Histological data from these rats, as well as prior data from the Gaa-/- mouse model of PD, show that respiratory neuromuscular pathology is present at a very young age. Accordingly, the current ventilatory data suggest that animals with PD initially increase breathing in response to the onset of pathology, possibly representing a period of “overcompensation”. However, this is followed by respiratory failure as the respiratory neuromuscular pathology progresses towards disease end-stage.

Optogenetic diaphragm muscle activation in mice

Breathing impairments are the leading cause of morbidity and mortality across all forms of neuromuscular disease. When voluntarily diaphragm activation is insufficient, clinical options include mechanical ventilation or electrical stimulation via intramuscular wires. Here we tested the hypothesis that an optogenetic approach would enable light to serve as an adequate stimulus for inducing diaphragm contraction to sustain breathing during neuromuscular impairments. Wild type, C57/bl6 mice (n=10) received an intrapleural injection of an adeno-associated virus (AAV) construct containing the transgene for the light activated ion channel channelrhodopsin-2 (34 µl, AAV9-ACAGW-ChR2-mVenus, titer: 1.8x1013 vg/ml). After allowing 8-10 weeks for transgene expression, electromyography (EMG) and pneumotachography were measured during spontaneous breathing under isoflurane anesthesia. To test optogenetic activation, a high-power, 472 nm, micro-LED was directed at the inferior diaphragm surface. Stimulus pulse durations (PD) ranging from 0.1-1.0 ms and interpulse intervals (IPI) of 0.1, 0.5, 1.0, and 5.0 ms were tested. Directing light at the diaphragm evoked clearly discernable EMG activity in 10 of 10 animals treated with the AAV9 vector. The 5 ms IPI induced the largest EMG activation, occurring at a level comparable to endogenous diaphragm bursts. Stimulation with a 0.1 ms PD / 0.1 ms IPI, and 1 ms PD / 5 ms IPI both were able to generate robust increases in respiratory airflow. Optogenetic stimulation was repeated following an acute unilateral phrenic nerve section which abolished ipsilateral diaphragm EMG. The contralateral diaphragm inspiratory EMG signal was then used to “trigger” the light stimulation of the paralyzed hemi-diaphragm. This procedure enabled a robust, bilateral diaphragm activation in all mice that received the unilateral phrenicotomy (n= 5). Histology confirmed robust expression of mVenus in diaphragm myofibers in mice treated with the vector. Directing light at the diaphragm of non-AAV treated control mice caused no discernible impact on diaphragm EMG activity (n=2). We conclude that intrapleural AAV9-ACAGW-ChR2-mVenus injection effectively drives transgene expression in the diaphragm, and this approach can be used to enable robust optogenetic activation of this critically important respiratory muscle. To our knowledge, this is the first demonstration of light activation of the diaphragm, and this success opens up new directions for therapeutic targeting of diaphragm paralysis and respiratory insufficiency.

Neuromuscular mechanisms that contribute to gross motor performance in survivors of childhood acute lymphoblastic leukemia.

This study explored neuromuscular mechanisms and clinical measures that contribute to countermovement jump performance in survivors of childhood acute lymphoblastic leukemia (ALL CCS) compared to age- and sex-matched peers. This exploratory cross-sectional observational study examined 12 participants, six ALL CCS and six age- and sex-matched peers (7-16 years). During a countermovement jump, rates of muscle activation of lower leg muscles were measured with electromyography, and joint torques and peak jump height with force plates and a motion capture system. Clinical measures included muscle extensibility, balance, and mobility measured by active ankle dorsiflexion, Bruininks-Oseretsky Motor Proficiency (BOT-2), and Timed Up and Go (TUG) tests. Compared to peers, ALL CCS demonstrated reduced gastrocnemius muscle extensibility and tibialis anterior rate of muscle activation, decreased jump height, and poorer performance on the BOT-2 and TUG. Jump height was significantly correlated with clinical measures of the BOT-2 and TUG. These ALL CCS demonstrated neuromuscular impairments that may impact jump performance, an essential childhood physical activity. Further research is needed to explore intervention strategies to improve the neuromuscular mechanisms that contribute to high-level gross motor skills in ALL CCS.

Effect of iliopsoas muscle tightness on electromyographic activity of hip extensor synergists during gait

Background: Hip flexor muscles' tightness has been considered as one of the main risk factors for neuromuscular impairment of lower extremities not only lead to change the movement patterns but also probably result in changing the neuromuscular features of other muscles. The purpose of this research is study was to evaluate the iliopsoas tightness’ effect on electromyographic activity of hip extensor synergists during gait. Methods: In this case-control study fifteen 11-14 years old adolescents with iliopsoas tightness as experimental group, and 15 healthy adolescents which matched based on age, height, weight, body mass index, dominant leg and sport experience participated voluntarily as control group. Surface electromyographic activity of the gluteus maximus, adductor magnus and biceps femoris, were measured between groups during stance phase of gait. Results: Individuals with restricted hip flexor muscle length demonstrated more gluteus maximus activation during terminal stance (p=.001), more biceps femoris activation during mid stance (p=.002) and late stance (p=.001) and more adductor magnus activation during mid stance (p=.04) and late stance (p=.001). Conclusion: Adolescent soccer athletes with hip flexor muscle tightness exhibit more biceps femoris and adductor magnus and gluteus maximus activation during stance phase of gait. Thus, individuals with hip flexor muscle tightness appear to utilize different neuromuscular strategies to control lower extremity motion.

A comparison of leg stiffness in running between typically developing children and children with cerebral palsy

BackgroundLeg stiffness is important during running to increase velocity and maximise efficiency by facilitating use of the stretch-shortening cycle. Children with cerebral palsy who have neuromuscular impairments may have altered leg stiffness. The aim of this study was to describe leg stiffness during running in typically developing children and those with cerebral palsy in Gross Motor Function Classification Scale levels I and II at a range of speeds. MethodsThis cross-sectional study examined kinematic data collected from typically developing children (n = 21) and children with cerebral palsy (Gross Motor Function Classification Scale level I n = 25, Gross Motor Function Classification Scale level II n = 13) during jogging, running and sprinting. Derived variables were resultant ground reaction force, change in leg length and three-dimensional leg stiffness. Linear mixed models were developed for statistical analysis. FindingsChildren with cerebral palsy had reduced stiffness when jogging (Gross Motor Function Classification Scale level I affected t = 3.81 p < 0.01; non-affected t = 2.19 p = 0.03; Gross Motor Function Classification Scale level II affected t = 2.04 p = 0.04) and running (Gross Motor Function Classification Scale level I affected t = 3.23 p < 0.01) compared to typically developing children. Affected legs were less stiff than non-affected legs only in Gross Motor Function Classification Scale level I during running (t = 2.26 p = 0.03) and sprinting (t = 2.95 p < 0.01). InterpretationChildren with cerebral palsy have atypical leg stiffness profiles which differ according to functional classification.

Meaningful measurements of maneuvers: People with incomplete spinal cord injury \u2018step up\u2019 to the challenges of altered stability requirements

BackgroundMany people with incomplete spinal cord injury (iSCI) have the ability to maneuver while walking. However, neuromuscular impairments create challenges to maintain stability. How people with iSCI maintain stability during walking maneuvers is poorly understood. Thus, this study compares maneuver performance in varying external conditions between persons with and without iSCI to better understand maneuver stabilization strategies in people with iSCI.MethodsParticipants with and without iSCI walked on a wide treadmill and were prompted to perform lateral maneuvers between bouts of straight walking. Lateral force fields applied to the participants’ center of mass amplified or attenuated the participants’ movements, thereby increasing the capability of the study to capture behavior at varied levels of challenge to stability.ResultsBy examining metrics of stability, step width, and center of mass dynamics, distinct strategies emerged following iSCI. The minimum margin of stability (MOSmin) on each step during maneuvers indicated persons with iSCI generally adapted to amplified and attenuated force fields with increased stability compared to persons without iSCI, particularly using increased step width and reduced center of mass excursion on maneuver initiation. In the amplified field, however, persons with iSCI had a reduced MOSmin when terminating a maneuver, likely due to the challenge of the force field opposing the necessary lateral braking. Persons without iSCI were more likely to rely on or oppose the force field when appropriate for movement execution. Compared to persons with iSCI, they reduced their MOSmin to initiate maneuvers in the attenuated and amplified fields and increased their MOSmin to arrest maneuvers in the amplified field.ConclusionsThe different force fields were successful in identifying relatively subtle strategy differences between persons with and without iSCI. Specifically, persons with iSCI adopted increased step width and reduction in center of mass excursion to increase maneuver stability in the amplified field. The amplified field may provoke practice of stable and efficient initiation and arrest of walking maneuvers. Overall, this work allows better framing of the stability mechanisms used following iSCI to perform walking maneuvers.

Exercise intervention protocol in children and young adults with cerebral palsy: the effects of strength, flexibility and gait training on physical performance, neuromuscular mechanisms and cardiometabolic risk factors (EXECP)

BackgroundIndividuals with cerebral palsy (CP) have problems in everyday tasks such as walking and climbing stairs due to a combination of neuromuscular impairments such as spasticity, muscle weakness, reduced joint flexibility and poor coordination. Development of evidence-based interventions are in pivotal role in the development of better targeted rehabilitation of CP, and thus in maintaining their motor function and wellbeing. Our aim is to investigate the efficacy of an individually tailored, multifaceted exercise intervention (EXECP) in children and young adults with CP. EXECP is composed of strength, flexibility and gait training. Furthermore, this study aims to verify the short-term retention of the adaptations three months after the end of the EXECP intervention.MethodsTwenty-four children and young adults with spastic CP will be recruited to participate in a 9-month research project with a 3-month training intervention, consisting of two to three 90-min sessions per week. In each session, strength training for the lower limbs and trunk muscles, flexibility training for the lower limbs and inclined treadmill gait training will be performed. We will evaluate muscle strength, joint flexibility, neuromuscular and cardiometabolic parameters. A nonconcurrent multiple baseline design with two pre-tests and two post-tests all interspaced by three months is used. In addition to the CP participants, 24 typically developing age and sex-matched participants will perform the two pre-tests (i.e. no intervention) to provide normative data.DiscussionThis study has a comprehensive approach examining longitudinal effects of wide variety of variables ranging from physical activity and gross motor function to sensorimotor functions of the brain and neuromuscular and cardiometabolic parameters, providing novel information about the adaptation mechanisms in cerebral palsy. To the best of our knowledge, this is the first intervention study providing supervised combined strength, flexibility and gait training for young individuals with CP.Trial registration numberISRCTN69044459, prospectively registered (21/04/2017).

Identification of protein quality control regulators using a Drosophila model of TPI deficiency

Triosephosphate isomerase (TPI) deficiency (Df) is a rare recessive metabolic disorder that manifests as hemolytic anemia, locomotor impairment, and progressive neurodegeneration. Research suggests that TPI Df mutations, including the “common” TPIE105Dmutation, result in reduced TPI protein stability that appears to underlie disease pathogenesis. Drosophila with the recessive TPIsugarkill allele (a.k.a. sgk or M81T) exhibit progressive locomotor impairment, neuromuscular impairment and reduced longevity, modeling the human disorder. TPIsugarkill produces a functional protein that is degraded by the proteasome. Molecular chaperones, such as Hsp70 and Hsp90, have been shown to contribute to the regulation of TPIsugarkill degradation. In addition, stabilizing the mutant protein through chaperone modulation results in improved TPI deficiency phenotypes. To identify additional regulators of TPIsugarkill degradation, we performed a genome-wide RNAi screen that targeted known and predicted quality control proteins in the cell to identify novel factors that modulate TPIsugarkill turnover. Of the 430 proteins screened, 25 regulators of TPIsugarkill were identified. Interestingly, 10 proteins identified were novel, previously undescribed Drosophila proteins. Proteins involved in co-translational protein quality control and ribosome function were also isolated in the screen, suggesting that TPIsugarkill may undergo co-translational selection for polyubiquitination and proteasomal degradation as a nascent polypeptide. The proteins identified in this study may reveal novel pathways for the degradation of a functional, cytosolic protein by the ubiquitin proteasome system and define therapeutic pathways for TPI Df and other biomedically important diseases.

Structural and functional impact of clinically relevant E1α variants causing pyruvate dehydrogenase complex deficiency

Pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate to acetyl-coenzyme A, hinging glycolysis and the tricarboxylic acid cycle. PDC deficiency, an inborn error of metabolism, has a broad phenotypic spectrum. Symptoms range from fatal lactic acidosis or progressive neuromuscular impairment in the neonatal period, to chronic neurodegeneration. Most disease-causing mutations in PDC deficiency affect the PDHA1 gene, encoding the α subunit of the PDC-E1 component. Detailed biophysical analysis of pathogenic protein variants is a challenging approach to support the design of therapies based on improving and correcting protein structure and function. Herein, we report the characterization of clinically relevant PDC-E1α variants identified in Portuguese PDC deficient patients. These variants bear amino acid substitutions in different structural regions of PDC-E1α. The structural and functional analyses of recombinant heterotetrameric (αα’ββ’) PDC-E1 variants, combined with molecular dynamics (MD) simulations, show a limited impact of the amino acid changes on the conformational stability, apart from the increased propensity for aggregation of the p.R253G variant as compared to wild-type PDC-E1. However, all variants presented a functional impairment in terms of lower residual PDC-E1 enzymatic activity and ≈3–100 × lower affinity for the thiamine pyrophosphate (TPP) cofactor, in comparison with wild-type PDC-E1. MD simulations neatly showed generally decreased stability (increased flexibility) of all variants with respect to the WT heterotetramer, particularly in the TPP binding region. These results are discussed in light of disease severity of the patients bearing such mutations and highlight the difficulty of developing chaperone-based therapies for PDC deficiency.

The Effects of Electrical Stimulation on Gross Motor Function in Children with Spastic Cerebral Palsy: A Review Article

Cerebral Palsy (CP) is the most common childhood disability in children. The child’s motor development and functioning are affected by variety neuromuscular and musculoskeletal impairments. Both of upper and lower extremities motor function are important for many daily life activities. For example, children who has good fine motor function and who can sitting independently can manipulate the objects by using upper extremities and can realize transfer activities. Therefore, she/he can play effectively in daily life. Children who can play will be happy and independent in daily life activities. Spasticity is the most common problem in children with CP and can interfere with daily life activities. Children who have spastic CP constrained in daily life activity, participation and recreational activities. Working on gross motor skills helps to gain strength, increase postural control, to achieve motor milestones and to become independent in daily life activities. In treatment program, physical therapist used different approach, like, exercise programs (stretching, strengthening, aerobic exercise…), electrical stimulation, neurodevelopmental approaches, virtual reality, constrained induced movement therapy. Neuromuscular Electrical Stimulation, Functional Electrical Stimulation and Threshold Electrical Stimulation commonly used for this reason. There is a few evidence on positive effects of electrical stimulation applied in children with CP. This review study was planned to investigate the effects of electrical stimulation on gross motor function in children with CP.

COVID-19-related nationwide lockdown did not reduce the reported diagnoses of Chlamydia trachomatis and Neisseria gonorrhoeae in Finland

<h3>Abstract</h3> <h3>Objective</h3> To characterize the clinical features of children and adolescents hospitalized with SARS-CoV-2 infections and to explore predictors for disease severity. <h3>Design</h3> Nationwide prospective observational cohort study. <h3>Setting</h3> Data...

Narrative review of glycogen storage disorder type III with a focus on neuromuscular, cardiac and therapeutic aspects.

Glycogen storage disorder type III (GSDIII) is a rare inborn error of metabolism due to loss of glycogen debranching enzyme activity, causing inability to fully mobilize glycogen stores and its consequent accumulation in various tissues, notably liver, cardiac and skeletal muscle. In the pediatric population, it classically presents as hepatomegaly with or without ketotic hypoglycemia and failure to thrive. In the adult population, it should also be considered in the differential diagnosis of left ventricular hypertrophy or hypertrophic cardiomyopathy, myopathy, exercise intolerance, as well as liver cirrhosis or fibrosis with subsequent liver failure. In this review article, we first present an overview of the biochemical and clinical aspects of GSDIII. We then focus on the recent findings regarding cardiac and neuromuscular impairment associated with the disease. We review new insights into the pathophysiology and clinical picture of this disorder, including symptomatology, imaging and electrophysiology. Finally, we discuss current and upcoming treatment strategies such as gene therapy aimed at the replacement of the malfunctioning enzyme to provide a stable and long-term therapeutic option for this debilitating disease.