Key changes in denervated muscles and their impact on regeneration and reinnervation

The neuromuscular junction becomes progressively less receptive to regenerating axons if nerve repair is delayed for a long period of time. It is difficult to ascertain the denervated muscle＇s residual receptivity by time alone. Other sensitive markers that closely correlate with the extent of denervation should be found. After a denervated muscle develops a fibrillation potential, muscle fiber conduction velocity, muscle fiber diameter, muscle wet weight, and maximal isometric force all decrease; remodeling increases neuromuscular junction fragmentation and plantar area, and expression of myogenesis-related genes is initially up-regulated and then down-regulated. All these changes correlate with both the time course and degree of denervation. The nature and time course of these denervation changes in muscle are reviewed from the literature to explore their roles in assessing both the degree of detrimental changes and the potential success of a nerve repair. Fibrillation potential amplitude, muscle fiber conduction velocity, muscle fiber diameter, mRNA expression levels of myogenic regulatory factors and nicotinic acetylcholine receptor could all reflect the severity and length of denervation and the receptiveness of denervated muscle to regenerating axons, which could possibly offer an important clue for surgical choices and predict the outcomes of delayed nerve repair.     

Evaluating cardiac substructure radiation exposure in breast rotational intensity modulated radiation therapy: Effects of cancer laterality,fractionation and deep inspiration breath-hold

PurposeRotational intensity-modulated radiation therapy currently has a growing role in breast cancer radiation therapy, since this radiation technique reduces cardiac radiation exposure while homogeneously covering target volumes. This study aims to evaluate radiation exposure of cardiac substructures across a broad spectrum of breast cancer cases differing by cancer laterality, fractionation regimen and addition of deep-inspiration breath hold.Materials and methodsCardiac substructures were delineated following guidelines endorsed by the European Society for Radiotherapy and Oncology (ESTRO) for forty-four breast cancer patients having undergone conserving surgery and adjuvant rotational intensity-modulated radiation therapy. Target volumes consisted of the whole breast with a boost, axillary and internal mammary nodes. Patients were treated using free-breathing technique for left-sided or right-sided, normofractionated or hypofractionated helical tomotherapy or volumetric modulated arc therapy, or using deep-inspiration breath hold for left-sided normofractionated volumetric modulated arc therapy. Mean and maximum doses to cardiac substructures were retrieved. Correlations were performed between mean- and maximum radiation doses to cardiac substructures.ResultsLeft-sided and right-sided irradiations were associated with different cardiac substructure exposure patterns despite comparable mean heart dose: 7.21 Gy for left-sided normofractionated regimen, 6.28 Gy for right-sided normofractionated regimen. Deep-inspiration breath hold reduced mean doses to almost all cardiac substructures for left-sided irradiation, but did not decrease maximum doses to coronary arteries. Correlations between mean- and maximum doses to cardiac substructures were usually moderate, but stronger for right-sided irradiation.ConclusionDespite comparable mean heart dose, cardiac substructure radiation exposure patterns with rotational intensity-modulated radiation therapy strongly depend on the breast side, which could trigger clinically different long-term cardiotoxicity events. Deep-inspiration breath hold improves cardiac substructure dosimetry. Mean- and maximum heart dose could probably not be used as surrogate markers for precise cardiac substructure evaluation. In a near future, clinical practice and cardiotoxicity studies could possibly gain by considering cardiac substructure in a more systematic manner, possibly relying on cardiac autosegmentation algorithms.     

Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.     

Cortical mechanisms underlying variability in intermittent theta-burst stimulation-induced plasticity: A TMS-EEG study

ObjectiveTo test the hypothesis that intermittent theta burst stimulation (iTBS) variability depends on the ability to engage specific neurons in the primary motor cortex (M1).MethodsIn a sham-controlled interventional study on 31 healthy volunteers, we used concomitant transcranial magnetic stimulation (TMS) and electroencephalography (EEG). We compared baseline motor evoked potentials (MEPs), M1 iTBS-evoked EEG oscillations, and resting-state EEG (rsEEG) between subjects who did and did not show MEP facilitation following iTBS. We also investigated whether baseline MEP and iTBS-evoked EEG oscillations could explain inter and intraindividual variability in iTBS aftereffects.ResultsThe facilitation group had smaller baseline MEPs than the no-facilitation group and showed more iTBS-evoked EEG oscillation synchronization in the alpha and beta frequency bands. Resting-state EEG power was similar between groups and iTBS had a similar non-significant effect on rsEEG in both groups. Baseline MEP amplitude and beta iTBS-evoked EEG oscillation power explained both inter and intraindividual variability in MEP modulation following iTBS.ConclusionsThe results show that variability in iTBS-associated plasticity depends on baseline corticospinal excitability and on the ability of iTBS to engage M1 beta oscillations.SignificanceThese observations can be used to optimize iTBS investigational and therapeutic applications.     

Consistency of strength curves for determining maximal effort production during isokinetic knee testing of anterior cruciate ligament-deficient patients

The purpose of this investigation was to attempt to establish decision rules for determining maximal effort production during isokinetic strength testing of unilateral anterior cruciate ligament-deficient patients based on the degree of strength curve consistency within a set. Thirty-three participants performed six bilateral knee extension and flexion exertions at maximal effort and at 80% of perceived maximum at testing velocities of 60 and 180°s^–1. Within-set consistency was quantified by computation of the variance ratio across strength curves. Tolerance interval-based cutoff scores covering 99% of the population were calculated for declaring efforts as being maximal or not at confidence levels of 90%, 95%, and 99%. The sensitivity percentages attained for the injured knee for both testing velocities ranged between 9.1% and 27.2%, while specificity percentages ranged between 84.8% and 100%. For the non-injured knee, sensitivity values for both testing velocities ranged between 21.2% and 45.0%, while specificity percentages ranged between 97.0% and 100%. The developed decision rules do not effectively discriminate on an individual patient basis between maximal and non-maximal isokinetic knee musculature efforts. Further research is needed for development of methods that would enable to ascertain maximal effort production in this patient population during knee muscle strength testing.     

Effects of Classic Progressive Resistance Training Versus Eccentric-Enhanced Resistance Training in People With Multiple Sclerosis

Objective

To compare the effects of classic progressive resistance training (PRT) versus eccentric strength-enhanced training (EST) on the performance of functional tests and different strength manifestations in the lower limb of people with multiple sclerosis (PwMS).

Monitoring recovery from diaphragm paralysis with ultrasound

BACKGROUND: Diaphragmatic paralysis is an uncommon, yet underdiagnosed cause of dyspnea. Data regarding the time course and potential for recovery has come from a few small case series. The methods that have been traditionally employed to diagnose diaphragmatic weakness or paralysis are either invasive or limited in sensitivity and specificity. A new technique utilizing two-dimensional, B-mode ultrasound (US) measurements of diaphragm muscle thickening during inspiration (Deltatdi%) has been validated in the diagnosis of diaphragm paralysis (DP). The purpose of this study was to assess whether serial US evaluation might be utilized to monitor the potential recovery of diaphragm function. METHODS: Twenty-one consecutive patients with clinically suspected DP were referred to the pulmonary physiology laboratory. Sixteen patients were found to have DP by US (unilateral, 10 patients; bilateral, 6 patients). Subjects were followed up for up to 60 months. On initial and subsequent visits, Deltatdi% was measured by US. Additional measurements included upright and supine vital capacity (VC), maximal inspiratory pressure (Pimax), and maximal expiratory pressure. RESULTS: Eleven of 16 patients functionally recovered from DP. The mean (+/- SD) recovery time was 14.9 +/- 6.1 months. No diaphragm thickening was noted in those patients who did not recover. Positive correlations were found between improvement in Deltatdi% and interval changes in VC, Pimax, and end-expiratory measurements of diaphragm thickness. CONCLUSIONS: US may be used to assess for potential functional recovery from diaphragm weakness or DP. As in previous series, recovery occurs in a substantial number of individuals, but recovery time may be prolonged.     

Diffuse Myocardial Fibrosis and Diastolic Function in Aortic Stenosis

ObjectivesThe aim of this study was to investigate the relationship between extracellular volume fraction (ECV), a noninvasive parameter that quantifies the degree of diffuse myocardial fibrosis on cardiac magnetic resonance (CMR), and left ventricular diastolic dysfunction (LVDD) in patients with aortic stenosis (AS).BackgroundMyocardial fibrosis on invasive myocardial biopsy is associated with LVDD. However, there is a paucity of data on the association between noninvasively quantified diffuse myocardial fibrosis and the degree of LVDD and how these are related to symptoms and long-term prognosis in patients with AS.MethodsPatients with moderate or severe AS (n = 191; mean age 68.4 years) and 30 control subjects without cardiovascular risk factors underwent CMR. LVDD grade was evaluated using echocardiography according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. Clinical outcomes were defined as a composite of all-cause mortality or hospitalization for heart failure aggravation.ResultsPatients in higher ECV quintiles had a significantly higher prevalence of LVDD. Higher ECV was particularly associated with decreased myocardial relaxation (septal e′ <7 cm/s) and increased LV filling pressure (E/e′ ratio ≥15). Although both impaired diastolic function and higher ECV were significantly associated with a worse degree of dyspnea, patients with higher ECV showed greater dyspnea within the same grade of LVDD. During a median follow-up period of 5.6 years, 37 clinical events occurred. Increased ECV, as well as lower septal e′ and higher E/septal e′ ratio, were independent predictors of clinical events, irrespective of age, AS severity, aortic valve replacement, and left ventricular (LV) ejection fraction. ECV provided incremental prognostic value on top of clinical factors and LV systolic and diastolic function.ConclusionsDiffuse myocardial fibrosis, assessed using ECV on CMR, was associated with LVDD in patients with AS, but both ECV and LV diastolic function parameters provided a complementary explanation for dyspnea and clinical outcomes. Concomitant assessment of both LVDD and diffuse myocardial fibrosis may further identify patients with AS with greater symptoms and worse prognosis.