Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independently of pathophysiological changes

BackgroundMyotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardiorespiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown.MethodsEleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12 weeks of cycling can recuperate clinical and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients.RESULTSDM1 was associated with impaired muscle function, fitness, and lung capacity. Cycling evoked several clinical, physical, and metabolic advantages in DM1 patients. We highlight that exercise-induced molecular and cellular alterations in patients do not conform with previously published data in murine models and propose a significant role of mitochondrial function in DM1 pathology. Finally, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity.ConclusionWith no available cures, our data support the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1. Additionally, we provide evidence for the involvement of snoRNAs and other noncoding RNAs in DM1 pathophysiology.Trial registrationThis trial was approved by the HiREB committee (no. 7901) and registered under ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT04187482","term_id":"NCT04187482"}}NCT04187482).FundingNeil and Leanne Petroff. Canadian Institutes of Health Research Foundation (no. 143325).     

Rational design of large flat nitrogen-doped graphene oxide quantum dots with green-luminescence suitable for biomedical applications

Rational synthesis and simple methodology for the purification of large (35–45 nm in lateral size) and flat (1.0–1.5 nm of height) nitrogen-doped graphene oxide quantum dots (GOQDs) are presented. The methodology allows robust metal-free and acid-free preparation of N-GOQDs with a yield of about 100% and includes hydrothermal treatment of graphene oxide with hydrogen peroxide and ammonia. It was demonstrated that macroscopic impurities can be separated from N-GOQD suspension by their coagulation with 0.9% NaCl solution. Redispersible in water and saline solutions, particles of N-GOQDs were characterized using tip-enhanced Raman spectroscopy (TERS), photoluminescent, XPS, and UV-VIS spectroscopies. The size and morphology of N-GOQDs were studied by dynamic light scattering, AFM, SEM, and TEM. The procedure proposed allows nitrogen-doped GOQDs to be obtained, having 60–51% of carbon, 34–45% of oxygen, and up to 7.2% of nitrogen. The N-GOQD particles obtained in two hours of synthesis contain only pyrrolic defects of the graphene core. The fraction of pyridine moieties grows with the time of synthesis, while the fraction of quaternary nitrogen declines. Application of TERS allows demonstration that the N-GOQDs consist of a graphene core with an average crystallite size of 9 nm and an average distance between nearest defects smaller than 3 nm. The cytotoxicity tests reveal high viability of the monkey epithelial kidney cells Vero in the presence of N-GOQDs in a concentration below 60 mg L⁻¹. The N-GOQDs demonstrate green luminescence with an emission maximum at 505 nm and sedimentation stability in the cell culture medium.

This paper reveals the methodology for robust preparation of purified nitrogen-doped graphene oxide quantum dots with non-cytotoxic activity against monkey epithelial kidney cells (Vero ATCC® CCL-81™).     

Hemangiomas of the external auditory canal:a literature review and two new case reports

Aim  

The aim of this paper is to present two case reports of patients with hemangiomas of the external auditory canal, and to overview all cases published in English language literature so far.     

Evaluation of 5‐Year Risk of Cardiovascular Events in Patients after Acute Myocardial Infarction Using Synchronization of 0.1‐Hz Rhythms in Cardiovascular System

Background: Synchronization between 0.1‐Hz rhythms in cardiovascular system is deteriorated at acute myocardial infarction (AMI) leading to a disruption of natural functional couplings within the system of autonomic regulation. Objective: This study evaluates the prognostic value of autonomic regulation indices for the 5‐year risk of fatal and nonfatal cardiovascular events in patients after AMI. Methods and Results: We studied 125 patients (53 [42%] female) after AMI aged between 30 and 83 years. The period of observation was 5 years with checkpoints at the first week after AMI and after each year after AMI. We compared the prognostic value of established clinical characteristics and degree S of synchronization between 0.1‐Hz rhythms in heart rate and microcirculation for evaluation of the 5‐year risk of mortality and recurrent myocardial infarction (MI) in patients after AMI. Acute heart failure Killip 2–4 at AMI and S < 20% at the first week after AMI were identified as the most important factors for evaluation of the risk of 5‐year mortality in patients after AMI (χ²= 14.2, P = 0.003). Sensitivity and specificity of low S (<20%) at the first week after AMI were 76% and 43%, respectively. For evaluation of the 5‐year risk of recurrent MI index S had no advantage over established clinical characteristics. Conclusion: The value of S below 20% in patients with AMI is a sensitive marker of high risk of mortality during the subsequent five years. It is characterized by better prognostic value than most of established clinical characteristics.     

Agonist high- and low-affinity states of dopamine D2 receptors: methods of detection and clinical implications

Dopamine D₂ receptors, similar to other G-protein-coupled receptors, exist in a high- and low-affinity state for agonists. Based upon a review of the methods for detecting D₂ receptor agonist high-affinity states, we discuss alterations of such states in animal models of disease and the implications of such alterations for their labelling with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers. The classic approach of detecting agonist high-affinity states compares agonist competition for antagonist radioligands, in most cases using [³H]-spiperone as the radioligand; alternative approaches and radioligands have been proposed, but their claimed advantages have not been substantiated by other investigators. In view of the advantages and disadvantages of various techniques, we critically have reviewed reported findings on the detection of D₂ receptor agonist high-affinity states in a variety of animal models. These data are compared to the less numerous findings from human in vivo studies based on PET and SPECT tracers; they are interpreted in light of the finding that D₂ receptor agonist high-affinity states under control conditions may differ between rodent and human brain. The potential advantages of agonist ligands in studies of pathophysiology and as diagnostics are being discussed.     

Laparoscopic live donor nephrectomy: trends in donor and recipient morbidity following 381 consecutive cases

OBJECTIVE: To review a single-institution 6-year experience with laparoscopic live donor nephrectomy detailing the technical modifications, clinical results, as well as the trends in donor and recipient morbidity. SUMMARY BACKGROUND DATA: Since 1995, laparoscopic donor nephrectomy has had a significant impact on the field of renal transplantation, resulting in decreased donor morbidity, without jeopardizing procurement of a high-quality renal allograft. This technique has become the preferred method of allograft procurement for many transplantation centers worldwide but still remains technically challenging with a steep learning curve. METHODS: Records from 381 consecutive laparoscopic donor nephrectomies were reviewed with evaluation of both donor and recipient outcomes. Trends in donor and recipient complications were assessed over time by comparing the outcomes between four equally divided groups. RESULTS: All 381 kidneys were procured and transplanted successfully with only 8 (2.1%) open conversions. Mean operative time was 252.9 +/- 55.7 minutes, estimated blood loss 344.2 +/- 690.3 mL, warm ischemia time 4.9 +/- 3.4 minutes, and donor length of stay was 3.3 +/- 4.5 days. There was a significant decline in total donor complications, allograft loss, and rate of vascular thrombosis with experience. The rate of ureteral complications declined significantly when comparing our early (Group A) versus later (Groups B-D) experience. CONCLUSION: Laparoscopic donor nephrectomy has remained a safe, less invasive, and effective technique for renal allograft procurement. Over our 6-year experience and with specific refinements in surgical technique, we have observed a decline in both donor and recipient morbidity following laparoscopic live donor nephrectomy.     

A back propagation through time‐like min–max optimal control algorithm for nonlinear systems

This paper presents a conjugate gradient‐based algorithm for feedback min–max optimal control of nonlinear systems. The algorithm has a backward‐in‐time recurrent structure similar to the back propagation through time (BPTT) algorithm. The control law is given as the output of the one‐layer NN. Main contribution of the paper includes the integration of BPTT techniques, conjugate gradient methods, Adams method for solving ODEs and automatic differentiation, to provide an effective, numerically robust algorithm for solving optimal min–max control problems. The proposed algorithm is evaluated on a robotic system with two DOFs. Copyright © 2012 John Wiley & Sons, Ltd.     

Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes

The current study addresses a novel hypothesis of subcellular distribution of mitochondrial dysfunction in skeletal muscle in type 2 diabetes. Vastus lateralis muscle was obtained by percutaneous biopsy from 11 volunteers with type 2 diabetes; 12 age-, sex-, and weight-matched obese sedentary nondiabetic volunteers; and 8 lean volunteers. Subsarcolemmal and intermyofibrillar mitochondrial fractions were isolated by differential centrifugation and digestion techniques. Overall electron transport chain activity was similar in type 2 diabetic and obese subjects, but subsarcolemmal mitochondria electron transport chain activity was reduced in type 2 diabetic subjects (0.017 +/- 0.003 vs. 0.034 +/- 0.007 units/mU creatine kinase [CK], P = 0.01) and sevenfold reduced compared with lean subjects (P < 0.01). Electron transport chain activity in intermyofibrillar mitochondria was similar in type 2 diabetic and obese subjects, though reduced compared with lean subjects. A reduction in subsarcolemmal mitochondria was confirmed by transmission electron microscopy. Although mtDNA was lower in type 2 diabetic and obese subjects, the decrement in electron transport chain activity was proportionately greater, indicating functional impairment. Because of the potential importance of subsarcolemmal mitochondria for signal transduction and substrate transport, this deficit may contribute to the pathogenesis of muscle insulin resistance in type 2 diabetes.