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.     

Late whiplash syndrome: correlation of brain SPECT with neuropsychological tests and P300 event-related potential

BACKGROUND: The acceleration forces infringing the cervical spine in whiplash injury are frequently associated with multiple cerebral symptoms. The purpose of this study was to determine whether there is a correlation between cerebral perfusion findings, P300 recording (an electrophysiologic marker of cognitive ability), and neuropsychological tests in patients with whiplash injury. METHODS: Twenty patients with chronic whiplash injury underwent extensive clinical evaluation and neuropsychological testing. A brain single-photon emission computed tomography (SPECT) study using 99mTc-HMPAO was performed in all patients within 24 hours of neuropsychological evaluation. P300 event-related potentials were performed in 15 patients and in 9 normal volunteers. RESULTS: Thirteen of 20 patients had brain perfusion abnormalities on the SPECT studies, in one or more regions. Eight of 15 patients had abnormal P300 studies. Seven of eight patients with abnormal P300 had also an abnormal SPECT study. Seven of 15 patients had normal P300 results, 6 of them with a normal SPECT and 1 with SPECT abnormalities. There was no significant correlation between the SPECT findings or the P300 results and the scores of attention and working memory. There was, however, close agreement between the SPECT and P300. CONCLUSION: SPECT perfusion abnormalities in patients with chronic whiplash syndrome correlate well with P300 recording. The combination of these studies with neurocognitive and neurobehavioral tests may be useful in identifying a subgroup of patients having organic brain lesions.     

Enhancement of tendon-bone integration of anterior cruciate ligament grafts with bone morphogenetic protein-2 gene transfer: a histological and biomechanical study

BACKGROUND: The integration of tendon grafts used for replacement of the anterior cruciate ligament is still sometimes unsatisfactory and may be associated with postoperative anterior-posterior laxity. The goal of this study was to examine the capacity of bone morphogenetic protein-2 (BMP-2) gene transfer to improve the integration of semitendinosus tendon grafts at the tendon-bone interface after reconstruction of the anterior cruciate ligament in rabbits. METHODS: The anterior cruciate ligaments of adult New Zealand White rabbits were replaced with autologous double-bundle semitendinosus tendon grafts. The semitendinosus tendon grafts had been infected in vitro with adenovirus-luciferase, adenovirus-LacZ (AdLacZ), or adenovirus-BMP-2 (AdBMP-2); untreated grafts served as controls. The grafts were examined histologically at two, four, six, and eight weeks after surgery. In additional experiments, the structural properties of the femur-anterior cruciate ligament graft-tibia complexes, from animals killed eight weeks postoperatively, were determined from uniaxial tests. The stiffness (N/mm) and ultimate load to failure (N) were determined from the resulting load-elongation curves. RESULTS: Genetically engineered semitendinosus tendon grafts expressed reporter genes as well as BMP-2 in vitro. The AdLacZ-infected grafts showed two different histological patterns of transduction. Intra-articularly, infected cells were mostly aligned along the surface, and they decreased in number between two and eight weeks after surgery. In the intra-tunnel portions of the grafts, the number of infected cells did not decrease during the observation period. Moreover, a high number of transduced cells was found in the deeper layers of the tendons. In the control group, granulation-type tissue at the tendon-bone interface showed progressive reorganization into a dense connective tissue, and a later establishment of fibers resembling Sharpey fibers. In the specimens with an AdBMP-2-infected anterior cruciate ligament graft, a broad zone of newly formed matrix resembling chondro-osteoid had formed at the tendon-bone interface at four weeks after surgery. This area was increased at six weeks, showing a transition from bone to mineralized cartilage and nonmineralized fibrocartilage. In addition, in the AdBMP-2-treated specimens, the tendon-bone interface in the osseous tunnel was similar to that of a normal anterior cruciate ligament insertion. The stiffness (29.0 +/- 7.1 N/mm compared with 16.7 +/- 8.3 N/mm) and the ultimate load to failure (108.8 +/- 50.8 N compared with 45.0 +/- 18.0 N) were significantly enhanced in the specimens with an AdBMP-2-transduced graft when compared with the control values (p < 0.05). CONCLUSION: This study demonstrates that BMP-2 gene transfer significantly improves the integration of semitendinosus tendon grafts in bone tunnels after reconstruction of the anterior cruciate ligament in rabbits. Clinical Relevance: Novel technologies including gene therapy and tissue engineering, such as those described in this study, may provide useful therapeutic procedures to enhance biological healing after reconstruction of the anterior cruciate ligament.