Blood flow characteristics after aortic valve neocuspidization in paediatric patients: a comparison with the Ross procedure.

AIMS: The aortic valve (AV) neocuspidization (Ozaki procedure) is a novel surgical technique for AV disease that preserves the natural motion and cardiodynamics of the aortic root. In this study, we sought to evaluate, by 4D-flow magnetic resonance imaging, the aortic blood flow characteristics after AV neocuspidization in paediatric patients. METHODS AND RESULTS: Aortic root and ascending aorta haemodynamics were evaluated in a population of patients treated with the Ozaki procedure; results were compared with those of a group of patients operated with the Ross technique. Cardiovascular magnetic resonance studies were performed at 1.5 T using a 4D flow-sensitive sequence acquired with retrospective electrocardiogram-gating and respiratory navigator. Post-processing of 4D-flow analysis was performed to calculate flow eccentricity and wall shear stress. Twenty children were included in this study, 10 after Ozaki and 10 after Ross procedure. Median age at surgery was 10.7 years (range 3.9-16.5 years). No significant differences were observed in wall shear stress values measured at the level of the proximal ascending aorta between the two groups. The analysis of flow patterns showed no clear association between eccentric flow and the procedure performed. The Ozaki group showed just a slightly increased transvalvular maximum velocity. CONCLUSION: Proximal aorta flow dynamics of children treated with the Ozaki and the Ross procedure are comparable. Similarly to the Ross, Ozaki technique restores a physiological laminar flow pattern in the short-term follow-up, with the advantage of not inducing a bivalvular disease, although further studies are warranted to evaluate its long-term results

High motor variability in DYT1 dystonia is associated with impaired visuomotor adaptation.

For the healthy motor control system, an essential regulatory role is maintaining the equilibrium between keeping unwanted motor variability in check whilst allowing informative elements of motor variability. Kinematic studies in children with generalised dystonia (due to mixed aetiologies) show that movements are characterised by increased motor variability. In this study, the mechanisms by which high motor variability may influence movement generation in dystonia were investigated. Reaching movements in the symptomatic arm of 10 patients with DYT1 dystonia and 12 age-matched controls were captured using a robotic manipulandum and features of motor variability were extracted. Given that task-relevant variability and sensorimotor adaptation are related in health, markers of variability were then examined for any co-variance with performance indicators during an error-based learning visuomotor adaptation task. First, we confirmed that motor variability on a trial-by-trial basis was selectively increased in the homogenous and prototypical dystonic disorder DYT1 dystonia. Second, high baseline variability predicted poor performance in the subsequent visuomotor adaptation task offering insight into the rules which appear to govern dystonic motor control. The potential mechanisms behind increased motor variability and its corresponding implications for the rehabilitation of patients with DYT1 dystonia are highlighted

Atypical cardiac defects in patients with RASopathies: Updated data on CARNET study

Background: RASopathies are a set of relatively common autosomal dominant clinically and genetically heterogeneous disorders. Cardiac outcomes in terms of mortality and morbidity for common heart defects (such as pulmonary valve stenosis and hypertrophic cardiomyopathy) have been reported. Nevertheless, also Atypical Cardiac Defects (ACDs) are described. The aim of the present study was to report both prevalence and cardiac outcome of ACDs in patients with RASopathies. Methods: A retrospective, multicentric observational study (CArdiac Rasopathy NETwork—CARNET study) was carried out. Clinical, surgical, and genetic data of the patients who were followed until December 2019 were collected. Results: Forty‐five patients out of 440 followed in CARNET centers had ACDs. Noonan Syndrome (NS), NS Multiple Lentigines (NSML) and CardioFacioCutaneous Syndrome (CFCS) were present in 36, 5 and 4 patients, respectively. Median age at last follow‐up was 20.1 years (range 6.9–47 years). Different ACDs were reported, including mitral and aortic valve dysfunction, ascending and descending aortic arch anomalies, coronary arteries dilation, enlargement of left atrial appendage and isolated pulmonary branches diseases. Five patients (11%) underwent cardiac surgery and one of them underwent a second intervention for mitral valve replacement and severe pericardial effusion. No patients died in our cohort until December 2019. Conclusions: Patients with RASopathies present a distinct CHD spectrum. Present data suggest that also ACDs must be carefully investigated for their possible impact on the clinical outcome. A careful longitudinal follow up until the individuals reach an adult age is recommended

Fixed Dystonia in Complex Regional Pain Syndrome: a Descriptive and Computational Modeling Approach

Background: Complex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. Involvement of dysfunctional GABAergic interneurons has been suggested, however the mechanisms that underpin fixed dystonia are still unknown. We hypothesized that dystonia could be the result of aberrant proprioceptive reflex strengths of position, velocity or force feedback. Methods: We systematically characterized the pattern of dystonia in 85 CRPS-patients with dystonia according to the posture held at each joint of the affected limb. We compared the patterns with a neuromuscular computer model simulating aberrations of proprioceptive reflexes. The computer model consists of an antagonistic muscle pair with explicit contributions of the musculotendinous system and reflex pathways originating from muscle spindles and Golgi tendon organs, with time delays reflective of neural latencies. Three scenarios were simulated with the model: (i) increased reflex sensitivity (increased sensitivity of the agonistic and antagonistic reflex loops); (ii) imbalanced reflex sensitivity (increased sensitivity of the agonistic reflex loop); (iii) imbalanced reflex offset (an offset to the reflex output of the agonistic proprioceptors). Results: For the arm, fixed postures were present in 123 arms of 77 patients. The dominant pattern involved flexion of the fingers (116/123), the wrists (41/123) and elbows (38/123). For the leg, fixed postures were present in 114 legs of 77 patients. The dominant pattern was plantar flexion of the toes (55/114 legs), plantar flexion and inversion of the ankle (73/114) and flexion of the knee (55/114). Only the computer simulations of imbalanced reflex sensitivity to muscle force from Golgi tendon organs caused patterns that closely resembled the observed patient characteristics. In parallel experiments using robot manipulators we have shown that patients with dystonia were less able to adapt their force feedback strength. Conclusions: Findings derived from a neuromuscular model suggest that aberrant force feedback regulation from Golgi tendon organs involving an inhibitory interneuron may underpin the typical fixed flexion postures in CRPS patients with dystonia.Biomechanical EngineeringMechanical, Maritime and Materials Engineerin

Data on cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results

A comprehensive description of morbidity and mortality in patients affected by mutations in genes encoding for signal transducers of the RAS-MAPK cascade (RASopathies) was performed in our study recently published in the International Journal of Cardiology. Seven European cardiac centres participating to the CArdiac Rasopathy NETwork (CARNET), collaborated in this multicentric, observational, retrospective data analysis and collection. In this study, clinical records of 371 patients with confirmed molecular diagnosis of RASopathy were reviewed. Cardiac defects, crude mortality, survival rate of patients with 1) hypertrophic cardiomyopathy (HCM) and age <2 years or young adults; 2) individuals with Noonan syndrome and pulmonary stenosis carrying PTPN11 mutations; 3) biventricular obstruction and PTPN11 mutations; 4) Costello syndrome or cardiofaciocutaneous syndrome were analysed. Mortality was described as crude mortality, cumulative survival and restricted estimated mean survival. In particular, with this Data In Brief (DIB) paper, the authors aim to report specific statistic highlights of the multivariable regression analysis that was used to assess the impact of mutated genes on number of interventions and overall prognosis

Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results

BACKGROUND: RASopathies are developmental disease caused by mutations in genes encoding for signal transducers of the RAS-MAPK cascade. The aim of the present study was to provide a comprehensive description of morbidity and mortality in patients with molecularly confirmed RASopathy. METHODS: A multicentric, observational, retrospective study was conducted in seven European cardiac centres participating to the CArdiac Rasopathy NETwork (CARNET). Clinical records of 371 patients with confirmed molecular diagnosis of RASopathy were reviewed. Mortality was described as crude mortality, cumulative survival and restricted estimated mean survival. Multivariable regression analysis was used to assess the impact of mutated genes on number of interventions and overall prognosis. RESULTS: Cardiac defects occurred in 80.3% of cases, almost half of them underwent at least one intervention. Overall, crude mortality was 0.29/100 patients-year. Cumulative survival was 98.8%, 98.2%, 97.7%, 94.3%, at 1, 5, 10, and 20 years, respectively. Restricted estimated mean survival at 20 years follow-up was 19.6 years. Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic cardiomyopathy (HCM) and age < 2 years or young adults, as well as subjects with biventricular obstruction and PTPN11 mutations had a higher risk of cardiac death. CONCLUSIONS: The risk of intervention was higher in individuals with Noonan syndrome and pulmonary stenosis carrying PTPN11 mutations. Overall, mortality was relatively low, even though the specific association between HCM, biventricular outflow tract obstructions and PTPN11 mutations appeared to be associated with early mortality, including immediate post-operative events and sudden death

Hsf1 Activation Inhibits Rapamycin Resistance and TOR Signaling in Yeast Revealed by Combined Proteomic and Genetic Analysis

TOR kinases integrate environmental and nutritional signals to regulate cell growth in eukaryotic organisms. Here, we describe results from a study combining quantitative proteomics and comparative expression analysis in the budding yeast, S. cerevisiae, to gain insights into TOR function and regulation. We profiled protein abundance changes under conditions of TOR inhibition by rapamycin treatment, and compared this data to existing expression information for corresponding gene products measured under a variety of conditions in yeast. Among proteins showing abundance changes upon rapamycin treatment, almost 90% of them demonstrated homodirectional (i.e., in similar direction) transcriptomic changes under conditions of heat/oxidative stress. Because the known downstream responses regulated by Tor1/2 did not fully explain the extent of overlap between these two conditions, we tested for novel connections between the major regulators of heat/oxidative stress response and the TOR pathway. Specifically, we hypothesized that activation of regulator(s) of heat/oxidative stress responses phenocopied TOR inhibition and sought to identify these putative TOR inhibitor(s). Among the stress regulators tested, we found that cells (hsf1-R206S, F256S and ssa1-3 ssa2-2) constitutively activated for heat shock transcription factor 1, Hsf1, inhibited rapamycin resistance. Further analysis of the hsf1-R206S, F256S allele revealed that these cells also displayed multiple phenotypes consistent with reduced TOR signaling. Among the multiple Hsf1 targets elevated in hsf1-R206S, F256S cells, deletion of PIR3 and YRO2 suppressed the TOR-regulated phenotypes. In contrast to our observations in cells activated for Hsf1, constitutive activation of other regulators of heat/oxidative stress responses, such as Msn2/4 and Hyr1, did not inhibit TOR signaling. Thus, we propose that activated Hsf1 inhibits rapamycin resistance and TOR signaling via elevated expression of specific target genes in S. cerevisiae. Additionally, these results highlight the value of comparative expression analyses between large-scale proteomic and transcriptomic datasets to reveal new regulatory connections

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)