miRNA-mediated inhibition of an actomyosin network in hippocampal pyramidal neurons restricts sociability in adult male mice.

Social deficits are frequently observed in patients suffering from neurodevelopmental disorders, but the molecular mechanisms regulating sociability are still poorly understood. We recently reported that the loss of the microRNA (miRNA) cluster miR-379-410 leads to hypersocial behavior and anxiety in mice. Here, we show that ablating miR-379-410 in excitatory neurons of the postnatal mouse hippocampus recapitulates hypersociability, but not anxiety. At the cellular level, miR-379-410 loss in excitatory neurons leads to larger dendritic spines, increased excitatory synaptic transmission, and upregulation of an actomyosin gene network. Re-expression of three cluster miRNAs, as well as pharmacological inhibition of the actomyosin activator ROCK, is sufficient to reinstate normal sociability in miR-379-410 knockout mice. Several actomyosin genes and miR-379-410 family members are reciprocally dysregulated in isogenic human induced pluripotent stem cell (iPSC)-derived neurons harboring a deletion present in patients with Williams-Beuren syndrome, characterized by hypersocial behavior. Together, our results show an miRNA-actomyosin pathway involved in social behavior regulation.

Esophageal schwannoma mimicking non-functional parathyroid adenoma on 99mTc-sestamibi imaging: a case report.

Technetium-99m sestamibi single-photon emission computed tomography/computed tomography (99mTc-sestamibi SPECT/CT) is a mainstay of the pre-operative localization of parathyroid lesions. We report here the case of a 30 year-old woman with a fortuitously discovered 2 cm cervical mass for which a parathyroid origin was originally suspected due to its retro-thyroidal localization and a personal history of nephrolithiasis. Normal serum calcium and parathyroid hormone (PTH) levels excluded primary hyperparathyroidism, raising suspicion of a non-functional parathyroid adenoma, and SPECT/CT imaging showed that the mass was 99mTc-sestamibi-avid. Fine-needle aspiration (FNA) was performed; cytology was non-diagnostic but the needle washout was negative for thyroglobulin, calcitonin and PTH, arguing against a thyroidal or parathyroidal origin of the mass. Core needle biopsy revealed a schwannoma, ostensibly originating from the recurrent laryngeal nerve; upon surgical resection, it was finally found to arise from the esophageal submucosa. This case illustrates the fact that endocrinologists, radiologists, nuclear medicine, head and neck, and other specialists investigating patients with cervical masses should be aware that schwannomas need to be considered in the differential diagnosis of focal 99mTc-sestamibi uptake in the neck region.

Long-Term Evaluation of Lipid Profile Changes in Olympic Athletes.

Dyslipidemia is a major contributor to the development of atherosclerotic cardiovascular disease. Despite high level of physical activity, athletes are not immune from dyslipidemia, but longitudinal data on the variation of lipids are currently lacking. We sought to assess lipid profile changes over time in Olympic athletes practicing different sports disciplines (power, skills, endurance, and mixed). We enrolled 957 consecutive athletes evaluated from London 2012 to Beijing 2022 Olympic Games. Dyslipidemia was defined as low-density lipoprotein (LDL) ≥115 mg/dl, high-density lipoprotein (HDL) <40 mg/dl for males, or HDL <50 mg/dl for females. Hypertriglyceridemia was defined as triglycerides >150 mg/dl. At the follow-up, a variation of ±40 mg/dl for LDL, ±6 mg/dl for HDL, and ±50 mg/dl for triglycerides was considered relevant. Athletes with follow-up <10 months or taking lower lipid agents were excluded. Follow-up was completed in 717 athletes (74.9%), with a mean duration of 55.6 months. Mean age was 27.2 ± 4.8 years old, 54.6% were male (n = 392). Overall, 19.8% (n = 142) athletes were dyslipidemic at both blood tests, being older, practicing nonendurance sports, and predominantly male. In 69.3% (n = 129) of those with elevated LDL at t0, altered values were confirmed at follow-up, while the same occurred in 36.5% (n = 15) with hypo-HDL and 5.3% (n = 1) in those with elevated triglycerides. Weight and fat mass percentage modifications did not affect lipid profile variation. LDL hypercholesterolemia tends to persist over time especially among male, older, and nonendurance athletes. LDL hypercholesterolemia detection in athletes should prompt early preventive intervention to reduce the risk of future development of atherosclerotic disease.

Prevalence of Hyperuricemia and Associated Cardiovascular Risk Factors in Elite Athletes Practicing Different Sporting Disciplines: A Cross-Sectional Study.

Uricemia has been identified as an independent risk factor for cardiovascular disease. In the general population, hyperuricemia is associated with hypertension, endothelial dysfunction, and other cardiovascular risk (CVR) factors. Our aim was to explore the prevalence of hyperuricemia among Olympic athletes, evaluating the influence of sporting discipline and its correlation with CVR factors. We enrolled 1173 Olympic athletes classified into four disciplines: power, skill, endurance, and mixed. Clinical, anthropometric data, and complete blood test results were collected. Hyperuricemia was present in 4.4% of athletes, 0.3% were hypertensive, 11.7% had high-normal blood pressure values, 0.2% were diabetic, 1.2%. glucose intolerance, 8.2% active smokers, and 3% were obese. Males had a higher prevalence of hyperuricemia (5.3%) than females (3.4%) with no significant differences between different sporting disciplines (male, p = 0.412; female p = 0.561). Males with fat mass >22% presented higher uricemia (5.8 ± 1 vs. 5.3 ± 1 mg/dL, p = 0.010) like hypertensive athletes (6.5 ± 0.3 vs. 5.3 ± 1 mg/dL, p = 0.031), those with high-normal blood pressure (5.13 ± 1 vs. 4.76 ± 1.1 mg/dL, p = 0.0004) and those with glucose intolerance (6 ± 0.8 vs. 5.3 ± 1 mg/dL, p = 0.066). The study provides a comprehensive evaluation of hyperuricemia among Olympic athletes, revealing a modest prevalence, lower than in the general population. However, aggregation of multiple CVR factors could synergistically elevate the risk profile, even in a population assumed to be at low risk. Therefore, uric acid levels should be monitored as part of the CVR assessment in athletes.

Nebulization of pharmacological solutions with an innovative medical device based on microvaporization.

The currently available nebulization devices have a slow aerosol flow and produce vapor with large microdrops. Improved devices that achieve higher airflow and produce smaller microdrops are needed to improve the clinical care of patients. To address this critical need, we developed a novel system for the molecular vaporization of liquids. This device vaporizes an active pharmacological substance dissolved in water, alcohol, or a mixture of water and alcohol using two energy sources at the same time: high-frequency ultrasound and thermal induction. Application of energy to a solution contained in the device's tank allows, within tens of seconds, for the vaporization of the solution itself, with the generation of a vapor consisting of microdrops of very small diameter (0.2-0.3 µm). In this article, we illustrate the technology used, the main verification tests performed, and the primary fields of application for this device. In particular, the advantages of both the aerosol delivery system and the administration system are highlighted.

Two novel HLA class I alleles HLA-A*03:409 and -B*49:72 and the extension of the -B*40:19 allele sequence.

Two novel HLA class I alleles, HLA-A*03:409 and -B*49:72 were characterized by next generation sequencing.

Low prevalence of cardiac abnormalities in competitive athletes at return-to-play after COVID-19.

OBJECTIVE: to evaluate the prevalence of cardiac involvement after COVID-19 in competitive athletes at return-to-play (RTP) evaluation, following the recommended Italian protocol including cardiopulmonary exercise test (CPET) and 24-Hour Holter monitoring. DESIGN AND METHODS: this is a single centre observational, cross-sectional study. Since October 2020, all competitive athletes (age ≥ 14 years) evaluated in our Institute after COVID-19, prior RTP were enrolled. The protocol dictated by the Italian governing bodies included: 12­lead ECG, blood test, CPET, 24-h ECG monitoring, spirometry. Cardiovascular Magnetic Resonance (CMR) was performed based on clinical indication. RESULTS: 219 consecutive athletes were examined (59% male), age 23 years (IQR 19-27), 21% asymptomatic, 77% mildly symptomatic, 2% with previous pneumonia. The evaluation was performed after a median of 10 (6-17) days from negative SARS-CoV-2 swab. All athletes showed a good exercise capacity at CPET without cardiovascular and respiratory limitations. Uncommon premature ventricular contractions (PVCs) were found in 9.5% (n = 21) at CPET/Holter ECG monitoring. Two athletes (0.9%) were diagnosed with acute myocarditis (by CMR) and another one with new pericardial effusion. All the three athletes were temporally restricted from sport participation. CONCLUSIONS: Myocarditis in competitive athletes screened after COVID-19 resolution was detected in a low minority of the cases (0.9%). However, a non-negligible prevalence of uncommon PVCs (9%) was observed, either at CPET and/or Holter ECG monitoring, including all athletes with COVID-19 related cardiovascular abnormalities.

Consumptive hypothyroidism in a patient with malignant rhabdoid tumor of the kidney: case report on a newly found association.

Introduction: Consumptive hypothyroidism is a rare paraneoplastic condition most commonly associated with infantile hemangiomas. It is caused by overexpression of deiodinase type 3 (D3), which leads to preferential conversion of thyroxine to the metabolically inactive reverse triiodothyronine (rT3), paralleled by a decrease of the biologically active T3. Case presentation: A 46-year-old male patient with previously normal thyroid function was diagnosed with a renal carcinoma with rhabdoid differentiation. He was treated with sunitinib, followed by the immune checkpoint inhibitors ipilimumab and nivolumab, and he developed primary hypothyroidism secondary to thyroiditis. Substitution with unusually high doses of levothyroxine as high as 4.3 µg/kg/day did not normalize his thyroid function. Poor compliance was refuted because there was no improvement after observed administration. He had no malabsorption. Although tyrosine kinase inhibitors can increase the expression of D3, this effect tends to be modest. Therefore, the suspicion of tumor-related consumptive hypothyroidism was raised and supported by low free T3 and elevated rT3 levels. The therapy could not be further modified because the patient opted for palliative care and passed away 12 days later. Immunohistochemistry of the tumor from a sample obtained prior to systemic therapy documented abundant expression of D3, corroborating the diagnosis of consumptive hypothyroidism. Conclusions: This observation extends the spectrum of malignancies overexpressing D3. Although rare, increased awareness of this paraneoplastic syndrome is key, if persistent hypothyroidism cannot be explained by compliance issues or malabsorption. Substitution with high doses of levothyroxine, and combination therapy with liothyronine, can correct hypothyroidism in these patients.

Systematic Cardiovascular Screening in Olympic Athletes before and after SARS-CoV-2 Infection.

Conflicting results on the cardiovascular involvement after SARS-CoV-2 infection generated concerns on the safety of return-to-play (RTP) in athletes. The aim of this study was to evaluate the prevalence of cardiac involvement after COVID-19 in Olympic athletes, who had previously been screened in our pre-participation program. Since November 2020, all consecutive Olympic athletes presented to our Institute after COVID-19 prior to RTP were enrolled. The protocol was dictated by the Italian governing bodies and comprised: 12-lead ECG, blood test, cardiopulmonary exercise test (CPET), 24-h ECG monitoring, and spirometry. Cardiovascular Magnetic Resonance (CMR) was also performed. All Athletes were previously screened in our Institute as part of their periodical pre-participation evaluation. Forty-seven Italian Olympic athletes were enrolled: 83% asymptomatic, 13% mildly asymptomatic, and 4% had pneumonia. Uncommon premature ventricular contractions (PVCs) were found in 13% athletes; however, only 6% (n = 3) were newly detected. All newly diagnosed uncommon PVCs were detected by CPET. One of these three athletes had evidence for acute myocarditis by CMR, along with Troponin raise; another had pericardial effusion. No one of the remaining athletes had abnormalities detected by CMR. Cardiac abnormalities in Olympic athletes screened after COVID-19 resolution were detected in a minority, and were associated with new ventricular arrhythmias. Only one had evidence for acute myocarditis (in the presence of symptoms and elevated biomarkers). Our data support the efficacy of the clinical assessment including exercise-ECG to raise suspicion for cardiovascular abnormalities after COVID-19. Instead, the routine use of CMR as a screening tool appears unjustified.

MicroRNA-138 controls hippocampal interneuron function and short-term memory in mice.

The proper development and function of neuronal circuits rely on a tightly regulated balance between excitatory and inhibitory (E/I) synaptic transmission, and disrupting this balance can cause neurodevelopmental disorders, for example, schizophrenia. MicroRNA-dependent gene regulation in pyramidal neurons is important for excitatory synaptic function and cognition, but its role in inhibitory interneurons is poorly understood. Here, we identify miR138-5p as a regulator of short-term memory and inhibitory synaptic transmission in the mouse hippocampus. Sponge-mediated miR138-5p inactivation specifically in mouse parvalbumin (PV)-expressing interneurons impairs spatial recognition memory and enhances GABAergic synaptic input onto pyramidal neurons. Cellular and behavioral phenotypes associated with miR138-5p inactivation are paralleled by an upregulation of the schizophrenia (SCZ)-associated Erbb4, which we validated as a direct miR138-5p target gene. Our findings suggest that miR138-5p is a critical regulator of PV interneuron function in mice, with implications for cognition and SCZ. More generally, they provide evidence that microRNAs orchestrate neural circuit development by fine-tuning both excitatory and inhibitory synaptic transmission.

Function and Fiber-Type Specific Distribution of Hsp60 and αB-Crystallin in Skeletal Muscles: Role of Physical Exercise.

Skeletal muscle is a plastic and complex tissue, rich in proteins that are subject to continuous rearrangements. Skeletal muscle homeostasis can be affected by different types of stresses, including physical activity, a physiological stressor able to stimulate a robust increase in different heat shock proteins (HSPs). The modulation of these proteins appears to be fundamental in facilitating the cellular remodeling processes related to the phenomenon of training adaptations such as hypertrophy, increased oxidative capacity, and mitochondrial activity. Among the HSPs, a special attention needs to be devoted to Hsp60 and αB-crystallin (CRYAB), proteins constitutively expressed in the skeletal muscle, where their specific features could be highly relevant in understanding the impact of different volumes of training regimes on myofiber types and in explaining the complex picture of exercise-induced mechanical strain and damaging conditions on fiber population. This knowledge could lead to a better personalization of training protocols with an optimal non-harmful workload in populations of individuals with different needs and healthy status. Here, we introduce for the first time to the reader these peculiar HSPs from the perspective of exercise response, highlighting the control of their expression, biological function, and specific distribution within skeletal muscle fiber-types.

The eSports conundrum: is the sports sciences community ready to face them? A perspective.

The reality of eSports is something much more complex than individual users playing video games. There are several characteristics that eSports have in common with traditional sports: from the spirit of competition to the structural composition of the teams, including the increase in performance with training and practice, up to the injuries and physical and psychological stress of the athlete. The number of scientific papers interested in this reality is still relatively low, although in recent years there has been a significant increase in this regard. Probably the lack of knowledge of the world of eSports by inexperts can represent an initial obstacle in the approach to this environment. Therefore, an all-round analysis of the eSports industry is fundamental: including the figures that characterize them, the different eSports disciplines, the possible physical and mental consequences for athletes. Emphasizing the similarities between electronic and non-electronic sports is essential in order to make people, and the scientific community in particular, understand how they should be considered equal to the "traditional" vision of sports especially in the need for professional medical support. The number of professional and amateur eSports players increase every day as well as the birth of professional organizations and national teams while medical monitoring seems to have fallen behind. In the near future, we hope that the scientific community and in particular the medical disciplines will be able to closely support the world of eSports to guarantee the correct assistance to all professional and non-professional athletes. An increase in the number of scientific work and specific studies will certainly bring benefits in countering physical attrition, reducing the risk of injury, in psychological support to athletes and in the fight against doping reality.

The posterior talocalcaneal ligament: an MRI evaluation.

PURPOSE: A wide inter-individual variability in terms of size, orientation and insertion is observed regarding ankle ligaments. The aim of this study is to identify and describe the anatomical features of the posterior talocalcaneal ligament (PTCL) observed through the use of magnetic resonance imaging (MRI) of the ankle. METHODS: The study was retrospectively carried out on 893 ankle MRI's exams. The exams have all been performed using a 1.5-T (T) MRI. The same scanning protocols and scan planes were carried out in all the exams. The first evaluated parameter was the recognition of the PTCL. Subsequently, in all those cases where the ligament was present, its features such as insertion sites, length, and thickness were evaluated. RESULTS: The PTCL identification was possible in 77 exams (8.6% of the total number). Among these, we were able to identify some variants regarding insertion sites, length, and thickness. The PTCL could be further classified into four categories based on the most common characteristics observed. CONCLUSIONS: Our study has identified different characteristics of the PTCL that allow us to further understand the characteristics of the ligament itself. In conclusion, the need for further studies focused on the biomechanical role of the PTCL in the ankle joint appears mandatory.

A placental mammal-specific microRNA cluster acts as a natural brake for sociability in mice.

Aberrant synaptic function is thought to underlie social deficits in neurodevelopmental disorders such as autism and schizophrenia. Although microRNAs have been shown to regulate synapse development and plasticity, their potential involvement in the control of social behaviour in mammals remains unexplored. Here, we show that deletion of the placental mammal-specific miR379-410 cluster in mice leads to hypersocial behaviour, which is accompanied by increased excitatory synaptic transmission, and exaggerated expression of ionotropic glutamate receptor complexes in the hippocampus. Bioinformatic analyses further allowed us to identify five "hub" microRNAs whose deletion accounts largely for the upregulation of excitatory synaptic genes observed, including Cnih2, Dlgap3, Prr7 and Src. Thus, the miR379-410 cluster acts a natural brake for sociability, and interfering with specific members of this cluster could represent a therapeutic strategy for the treatment of social deficits in neurodevelopmental disorders.

A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses.

Synaptic downscaling is a homeostatic mechanism that allows neurons to reduce firing rates during chronically elevated network activity. Although synaptic downscaling is important in neural circuit development and epilepsy, the underlying mechanisms are poorly described. We performed small RNA profiling in picrotoxin (PTX)-treated hippocampal neurons, a model of synaptic downscaling. Thereby, we identified eight microRNAs (miRNAs) that were increased in response to PTX, including miR-129-5p, whose inhibition blocked synaptic downscaling in vitro and reduced epileptic seizure severity in vivo Using transcriptome, proteome, and bioinformatic analysis, we identified the calcium pump Atp2b4 and doublecortin (Dcx) as miR-129-5p targets. Restoring Atp2b4 and Dcx expression was sufficient to prevent synaptic downscaling in PTX-treated neurons. Furthermore, we characterized a functional crosstalk between miR-129-5p and the RNA-binding protein (RBP) Rbfox1. In the absence of PTX, Rbfox1 promoted the expression of Atp2b4 and Dcx. Upon PTX treatment, Rbfox1 expression was downregulated by miR-129-5p, thereby allowing the repression of Atp2b4 and Dcx. We therefore identified a novel activity-dependent miRNA/RBP crosstalk during synaptic scaling, with potential implications for neural network homeostasis and epileptogenesis.

A coding-independent function of an alternative Ube3a transcript during neuronal development.

The E3 ubiquitin ligase Ube3a is an important regulator of activity-dependent synapse development and plasticity. Ube3a mutations cause Angelman syndrome and have been associated with autism spectrum disorders (ASD). However, the biological significance of alternative Ube3a transcripts generated in mammalian neurons remains unknown. We report here that Ube3a1 RNA, a transcript that encodes a truncated Ube3a protein lacking catalytic activity, prevents exuberant dendrite growth and promotes spine maturation in rat hippocampal neurons. Surprisingly, Ube3a1 RNA function was independent of its coding sequence but instead required a unique 3' untranslated region and an intact microRNA pathway. Ube3a1 RNA knockdown increased activity of the plasticity-regulating miR-134, suggesting that Ube3a1 RNA acts as a dendritic competing endogenous RNA. Accordingly, the dendrite-growth-promoting effect of Ube3a1 RNA knockdown in vivo is abolished in mice lacking miR-134. Taken together, our results define a noncoding function of an alternative Ube3a transcript in dendritic protein synthesis, with potential implications for Angelman syndrome and ASD.

MiR-134-dependent regulation of Pumilio-2 is necessary for homeostatic synaptic depression.

Neurons employ a set of homeostatic plasticity mechanisms to counterbalance altered levels of network activity. The molecular mechanisms underlying homeostatic plasticity in response to increased network excitability are still poorly understood. Here, we describe a sequential homeostatic synaptic depression mechanism in primary hippocampal neurons involving miRNA-dependent translational regulation. This mechanism consists of an initial phase of synapse elimination followed by a reinforcing phase of synaptic downscaling. The activity-regulated microRNA miR-134 is necessary for both synapse elimination and the structural rearrangements leading to synaptic downscaling. Results from miR-134 inhibition further uncover a differential requirement for GluA1/2 subunits for the functional expression of homeostatic synaptic depression. Downregulation of the miR-134 target Pumilio-2 in response to chronic activity, which selectively occurs in the synapto-dendritic compartment, is required for miR-134-mediated homeostatic synaptic depression. We further identified polo-like kinase 2 (Plk2) as a novel target of Pumilio-2 involved in the control of GluA2 surface expression. In summary, we have described a novel pathway of homeostatic plasticity that stabilizes neuronal circuits in response to increased network activity.

[Deciduous dentition: anatomical study by µ-CT]. / Dentizione decidua: studio della complessità anatomica mediante µTC.

Endodontics is the branch of deciduous teeth pediatric dentistry that deals with the treatment of the root canal system. The goal of therapy is to maintain as long as possible the element in the dental arch to prevent alterations of orthognathodontic, infectious, and functional history and eruptive sequence. Although manual instrumentation has been widely used and still preferred by some practitioners, has limitations that affect the actual ability to clean the channel, the ability to create steps, perforations, dentinal plugs and fractures of the instrument. On the other hand, the disadvantages are the high cost of the instruments in nickel-titanium, which must be frequently replaced, and the risk of compromising the stability of the tooth due to an excessive consumption of dentinal tissue. The use of computed microtomography (µCT) of extracted elements has a considerable advantage in the study of dental hard tissues. The purpose of this study was to analyze the anatomy of the endodontic system of the elements deciduous.