Single muscle fiber proteomics reveals unexpected mitochondrial specialization

Mammalian skeletal muscles are composed of multinucleated cells termed slow or fast fibers according to their contractile and metabolic properties. Here, we developed a high-sensitivity workflow to characterize the proteome of single fibers. Analysis of segments of the same fiber by traditional and unbiased proteomics methods yielded the same subtype assignment. We discovered novel subtype-specific features, most prominently mitochondrial specialization of fiber types in substrate utilization. The fiber type-resolved proteomes can be applied to a variety of physiological and pathological conditions and illustrate the utility of single cell type analysis for dissecting proteomic heterogeneity

Plunging ranula in children: case report and literature review

Few cases of plunging ranulas (PRs) occur during childhood and the lesions are frequently misdiagnosed. Here, a PR in a child is reported along with a literature review. A seven-year-old female complaining of swelling in the midline neck, left-submandibular region, was evaluated. No oral cavity or major salivary glands abnormalities were detected. On palpation a soft, painless, and fluid-containing mass was observed. The suspicion PR was performed by ultrasound. The diagnosis was confirmed with a histopathological examination. The lesion was removed with a cervical approach, without recurrence. PR is an uncommon condition in children under 10 years of age. Differential diagnosis depends on clinical examination and ultrasonography. A computed tomography-scan and magnetic resonance imaging can be performed if the diagnosis remains uncertain. In pediatrics, the key to success of the treatment may rely on the radical excision of the cyst and sublingual gland, via an intraoral or submandibular approach

Superstar in Noncommutative Superspace via Covariant Quantization of the Superparticle

A covariant quantization method is developed for the off-shell superparticle in 10 dimensions. On-shell it is consistent with lightcone quantization, while off-shell it gives a noncommutative superspace that realizes non-linearly a hidden 11-dimensional super Poincare symmetry. The non-linear commutation rules are then used to construct the supersymmetric generalization of the covariant Moyal star product in noncommutative superspace. As one of the possible applications, we propose this new product as the star product in supersymmetric string field theory. Furthermore, the formalism introduces new techniques and concepts in noncommutative (super)geometry.Comment: 17 pages, LaTe

How to optimise drug study design : pharmacokinetics and pharmacodynamics studies introduced to paediatricians

Objectives In children, there is often lack of sufficient information concerning the pharmacokinetics (PK) and pharmacodynamics (PD) of a study drug to support dose selection and effective evaluation of efficacy in a randomised clinical trial (RCT). Therefore, one should consider the relevance of relatively small PKPD studies, which can provide the appropriate data to optimise the design of an RCT. Methods Based on the experience of experts collaborating in the EU-funded Global Research in Paediatrics consortium, we aimed to inform clinician-scientists working with children on the design of investigator-initiated PKPD studies. Key findings The importance of the identification of an optimal dose for the paediatric population is explained, followed by the differences and similarities of dose-ranging and efficacy studies. The input of clinical pharmacologists with modelling expertise is essential for an efficient dose-finding study. Conclusions The emergence of new laboratory techniques and statistical tools allows for the collection and analysis of sparse and unbalanced data, enabling the implementation of (observational) PKPD studies in the paediatric clinic. Understanding of the principles and methods discussed in this study is essential to improve the quality of paediatric PKPD investigations, and to prevent the conduct of paediatric RCTs that fail because of inadequate dosing.Peer reviewe

Comparison between in vitro chemical and ex vivo biological assays to evaluate antioxidant capacity of botanical extracts

The anti-oxidative activity of plant-derived extracts is well-known and confers health-promoting effects on functional foods and food supplements. Aim of this work is to evaluate the capability of two different assays to predict the real biological antioxidant efficiency. At this purpose, extracts from five different plant-derived matrices and commercial purified phytochemicals were analyzed for their anti-oxidative properties by using well-standardized in vitro chemical method (TEAC) and an ex vivo biological assay. The biological assay, a cellular membrane system obtained from erythrocytes of healthy volunteers, is based on the capability of phytochemicals treatment to prevent membrane lipid peroxidation under oxidative stress by UV-B radiation. Plant extracts naturally rich in phenols with different structure and purified phytochemicals showed different in vitro and ex vivo antioxidant capacities. A high correlation between phenolic contents of the plant-derived extracts and their ability to prevent oxidative injuries in a biological system was found, thus underlying the relevance of this class of metabolites in preventing oxidative stress. On the other hand, a low correlation between the antioxidant capacities was shown between in vitro and ex vivo antioxidant assay. Moreover, data presented in this work show how food complex matrices are more effective in preventing oxidative damages at biological level than pure phytochemicals, even if for these latter, the antioxidant activity was generally higher than that observed for food complex matrices

Population pharmacokinetics of NNZ-2566 in healthy subjects

NNZ-2566 is a novel, small molecule being developed as a treatment for cognitive impairment in different CNS conditions, including Rett and Fragile-X syndrome, both of which are associated with moderate to severe neurodevelopmental disorder. In current study we characterise the population pharmacokinetics of NNZ-2566 after administration of single and repeated ascending doses to healthy subjects. A meta-analytical approach was used to analyse pharmacokinetic data from 3 different studies, in which a total of 61 healthy subjects (median age 23years, range 19 to 38) were treated with NNZ-2566. Doses of NNZ-2566 ranged from 6.0 to 100mg/kg after oral administration and from 0.1 to 30mg/kg after intravenous administration. A two-compartment model with first order absorption and elimination was found to best describe the pharmacokinetics of NNZ-2566. Inter-individual variability was identified in clearance, absorption rate, central volume of distribution, peripheral volume of distribution and inter-compartmental clearance. Population predicted clearance and central volume of distribution were 10.35L/h and 20.23L, respectively. No accumulation, metabolic inhibition or induction was observed during the course of treatment. Dose proportionality was observed across the dose range evaluated in healthy subjects. In addition, oral bioavailability appeared to vary with food intake. The relatively short half-life of 1.4h suggests the need for a twice or three times daily regimen to maintain relevant systemic levels of NNZ-2566 in plasma

A Phase 2 Study of AMO-02 (tideglusib) in Congenital and Childhood Onset Myotonic Dystrophy Type 1 (DM1)

Background: GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in Type 1 myotonic dystrophy (DM1), a rare neuromuscular disorder that manifests at any age. AMO-02 (tideglusib) inhibits GSK3β activity in preclinical models of DM1 and promotes cellular maturation as well as normalizing aberrant molecular and behavioral phenotypes. This Phase 2 study assessed the pharmacokinetics, safety and tolerability, and preliminary efficacy, of AMO-02 in adolescents and adults with Congenital and Childhood-onset DM1. Methods: Sixteen subjects (aged 13 to 34) with Congenital and Childhood-onset DM1 received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n=8) or 1000 mg (n=8) of AMO-02 (NCT02858908). Blood samples were obtained for pharmacokinetic assessment. Safety assessments, such as laboratory tests and ECGs, as well as efficacy assessments of syndromal, cognitive and muscular functioning, were obtained. Results: AMO-02 plasma concentrations conformed to a two-compartment model with first-order absorption and elimination, and dose-dependent increases in exposure (area-under-the-curve, or AUC) were observed. AMO-02 was generally safe and well-tolerated. No early discontinuations due to adverse events nor dose adjustments of AMO-02 occurred. The majority of subjects manifested clinical improvement in their CNS and neuromuscular symptoms after 12 weeks of treatment compared to the placebo baseline, with a larger response noted at the 1000 mg/day dose level. AMO-02 exposure (cumulative AUC) was significantly correlated (p<0.01) with change from baseline on several key efficacy assessments. Conclusion: AMO-02 has favorable pharmacokinetic and clinical risk/benefit profiles meriting further study as a potential treatment for Congenital and Childhood-onset DM1

Joint statement on the role of respiratory rehabilitation in the COVID-19 crisis: the Italian position paper.

Due to an exponential growth of the number of subjects affected by coronavirus disease 2019 (COVID-19), the entire Italian healthcare system had to respond promptly and in a very short time with the need of semi-intensive and intensive care units. Moreover, trained dedicated COVID-19 teams consisting of physicians coming from different specialties (intensivists or pneumologists and infectivologists), while respiratory therapists and nurses have been recruited to work on and on with rest. However, due to still limited and evolving knowledge of COVID-19 disease, there are little recommendations for need in respiratory rehabilitation and physiotherapy interventions. The presentation of this manuscript is the result of a consensus promoted by the Italian societies of respiratory health care professionals who contacted pulmonologists directly involved in the treatment and rehabilitation of COVID-19. The aim was to formulate the more proper and common suggestions to be applied in different hospital settings in offering rehabilitative programs and physiotherapy workforce planning in COVID-19 patients. Two main areas of intervention were identified: organization and treatment, which were described in this paper to face with the emergency

Knowledge, attitudes and behaviors regarding influenza vaccination among Hygiene and Preventive Medicine residents in Calabria and Sicily.

Vaccinating health care workers is considered to be one of the most important steps in preventing the transmission of the influenza virus to vulnerable patients. Public Health physicians are the main promoters and executors of influenza vaccination campaigns for both healthcare workers and the general population. The objective of the present survey was to analyze the knowledge, attitudes and practices regarding influenza vaccination among Hygiene and Preventive Medicine Residents. 64% of the participants had not been vaccinated against the influenza virus in the past 5 years, and 29% had been vaccinated only occasionally , with only 7.2% of the study popu-lation having been vaccinated every year. 20.3% of those surveyed were vaccinated in the 2010/2011 season. The best strategy to increase vaccination rates among health care workers according to the study participants was the participation of future public health operators to multidisciplinary training (34.8%). the main factors associated with influenza vaccination compliance were having been vaccinated in the previous season for 2011/2012 (OR [95%]: 41.14 [7.56 - 223.87]) and having received the vaccination always or occasionally during the previous 5 years for both 2010/2011 (p-value <0.0001) and 2011/2012 (p-value <0.0001). The findings of this study suggest that future public health physicians with a history of refusing influenza vaccination in previous years usually tend to maintain their beliefs over time. Changing this trend among Hygiene and Preventive Medicine residents is the real challenge for the future, and it can be achieved through organization of multidisciplinary training, improvement of university education and increasing the involvement of Hygiene and Preventive Medicine residents in influenza vaccination campaigns both for the gen-eral population and health care workers