The role of histone lysine methylation in the response of mammalian cells to Ionizing radiation

Eukaryotic genomes are wrapped around nucleosomes and organized into different levels of chromatin structure. Chromatin organization has a crucial role in regulating all cellular processes involving DNA-protein interactions, such as DNA transcription, replication, recombination and repair. Histone post-translational modifications (HPTMs) have a prominent role in chromatin regulation, acting as a sophisticated molecular code, which is interpreted by HPTM-specific effectors. Here, we review the role of histone lysine methylation changes in regulating the response to radiation-induced genotoxic damage in mammalian cells. We also discuss the role of histone methyltransferases (HMTs) and histone demethylases (HDMs) and the effects of the modulation of their expression and/or the pharmacological inhibition of their activity on the radio-sensitivity of different cell lines. Finally, we provide a bioinformatic analysis of published datasets showing how the mRNA levels of known HMTs and HDMs are modulated in different cell lines by exposure to different irradiation conditions

Neuroserpin polymers cause oxidative stress in a neuronal model of the dementia FENIB

The serpinopathies are human pathologies caused by mutations that promote polymerisation and intracellular deposition of proteins of the serpin superfamily, leading to a poorly understood cell toxicity. The dementia FENIB is caused by polymerisation of the neuronal serpin neuroserpin (NS) within the endoplasmic reticulum (ER) of neurons. With the aim of understanding the toxicity due to intracellular accumulation of neuroserpin polymers, we have generated transgenic neural progenitor cell (NPC) cultures from mouse foetal cerebral cortex, stably expressing the control protein GFP (green fluorescent protein), or human wild type, G392E or delta NS. We have characterised these cell lines in the proliferative state and after differentiation to neurons. Our results show that G392E NS formed polymers that were mostly retained within the ER, while wild type NS was correctly secreted as a monomeric protein into the culture medium. Delta NS was absent at steady state due to its rapid degradation, but it was easily detected upon proteasomal block. Looking at their intracellular distribution, wild type NS was found in partial co-localisation with ER and Golgi markers, while G392E NS was localised within the ER only. Furthermore, polymers of NS were detected by ELISA and immunofluorescence in neurons expressing the mutant but not the wild type protein. We used control GFP and G392E NPCs differentiated to neurons to investigate which cellular pathways were modulated by intracellular polymers by performing RNA sequencing. We identified 747 genes with a significant upregulation (623) or downregulation (124) in G392E NS-expressing cells, and we focused our attention on several genes involved in the defence against oxidative stress that were up-regulated in cells expressing G392E NS (Aldh1b1, Apoe, Gpx1, Gstm1, Prdx6, Scara3, Sod2). Inhibition of intracellular anti-oxidants by specific pharmacological reagents uncovered the damaging effects of NS polymers. Our results support a role for oxidative stress in the cellular toxicity underlying the neurodegenerative dementia FENIB

Central metatarsal fractures: a review and current concepts

Central metatarsal fractures (CMF) are common injuries. More frequently fractures are those of the fifth metatarsal, followed by CMF and therefore by the first metatarsal. Third metatarsal is injured most frequently than the others and up to 63% is associated with second or fourth metatarsal fractures and up to 28% with both. Anatomy and metatarsal kinematics merits attention due to its influence on function, injuries and treatment options. Diagnosis is based on the history of trauma and clinical examination, relating with instrumental exams. Fractures with less than 10\ub0 of angulation and 3-4 mm of translation in any plane are typically treated conservatively, while operative treatment is generally reserved for fractures out if these values. Intramedullary fixation with K-wires seem to be the most common and valid surgical treatment in simple fractures. Spiral fractures should be treated by interfragmentary screws, which positioning may result difficult due to the adjacent metatarsals. Therefore, an alternative approach is an osteosynthesis with a dorsal plate. Multiple metatarsal fractures often occur in the contiguous bones, so clinicians will also have to carefully inspect metatarsals and adjacent joints such as Lisfranc articulation. The clinical and functional outcomes are often influenced by the pattern of fractures and patient conditions and are reported in the literature up to 39% of poor results

Total ankle replacement in young patients

High physical demand and younger age are currently considered contraindications for total ankle replacement. The number of Total Ankle Replacements (TAR) is widespread increasing and indications are expanding thanks to a steady improvement in prosthetic designs and better outcome. Commentary of the literature: in 1999 a study of 100 uncemented STAR\u2122 (Waldemar-Link, Hamburg, Germany) prostheses showed a survival rate of 75% at 6.8 years in patients under 50 years old. Other studies (es, Barg et Al.) shows the risk of failure age-related in young patients compared to older group. A report of 780 TAR from the Swedish Ankle Register showed patients with primary or post-traumatic osteoarthritis under  60 years of age to have a 1.8 higher chance of revision compared to older patients. Discussion: ankle replacement has been traditionally reserved for patients older 50 years old and with low physical demand. Contrariwise this belief, TAR have already been used with a wide range of ages, sometimes even patients younger than 30 years old. Most of the "negative" score and results showed before are related to "second-generation" prosthetic designs, while recent studies used a "third-generation" prosthetic design. Conclusions: recent evidences showed better clinical results and higher satisfaction in people under the age of 50 compared to ankle arthrodesis with comparable rate of complications and survivorship. Younger people will have however a higher rate of reoperation but in the meantime, they will prevent progressive degeneration of adjacent joints

Effect of the iodine atom position on the phosphorescence of BODIPY derivatives: a combined computational and experimental study

A new BODIPY derivative (o-I-BDP) containing an iodine atom in the ortho position of the meso-linked phenyl group was prepared. Photophysical and electrochemical properties of the molecule were compared to previously reported iodo BODIPY derivatives, as well as to the non-iodinated analog. While in the case of derivatives featuring iodine substituents in the BODIPY core, efficient population of the triplet state is accompanied by a substantial positive shift of the reduction potential compared to pristine BODIPY, o-I-BDP displays phosphorescence and simultaneously maintains the electrochemical properties of unsubstituted BODIPYs. A theoretical investigation was settled to analyze results and rationalize the influence of iodine position on electronic and photophysical properties, with the purpose of preparing a fully organic phosphorescent BODIPY derivative. TD-DFT and spin-orbit coupling calculations shed light on the subtle effects played by the introduction of iodine atom in different positions of BODIPY

Effectiveness of corticosteroid injections in Civinini-Morton's Syndrome: A systematic review

BACKGROUND: The aim of this paper is to analyze the effectiveness of corticosteroid injections (CI), in combination with or without a local anaesthetic, for Civinini-Morton's Syndrome to determine which protocol could be the most appropriate among conservative treatments.METHODS: All selected articles were screened using a thorough database search of PubMed, EMBASE and SCOPUS to assess their suitability to the research focus.RESULTS: Selection produced 10 articles as full-text, for a total of 590 patients, with a mean follow-up of 14 \ub1 14.2 (range 3-48) months. Johnson satisfaction scale, resulting from 6 studies, scored 25.6% (range 5-38) and 39.4% (range 15-51.8), respectively completely satisfied and satisfied with minor reservations. Mean VAS, declared in 5 studies, decreased from 70.7 \ub1 16.5 (range 67-89) to 33.4 \ub1 7.6 (26-42.5) points (p < 0.01). Most common complication was skin depigmentation in 7 (2.6%) cases.CONCLUSIONS: CI appear to be a safe treatment allowing good results with a very low complications rate. A neuroma of 6.3 mm seems to be the cut-off size; below which CI could have best indications and be considered as an intermediate treatment between shoe modifications and more invasive procedures such as percutaneous alcoholization or surgery.LEVEL OF EVIDENCE: Level II, systematic review

Value of three-dimensional printing of fractures in orthopaedic trauma surgery

Objective Information technology-based innovation is playing an increasingly key role in healthcare systems. The use of three-dimensional (3D)-printed bone fracture replicas in orthopaedic clinical practice could provide a new tool for fracture simulations and treatment, and change the interaction between patient and surgeon. We investigated the additional value of 3D-printing in the preparation and execution of surgical procedures and communication with patients, as well as its teaching and economic implications. Methods Fifty-two patients with complex articular displaced fractures of the calcaneus, tibial plateau, or distal radius were enrolled. 3D-printed real-size models of the fractured bone were obtained from computed tomography scans and exported to files suitable for 3D-printing. The models were handled by trauma surgeons, residents, and patients to investigate the potential advantages and procedural improvements. The patients' and surgeons' findings were recorded using specific questionnaires. Results 3D-printed replicas of articular fractures facilitated surgical planning and preoperative simulations, as well as training and teaching activities. They also strengthening the informed consent process and reduced surgical times and costs by about 15%. Conclusion 3D-printed models of bone fractures represent a significant step towards more-personalized medicine, with improved education and surgeon-patient relationships

Clinical Efficacy of A Nutraceutical Approach for the Management of Dyslipidemia in Metabolic Disorders: A One-Year Treatment With Armolipid Plus

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Trend of change of sperm count and concentration over the last two decades: A systematic review and meta‐regression analysis

Background: Since the 1970s, several studies found that sperm concentration (SC) and total sperm count (TSC) constantly worsened over time, mainly in high-income countries. Objectives: To evaluate whether the decreasing trend in sperm count is continuing in Western European countries and USA, we performed a systematic review and meta-regression analysis. Materials and methods: Embase and Pubmed/Medline were searched papers published in English in the 2000-2020 period limiting the search to data collected in the USA and Western European countries. Results: We identified 62 articles and pooled information on 24,196 men (range 10-2,523), collected from 1993 to 2018. Considering all the studies, random-effects meta-regression analyses showed no significant trend for SC (slope per year -0.07 mil/mL, p-value = 0.86). Negative trends of SC were detected in Scandinavian countries (slope per year -1.11 mil/mL, 95% CI: -2.40 to +0.19; p-value = 0.09), but the findings were statistically not significant. No significant trends of SC were detected in Central Europe (slope per year +0.23, 95% CI -2.51 to +2.96; p-value = 0.87), the USA (slope per year +1.08, 95% CI -0.42 to +2.57; p-value = 0.16), and Southern Europe (slope per year +0.19, 95% CI -0.99 to +1.37; p-value = 0.75). We have analyzed separately findings from studies including sperm donors, fertile men, young unselected men (unselected men, study mean age < 25 years) and unselected men (unselected men, study mean age ≥ 25 years). No significant trends of SC were observed among sperm donors (slope per year -2.80, 95% CI -6.76 to +1.17; p-value 0.16), unselected men (slope per year -0.23, 95% CI -1.58 to +1.12; p-value 0.73), young unselected men (slope per year -0.49, 95% CI -1.76 to +0.79; p-value 0.45), fertile men (slope per year +0.29, 95% CI -1.09 to +1.67; p-value 0.68). Discussion and conclusion: The results of this analysis show no significant trends in SC, in USA, and selected Western European countries

RELATIONSHIP BETWEEN POLYMORPHISMS OF TAS2R38 BITTER TASTE RECEPTOR AND CHRONIC UPPER AIRWAY INFECTIONS

1Department of Neuroscience, ENT Section, “Federico II” University of Naples, Italy 2Department of Translational Medical Sciences, European Laboratory for Food Induced Diseases, Napoli, Italy The presence of taste receptors in extra-oral tissues may suggest additional roles apart from taste perception. Recently, an increasing number of reports demonstrated that the bitter taste G-protein coupled receptors family T2R, expressed in ciliated epithelial cells of the respiratory tract, are able to detect bacterial products and to stimulate innate immune defense against pathogens. Most microbial agents, secretes chemical signals known as quorum-sensing molecules that regulate the expression of genes involved in biofilm formation, virulence and other vital processes for microorganisms. Among the quorum-sensing molecules, the AHLs produced by P. aeruginosa, activate the receptor for bitter T2R38 expressed in ciliated epithelial cells of the respiratory tract, whereas mutants of P. aeruginosa lacking the AHL are not able to activate it. The activation of the receptor results in an increase of the Ca2+ flow and the ciliary beat frequency, as well as stimulating the production of NO which acts as a bactericide against the pathogen. The Caucasian population express three common polymorphisms (Pro49Ala, Ala262Val, Val296Ile) for TAS2R38 that lead to two major haplotypes PAV and AVI. The expression of either haplotype gives respectively 2 forms of receptors ̶ functional or non-functional ̶ i.e. unable to respond to specific agonists such phenylthiocarbamide and propylthiouracil (PROP). The two haplotypes PAV and AVI segregate into two major phenotypic classes: the "functional", sensitive to bitter, are homo- or heterozygous for the allele PAV, the "non-functional", are homozygous for the allele AVI. The genetic variations of the receptor TAS2R38 that affect sensitivity to bitter taste can help determine individual differences in susceptibility to bacterial infections of the respiratory tract allowing to plan a “target therapy”. Cellular cultures from homozygous PAV/PAV individuals showed a more effective NO production, mucociliary clearance and bactericide effect than cultures from AVI/PAV or AVI/AVI individuals. As a consequence it is reasonable to assume that patients with genotype AVI/PAV or AVI/AVI are at greater risk of contracting infections from gram-negative, compared with homozygous PAV. Some authors have studied the correlation between genotype and microbiological results TAS2R38 tissue of respiratory mucosa. The result of this analysis proved to be very interesting, because it showed a significant difference in the frequency of non-functional (AVI) than functional (PAV) among patients whose cultures were positive for Gram-negative bacteria, including P. aeruginosa. The aim of the study was to characterize phenotypically the sensitivity to PROP and the receptor polymorphisms of TAS2R38, in patients with chronic or recurrent infections of the upper respiratory tract to identify high risk patients. The identification of high-risk individuals would allow to draw up protocols for specific follow-up and appropriate “target therapy”