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Abtract: Background: The life expectancy of people with Down syndrome (DS) has significantly increased in the last decades. We describe the congenital malformations and main comorbidities of a cohort of children and young people with DS and analyse their differences according to age and gender groups. Methods: This retrospective cross‐sectional study was conducted at DS centre of Bambino Gesù Children's Hospital in Rome (Italy). The period for reviewing all electronic health records ran from July 2016 to September 2017. We collected data on clinical conditions and compared them with the general paediatric population. Moreover, we compared the main comorbidities, dental diseases and body mass index data between age groups. Results: Seven hundred sixty‐three children and young people with DS included in this study were aged 7.45 ± 5.49 years. Gender distribution included 58.19% male patients. The majority of our population (71.04%) came from central regions of Italy. Respiratory diseases (19%), congenital heart defects (72.23%), malocclusions (58.62%), astigmatism (20.31%), farsightedness (16.51%), near‐sightedness (12.19%) and autoimmune hypothyroidism (3.28%) were more frequent in our population compared with the typical paediatric population. Upper respiratory tract infections and underweight were significantly more frequent in the youngest children, whereas dental diseases, refractive errors, obesity and autoimmune hypothyroidism increased over age. Conclusions: Children and young people with DS present a high prevalence of potentially treatable medical conditions making multidisciplinary teams a mandatory need for this population. [ABSTRACT FROM AUTHOR]

Robinson DO, Lin F, Lyon M, Raponi M, Cross E, White HE, Cox H, Clayton-Smith J, Baralle D. Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities. Defects at the level of pre-mRNA splicing are a common source of genetic mutation but such mutations are not always easy to identify from DNA sequence data alone. Clinical practice has only recently begun to incorporate analysis for this type of abnormality. Some base changes at the DNA level currently viewed as unclassified variants or missense mutations may influence RNA splicing. To address this problem for fibrillin 1 ( FBN1) gene missense mutations we have carried out RNA analysis and in silico analysis with splice site prediction programs on 40 cases with 36 different mutations. Direct analysis of RNA from blood was performed by cDNA preparation, PCR amplification of specific FBN1 fragments, gel electrophoresis and sequencing of the PCR products. Of the 36 missense base changes, direct RNA analysis identified 2 which caused an abnormality of splicing. In silico analysis using five splice site prediction programs did not always accurately predict the splicing seen by direct RNA analysis. In conclusion, some apparent missense mutations have an effect on splicing which can be identified by direct RNA analysis, however, in silico analysis of splice sites is not always accurate, should be carried out with more than one prediction program and results should be used with caution. [ABSTRACT FROM AUTHOR]

Nucleotide variations that do not alter the protein-coding sequence have been routinely considered as neutral. In light of the developments we have seen over the last decade or so in the RNA processing and translational field, it would be proper when assessing these variants to ask if this change is neutral, good or bad. This question has been recently partly addressed by genome-wide in silico analysis but significantly fewer cases by laboratory experimental examples. Of particular relevance is the effect these mutations have on the pre-mRNA splicing pattern. In fact, alterations in this process may occur as a consequence of translationally silent mutations leading to the expression of novel splicing isoforms and/or loss of an existing one. This phenomenon can either generate new substrates for evolution or cause genetic disease when aberrant isoforms altering the essential protein function are produced. In this review we briefly describe the current understanding in the field and discuss emerging directions in the study of the splicing mechanism by integrating disease-causing splicing mutations and evolutionary changes. [ABSTRACT FROM AUTHOR]

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the novel coronavirus responsible for worldwide coronavirus disease (COVID-19). We previously observed that Angiotensin-converting enzyme 2 (ACE2) and Dipeptidyl peptidase-4 (DPP4) are significantly overexpressed in naso-oropharyngeal swabs (NPS) of COVID-19 patients, suggesting their putative functional role in the disease progression. ACE2 and DPP4 overexpression in COVID-19 patients may be associated to epigenetic mechanism, such as miRNA differential expression. We investigated if hsa-let7b-5p, reported to target both ACE2 and DPP4 transcripts, could be involved in the regulation of these genes. We verified that the inhibition and overexpression of hsa-let7b-5p matched to a modulation of both ACE2 and DPP4 levels. Then, we observed a statistically significant downregulation (FC = -1.5; p < 0.05) of hsa-let7b-5p in the same COVID-19 and control samples of our previous study. This is the first study that shows hsa-let7b-5p low expression in naso-oropharyngeal swabs of COVID-19 patients and demonstrates a functional role of this miR in regulating ACE2 and DPP4 levels. These data suggest the involvement of hsa-let7b-5p in the regulation of genes necessary for SARS-CoV-2 infections and its putative role as a therapeutic target for COVID-19., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background & Aims: As dietary components are delivered directly to the periportal zone of the liver lobule, there is the potential for greater injury in this zone (zone 1) compared to the perivenous zone (zone 3). We investigated the associations between dietary fructose consumption and uric acid concentrations and differential zonal injury in periportal and perivenous zones., Methods: A total of 271 children's histological images were scored in 5 periportal and 5 perivenous zones for steatosis, ballooning, inflammation and fibrosis severity. Dietary fructose consumption (g/d) was assessed and uric acid measured in serum. Logistic regression was undertaken to test associations between both high fructose consumption and hyperuricaemia, and histological disease in periportal and perivenous zones., Results: Children with a mean age of 12.5 years were included in the study. Inflammation (mean ± SD) was increased in the periportal vs perivenous zones (0.78 ± 0.43 vs 0.41 ± 0.48, P = .041). There were non-significant trends towards greater steatosis, ballooning and fibrosis in the periportal zone. In the fully adjusted models, high fructose intake was associated with disease in both zones. Example for periportal and perivenous zones, respectively, steatosis 1.56 (1.12, 2.49) and 1.21 (1.09, 2.73); inflammation 4.29 (2.31, 5.88) and 3.69 (2.14, 4.56); and fibrosis 2.72 (1.43, 3.76) and 1.96 (1.24, 2.37). Hyperuricaemia (uric acid ≥5.9 mg/dL) was associated with inflammation in the periportal zone 1.71 (1.17, 2.35); and was associated with steatosis and fibrosis in both zones; for example, for periportal and perivenous zones, respectively, steatosis 2.98 (1.65, 3.23) and 1.14 (1.05, 1.99); and fibrosis, 2.65 (1.35, 2.99) and 1.31 (1.13, 2.17)., Conclusions: High fructose consumption is associated with disease severity in both lobular zones and hyperuricaemia may be associated with more severe disease in the periportal zone., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)