Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Genetics of disease, diagnosis and treatmen

Risky interpretations across the length scales: continuum vs. discrete models for soft tissue mechanobiology

Modelling and simulation in mechanobiology play an increasingly important role to unravel the complex mechanisms that allow resident cells to sense and respond to mechanical cues. Many of the in vivo mechanical loads occur on the tissue length scale, thus raising the essential question how the resulting macroscopic strains and stresses are transferred across the scales down to the cellular and subcellular levels. Since cells anchor to the collagen fibres within the extracellular matrix, the reliable representation of fibre deformation is a prerequisite for models that aim at linking tissue biomechanics and cell mechanobiology. In this paper, we consider the two-scale mechanical response of an affine structural model as an example of a continuum mechanical approach and compare it with the results of a discrete fibre network model. In particular, we shed light on the crucially different mechanical properties of the 'fibres' in these two approaches. While assessing the capability of the affine structural approach to capture the fibre kinematics in real tissues is beyond the scope of our study, our results clearly show that neither the macroscopic tissue response nor the microscopic fibre orientation statistics can clarify the question of affinity.ISSN:1617-7959ISSN:1617-794

The control of epidermal stem cells (holoclones) in the treatment of massive full-thickness burns with autologous keratinocytes cultured on fibrin. [5YIF: 3.60, Citations: 215]

BACKGROUND: Cell therapy is an emerging therapeutic strategy aimed at replacing or repairing severely damaged tissues with cultured cells. Epidermal regeneration obtained with autologous cultured keratinocytes (cultured autografts) can be life-saving for patients suffering from massive full-thickness burns. However, the widespread use of cultured autografts has been hampered by poor clinical results that have been consistently reported by different burn units, even when cells were applied on properly prepared wound beds. This might arise from the depletion of epidermal stem cells (holoclones) in culture. Depletion of holoclones can occur because of (i) incorrect culture conditions, (ii) environmental damage of the exposed basal layer of cultured grafts, or (iii) use of new substrates or culture technologies not pretested for holoclone preservation. The aim of this study was to show that, if new keratinocyte culture technologies and/or "delivery systems" are proposed, a careful evaluation of epidermal stem cell preservation is essential for the clinical performance of this life-saving technology. METHODS: Fibrin was chosen as a potential substrate for keratinocyte cultivation. Stem cells were monitored by clonal analysis using the culture system originally described by Rheinwald and Green as a reference. Massive full-thickness burns were treated with the composite allodermis/cultured autograft technique. RESULTS: We show that: (i) the relative percentage of holoclones, meroclones, and paraclones is maintained when keratinocytes are cultivated on fibrin, proving that fibrin does not induce clonal conversion and consequent loss of epidermal stem cells; (ii) the clonogenic ability, growth rate, and long-term proliferative potential are not affected by the new culture system; (iii) when fibrin-cultured autografts bearing stem cells are applied on massive full-thickness burns, the "take" of keratinocytes is high, reproducible, and permanent; and (iv) fibrin allows a significant reduction of the cost of cultured autografts and eliminates problems related to their handling and transportation. CONCLUSION: Our data demonstrate that: (i) cultured autografts bearing stem cells can indeed rapidly and permanently cover a large body surface; and (ii) fibrin is a suitable substrate for keratinocyte cultivation and transplantation. These data lend strength to the concept that the success of cell therapy at a clinical level requires cultivation and transplantation of stem cells. We therefore suggest that the proposal of a culture system aimed at the replacement of any severely damaged self-renewing tissue should be preceded by a careful evaluation of its stem cell population

Sibling Proactive and Reactive Aggression in Adolescence

We describe sibling proactive and reactive aggression in middle and late adolescence. Participants were 8th (n0303, Mage013.74 years, SD0.59) and 12th (n0300, Mage017.73 years, SD0.56) grade adolescents who completed an in-school survey. Findings revealed that these adolescents were significantly more likely to engage in reactive than proactive aggression with their closest-aged sibling. However, 8th grade adolescents reported greater aggression toward their closest-aged sibling than did 12th grade adolescents. In addition, sex composition of the sibling dyad moderated the association between sibling relationship quality (i.e., warmth and rivalry) and both proactive and reactive aggression indicating unique links for brotherbrother and older sister-younger brother pairs

Favorable effects of omega-3 PUFAs on glucose control in an adolescent with type 1 diabetes using continuous glucose monitoring : a case report

Omega-3 polyunsaturated fatty acids (PUFAs) represent valuable dietary adjuncts for subjects with hypertriglyceridemia and at increased risk of cardiovascular disease, including subjects with type 1 diabetes (T1D). However, the exact role of omega-3 PUFAs in the regulation of glucose homeostasis and chronic complications in patients with diabetes remains uncertain. Herein, we report a 3-year follow-up of an athlete adolescent with T1D who started to use continuous glucose monitoring (CGM) two years after the diagnosis, and initiated omega-3 PUFA supplementation four years after the clinical onset of T1D. CGM metrics related to a 18-month period of omega-3 PUFA supplementation (50 mg/Kg/day of EPA and DHA) was compared to CGM metrics referring to a 18-month period prior to the nutrition intervention. Omega-3 PUFA supplementation resulted in a significant reduction of mean glucose and glucose variability, along with a significant increase in Time in range (TIR) 70-180 mg/dL. No significant changes were observed in daily insulin requirements between the two study periods. Future studies will be of assistance to better understand the exact impact of omega-3 PUFAs on the regulation of glucose homeostasis in patients with type 1 and its complications

Immunofluorescence mapping, electron microscopy and genetics in the diagnosis and sub-classification of inherited epidermolysis bullosa: a single-centre retrospective comparative study of 87 cases with long-term follow-up

Background: Epidermolysis bullosa (EB) comprises a heterogeneous group of skin fragility disorders, classified in four major types based on skin cleavage level, i.e. EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), Kindler EB, and in more than 30 subtypes defined by the combination of laboratory and clinical data, including disease course. Objectives: Our aims were to address whether, in the age of genomics, electron microscopy (TEM) has still a role in diagnosing EB, and whether the genotype per se may be sufficient to sub-classify EB. Methods: A thoroughly characterized single-centre EB case series was retrospectively evaluated to compare the power of TEM with immunofluorescence mapping (IFM) in establishing the EB type, and the ability of TEM, IFM and genetics to predict selected EB subtypes, i.e. severe dominant EBS (DEBS), severe JEB, severe recessive DEB (RDEB) and DEB self-improving, using genetic and final diagnosis, respectively, as gold standard. Results: The series consisted of 87 patients, including 44 newborns, with a median follow-up of 54\ua0months. Ninety-five mutations were identified in EB-associated genes, including 25 novel variants. Both IFM and TEM were diagnostic in about all cases of JEB (21/21 for both) and DEB (43/44 for IFM, 44/44 for TEM). TEM sensitivity was superior to IFM for EBS (19/20 vs. 16/19). As to EB subtyping, IFM performed better than genetics in identifying severe JEB cases due to laminin-332 defect (14/14 vs. 10/14) and severe RDEB (eight/nine vs. seven/nine). Genetics had no role in self-improving DEB diagnosis; it almost equalled TEM in predicting severe DEBS (eight/nine vs. nine/nine) and enabled to discriminate dominant from recessive non-severe DEB phenotypes and to identify special subtypes, e.g. DEBS with KLHL24 mutations. Conclusions: Transmission electron microscopy remains relevant to the diagnosis of EBS. IFM and genetics are essential and complementary tools in the vast majority of EB cases

The role of PET in supratentorial and infratentorial pediatric brain tumors

Objective: This review aims to provide a summary of the clinical indications and limitations of PET imaging with different radiotracers, including 18F-fluorodeoxyglucose (18F-FDG) and other radiopharmaceuticals, in pediatric neuro-oncology, discussing both supratentorial and infratentorial tumors, based on recent literature (from 2010 to present). Methods: A literature search of the PubMed/MEDLINE database was carried out searching for articles on the use of PET in pediatric brain tumors. The search was updated until December 2020 and limited to original studies published in English after 1 January 2010. Results: 18F-FDG PET continues to be successfully employed in different settings in pediatric neuro-oncology, including diagnosis, grading and delineation of the target for stereotactic biopsy, estimation of prognosis, evaluation of recurrence, treatment planning and assessment of treatment response. Nevertheless, non-18F-FDG tracers, especially amino acid analogues seem to show a better performance in each clinical setting. Conclusions: PET imaging adds important information in the diagnostic work-up of pediatric brain tumors. International or national multicentric studies are encouraged in order to collect larger amount of data

DICER1-associated malignancies mimicking germ cell neoplasms: Report of two cases and review of the literature

DICER1 syndrome is characterized by a unique combination of features and a growing list of associated rare tumors. Traditionally, gonadal or extra-gonadal teratomas have not been considered part of this spectrum, with only rare DICER1-related teratoid neoplasms recently reported. Besides, their methylation profiles remain elusive. We report two DICER1-associated malignancies involving the lumbar spine of a 22-year-old man (case 1) and the pelvic cavity of a 14-year-old girl (case 2). Both tumors exhibited teratoma-like features with a high-grade malignant somatic component, including rhabdomyosarcomatous elements for case 1 and a malignant neuroectodermal neoplasm with features of an embryonal tumor with multilayered rosettes (ETMR) for case 2. Both tumors showed strong SALL4 expression and H3K27me3 loss by immunohistochemistry. Next-generation sequencing studies confirmed biallelic DICER1 mutations with additional pathogenic missense mutations in KRAS (case 1) and CTNNB1 (case 2). The methylation profile of case 1 clustered with DICER1-associated sarcomas, whereas case 2 classified as an ETMR (albeit low raw and calibrated score). In conclusion, we report two DICER1-related malignancies with teratoma-like features, further expanding their morphologic spectrum and highlighting the multipotentiality of their presumed cell of origin. Notably, we describe the first ETMR identified outside the CNS with a documented DICER1 biallelic inactivation. Our findings also highlight the potential role of other molecular alterations such as KRAS and CTNNB1 mutations in defining the phenotype of embryonal and primitive DICER1-associated neoplasms, a notion that deserves further studies