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Truncating mutations in PRNP have been associated with heterogeneous phenotypes ranging from chronic diarrhea and neuropathy to dementia, either rapidly or slowly progressive. We identified novel PRNP stop‐codon mutations (p.Y163X, p.Y169X) in two Italian kindreds. Disease typically presented in the third or fourth decade with progressive autonomic failure and diarrhea. Moreover, one proband (p.Y163X) developed late cognitive decline, whereas some of his relatives presented with isolated cognitive and psychiatric symptoms. Our results strengthen the link between PRNP truncating mutations and systemic abnormal PrP deposition and support a wider application of PRNP screening to include unsolved cases of familial autonomic neuropathy.

The C9orf72 repeat expansion (RE) is one of the most frequent causative mutations of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, it is still unclear how the C9orf72 RE can lead to a heterogeneous phenotype. Several reports have shown the coexistence of mutations in multiple ALS/FTD causative genes in the same family, suggesting an oligogenic etiology for ALS and FTD. Our aim was to investigate this phenomenon in an Italian group of ALS/FTD pedigrees carrying the C9orf72 RE. We included 11 subjects from 11 pedigrees with ALS/FTD and the C9orf72 RE. Mutation screening of FUS , SOD1 and TARDBP genes was performed by direct sequencing. A dementia-specific custom-designed targeted next-generation sequencing panel was used for screening dementia-associated genes mutations. We found genetic variants in additional ALS or dementia-related genes in four pedigrees, including the p.V47A variant in the TYROBP gene. As a group, double mutation carriers displayed a tendency toward a younger age at onset and a higher frequency of positive familiar history and of parkinsonism. Our observation supports the hypothesis that the co-presence of mutations in different genes may be relevant for the clinical expression of ALS/FTD and of their oligogenic nature.

Recurrent focal neuropathy with liability to pressure palsies is a relatively frequent autosomal-dominant demyelinating neuropathy linked to peripheral myelin protein 22 ( PMP22 ) gene deletions. The combination of PMP22 gene mutations with other genetic variants is known to cause a more severe phenotype than expected. We present the case of a patient with severe orthostatic hypotension since 12 years of age, who inherited a PMP22 gene deletion from his father. Genetic double trouble was suspected because of selective sympathetic autonomic disturbances. Through exome-sequencing analysis, we identified two novel mutations in the dopamine beta hydroxylase gene. Moreover, with interactome analysis, we excluded a further influence on the origin of the disease by variants in other genes. This case increases the number of unique patients presenting with dopamine-β-hydroxylase deficiency and of cases with genetically proven double trouble. Finding the right, complete diagnosis is crucial to obtain adequate medical care and appropriate genetic counseling.

This study investigates the potential reuse of Prunus spinosa (blackthorn) seeds, a food industry by-product. Traditionally discarded, these seeds are now being explored for their bioactive compounds. In this work, seeds were used as raw material for supercritical CO2 extraction. Two distinct extracts were obtained at low and high pressure (SFE90 and SFE200) and both extracts presented an aqueous phase (WE90 and WE200). SFE90 analysis by GC/MS allowed us to identify benzaldehyde and fatty acids (mainly oleic and linoleic acids). The fatty acid profile of SFE200, determined by HPLC-DAD/ELSD, showed that oleic and linoleic acids were predominant in supercritical oil. The phytochemical composition of the water extracts, analyzed via LC-DAD-ESI-MS, revealed that higher pressure enhanced the recovery of specific flavonols and anthocyanins, while lower pressure preserved various polyphenolic subclasses. WE90 was rich in 3-feruloylquinic acid and cyanidin-3-O-rutinoside, whereas WE200 was rich in caffeic acid hexoside 2 and dihydro-o-coumaric acid glucoside. Benzaldehyde was individuated in WE90 and WE200 by HPLC-DAD analysis. Cytotoxicity assays demonstrated that WE90, WE200 and SFE200 had anticancer effects on SH-SY5Y neuroblastoma cells, while all extracts did not remarkably affect the viability and morphology of human skin keratinocytes (HaCaT cells). These results suggest that P. spinosa seed extracts have potential nutraceutical and pharmaceutical applications.

This study investigates the chemical composition, nutritional, and biological properties of extracts obtained from A. melanocarpa berries using different extraction methods and solvents. Hydrodistillation and supercritical fluid extraction with CO2 allowed us to isolate fruit essential oil (HDEX) and fixed oil (SFEEX), respectively. A phenol-enriched extract was obtained using a mild ultrasound-assisted maceration with methanol (UAMM). The HDEX most abundant component, using gas chromatography-mass spectrometry (GC/MS), was italicene epoxide (17.2%), followed by hexadecanoic acid (12.4%), khusinol (10.5%), limonene (9.7%), dodecanoic acid (9.7%), and (E)-anethole (6.1%). Linoleic (348.9 mg/g of extract, 70.5%), oleic (88.9 mg/g, 17.9%), and palmitic (40.8 mg/g, 8.2%) acids, followed by α-linolenic and stearic acids, were the main fatty acids in SFEEX determined using high-performance liquid chromatography coupled with a photodiode array detector and an evaporative light scattering detector (HPLC-DAD/ELSD). HPLC-DAD analyses of SFEEX identified β-carotene as the main carotenoid (1.7 mg/g), while HPLC with fluorescence detection (FLU) evidenced α-tocopherol (1.2 mg/g) as the most abundant tocopherol isoform in SFEEX. Liquid chromatography-electrospray ionization-MS (LC-ESI-MS) analysis of UAMM showed the presence of quercetin-sulfate (15.6%, major component), malvidin 3-O-(6-O-p-coumaroyl) glucoside-4-vinylphenol adduct (pigment B) (9.3%), di-caffeoyl coumaroyl spermidine (7.6%), methyl-epigallocatechin (5.68%), and phloretin (4.1%), while flavonoids (70.5%) and phenolic acids (23.9%) emerged as the most abundant polyphenol classes. UAMM exerted a complete inhibition of the cholesterol oxidative degradation at 140 °C from 75 μg of extract, showing 50% protection at 30.6 μg (IA50). Furthermore, UAMM significantly reduced viability (31–48%) in A375 melanoma cells in the range of 500–2000 μg/mL after 96 h of incubation (MTT assay), with a low toxic effect in normal HaCaT keratinocytes. The results of this research extend the knowledge of the nutritional and biological properties of A. melanocarpa berries, providing useful information on specific extracts for potential food, cosmetic, and pharmaceutical applications.

Complement activation contributes to lung dysfunction in coronavirus disease 2019 (COVID-19). We assessed whether C5 blockade with eculizumab could improve disease outcome. In this single-centre, academic, unblinded study two 900 mg eculizumab doses were added-on standard therapy in ten COVID-19 patients admitted from February 2020 to April 2020 and receiving Continuous-Positive-Airway-Pressure (CPAP) ventilator support from ≤24 hours. We compared their outcomes with those of 65 contemporary similar controls. Primary outcome was respiratory rate at one week of ventilator support. Secondary outcomes included the combined endpoint of mortality and discharge with chronic complications. Baseline characteristics of eculizumab-treated patients and controls were similar. At baseline, sC5b-9 levels, ex vivo C5b-9 and thrombi deposition were increased. Ex vivo tests normalised in eculizumab-treated patients, but not in controls. In eculizumab-treated patients respiratory rate decreased from 26.8±7.3 breaths/min at baseline to 20.3±3.8 and 18.0±4.8 breaths/min at one and two weeks, respectively (p<0.05 for both), but did not change in controls. Between-group changes differed significantly at both time-points (p<0.01). Changes in respiratory rate correlated with concomitant changes in ex vivo C5b-9 deposits at one (rs = 0.706, p = 0.010) and two (rs = 0.751, p = 0.032) weeks. Over a median (IQR) period of 47.0 (14.0-121.0) days, four eculizumab-treated patients died or had chronic complications versus 52 controls [HRCrude (95% CI): 0.26 (0.09-0.72), p = 0.010]. Between-group difference was significant even after adjustment for age, sex and baseline serum creatinine [HRAdjusted (95% CI): 0.30 (0.10-0.84), p = 0.023]. Six patients and 13 controls were discharged without complications [HRCrude (95% CI): 2.88 (1.08-7.70), p = 0.035]. Eculizumab was tolerated well. The main study limitations were the relatively small sample size and the non-randomised design. In patients with severe COVID-19, eculizumab safely improved respiratory dysfunction and decreased the combined endpoint of mortality and discharge with chronic complications. Findings need confirmation in randomised controlled trials.

Background: Several challenges and emotional demands characterize adolescence, affecting the mental well-being of youths. Among these, bullying and cyberbullying are recognized nowadays as a major social problem, affecting more than one-third of adolescents, with extensive negative consequences for the victims involved, such as lower self-esteem, increased loneliness, depression, and anxiety. School programs and interventions that foster resilience, coping, and well-being are particularly important during adolescence as protective and preventive factors against the consequences of (cyber)bullying. The paper presents two recent co-designed interventions for (cyber)bullying prevention deployed in Europe, targeting early adolescents and their school communities. Methods: The UPRIGHT project developed an evidence-based, whole-school intervention to train resilience as a protective factor to promote mental well-being in adolescents, in a cross-national perspective. The CREEP project designed and implemented digital interventions to support schools in (i) early detection of cyberbullying events on social media and (ii) coaching adolescents (victims, bullies, bystanders) on how to cope with (cyber)bullying behaviors. Results: The main challenges and insights collected during the design and implementation of both interventions are discussed to inform future research and practice. Conclusion: The feasibility and acceptance of prevention programs are key to the reducing risk of (cyber)bullying and improving the psychological well-being of early adolescents.

Parkinson’s disease (PD) is a multisystem disorder, with early changes extending beyond basal ganglia circuitries and involving non-dopaminergic pathways, including cerebellar networks. Whether cerebellar dysfunction reflects a compensatory mechanism or an intrinsic hallmark of disease progression remains unresolved. In this cross-sectional study, we examined how cerebellar γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx) systems, as well as their excitatory/inhibitory (E/I) balance, are modulated along the disease course. As to ascertain how these mechanisms contribute to motor and non-motor features in the premotor and early stages of PD, 18 individuals with isolated REM sleep behavior disorder (iRBD), 20 de novo, drug-naïve PD (dnPD), and 18 matched healthy controls underwent clinical, cognitive, and neuropsychiatric assessments alongside cerebellar magnetic resonance spectroscopy (MRS, MEGA-PRESS, 3T). While cerebellar neurotransmitter levels did not differ significantly across groups, dnPD patients exhibited a shift toward hyperexcitability in the E/I ratio, without correlation to clinical or cognitive measures. In contrast, in iRBD, an inverse relationship between heightened GABAergic activity and neuropsychiatric symptoms emerged. These findings suggest an early, dynamic cerebellar involvement, potentially reflecting compensatory modulation of altered basal ganglia output. Our results support cerebellar GABA MRS as a promising biomarker and open perspectives for targeting non-dopaminergic pathways in PD.

This study investigates the potential reuse of Prunus spinosa (blackthorn) seeds, a food industry by-product. Traditionally discarded, these seeds are now being explored for their bioactive compounds. In this work, seeds were used as raw material for supercritical CO[sub.2] extraction. Two distinct extracts were obtained at low and high pressure (SFE90 and SFE200) and both extracts presented an aqueous phase (WE90 and WE200). SFE90 analysis by GC/MS allowed us to identify benzaldehyde and fatty acids (mainly oleic and linoleic acids). The fatty acid profile of SFE200, determined by HPLC-DAD/ELSD, showed that oleic and linoleic acids were predominant in supercritical oil. The phytochemical composition of the water extracts, analyzed via LC-DAD-ESI-MS, revealed that higher pressure enhanced the recovery of specific flavonols and anthocyanins, while lower pressure preserved various polyphenolic subclasses. WE90 was rich in 3-feruloylquinic acid and cyanidin-3-O-rutinoside, whereas WE200 was rich in caffeic acid hexoside 2 and dihydro-o-coumaric acid glucoside. Benzaldehyde was individuated in WE90 and WE200 by HPLC-DAD analysis. Cytotoxicity assays demonstrated that WE90, WE200 and SFE200 had anticancer effects on SH-SY5Y neuroblastoma cells, while all extracts did not remarkably affect the viability and morphology of human skin keratinocytes (HaCaT cells). These results suggest that P. spinosa seed extracts have potential nutraceutical and pharmaceutical applications.

ObjectivesType 1 diabetes mellitus (T1DM) is an auto-immune disease that requires an important effort in self-management. The onset of T1DM in a child places a significant burden on parents, requiring careful management of blood glucose levels through insulin injections, diet and exercise. The main aim of our study is to synthesise what is known about the consequences of T1DM onset for families and, in particular, how parents share the emotional, practical and educational burden of care connected with diabetes management.MethodsTo accomplish this goal, we conducted an integrative review of 29 studies concerned with the ways in which disease management permeates the daily lives of families. Based on our findings, we offer suggestions for future research. For this study, PubMed, SAGE Journals, Google Scholar, ERIC, Web of Science, Embase and Scopus databases from 2000 to 2017 were searched using keywords related to T1DM management in families, parental roles and learning processes. Our sample included qualitative, quantitative and mixed-method studies which assessed the consequences of T1DM onset for the family and, in particular, the ways through which disease management permeates the daily lives of mothers and fathers of children with T1DM (3–18 years of age).ResultsThe initial literature search returned 113 papers and 29 studies that met all the inclusion criteria. Through a content analysis, we identified three conceptual categories: (i) ‘managing emotions after diagnosis’, (ii) ‘reconstructing routines around new needs’ and (iii) ‘educating young patients to enhance autonomy’.ConclusionsThe review results strongly support that diabetes is a family illness in which patients and parents are at the centre of emotions, routines and knowledge strictly connected to diabetes. Strong emotions, new routines and educational processes arise after T1DM onset, changing family life definitively.