PRENYLATED CURCUMIN ANALOGUES AS MULTIPOTENT TOOLS TO TACKLE ALZHEIMER'S DISEASE

Alzheimer's disease is likely to be caused by copathogenic factors including aggregation of A\u3b2 peptides into oligomers and fibrils, neuroinflammation and oxidative stress. To date, no effective treatments are available and because of the multifactorial nature of the disease, it emerges the need to act on different and simultaneous fronts. Despite the multiple biological activities ascribed to curcumin as neuroprotector, its poor bioavailability and toxicity limit the success in clinical outcomes. To tackle Alzheimer's disease on these aspects, the curcumin template was suitably modified and a small set of analogues was attained. In particular, derivative 1 turned out to be less toxic than curcumin. As evidenced by capillary electrophoresis and transmission electron microscopy studies, 1 proved to inhibit the formation of large toxic A\u3b2 oligomers, by shifting the equilibrium towards smaller non-toxic assemblies and to limit the formation of insoluble fibrils. These findings were supported by molecular docking and steered molecular dynamics simulations which confirmed the superior capacity of 1 to bind A\u3b2 structures of different complexity. Remarkably, 1 also showed in vitro anti-inflammatory and anti-oxidant properties. In summary, the curcumin-based analogue 1 emerged as multipotent compound worth to be further investigated and exploited in the Alzheimer's disease multi-target context

Prenatal Biochemical and Ultrasound Markers in COVID-19 Pregnant Patients: A Prospective Case-Control Study

This prospective observational study aimed to evaluate whether women with SARS-CoV-2 infection during the first trimester of pregnancy are at higher risk of noninvasive prenatal screening test alterations and/or of congenital fetal anomalies at the second-trimester fetal anatomy scan. Maternal symptoms were secondly investigated. The study was carried out on 12-week pregnant women admitted for noninvasive prenatal testing (16 April and 22 June 2020). The cohort had seromolecular tests for SARS-CoV-2, after which they were divided into a positive case group and a negative control group. Both groups had 20-week ultrasound screening. Seventeen out of the 164 women tested positive for SARS-CoV-2 (10.3%). There were no significant differences in mean nuchal translucency thickness or biochemical markers (pregnancy-associated plasma protein A, alpha-fetoprotein, human chorionic gonadotropin, unconjugated estriol) between cases and controls (p = 0.77, 0.63, 0.30, 0.40, 0.28) or in the fetal incidence of structural anomalies at the second-trimester fetal anatomy scan (p = 0.21). No pneumonia or hospital admission due to COVID-19-related symptoms were observed. Asymptomatic or mildly symptomatic SARS-CoV-2 infection during the first trimester of pregnancy did not predispose affected women to more fetal anomalies than unaffected women. COVID-19 had a favorable maternal course at the beginning of pregnancy in our healthy cohort

The coding and long noncoding single-cell atlas of the developing human fetal striatum.

Deciphering how the human striatum develops is necessary for understanding the diseases that affect this region. To decode the transcriptional modules that regulate this structure during development, we compiled a catalog of 1116 long intergenic noncoding RNAs (lincRNAs) identified de novo and then profiled 96,789 single cells from the early human fetal striatum. We found that D1 and D2 medium spiny neurons (D1- and D2-MSNs) arise from a common progenitor and that lineage commitment is established during the postmitotic transition, across a pre-MSN phase that exhibits a continuous spectrum of fate determinants. We then uncovered cell type-specific gene regulatory networks that we validated through in silico perturbation. Finally, we identified human-specific lincRNAs that contribute to the phylogenetic divergence of this structure in humans. This work delineates the cellular hierarchies governing MSN lineage commitment

Validation of the Arm Profile Score in assessing upper limb functional impairments in people with multiple sclerosis

Background Although upper limb (UL) impairments are widespread in people with Multiple Sclerosis (pwMS), there is limited quantitative evidence concerning their specific features. The aim of this study is to validate a synthetic measure based on kinematic data to define the degree of deviation from a physiologic pattern during the “hand to mouth” (HTM) task. Methods Twenty pwMS (mean age 51.2 SD 11.1) years, Expanded Disability Status Scale (EDSS) score in the range 2–6.5), underwent a kinematic analysis of the HTM task using a motion capture system. Spatio-temporal parameters and synthetic indexes (Arm Variable Score, AVS and Arm Profile Score, APS) were calculated and compared with those of age-matched healthy individuals. Kinematic data were correlated with the EDSS score and clinical tests such as the Nine Hole Peg Test (NHPT) and hand-grip strength (HGS). Findings PwMS exhibit reduced velocity, increased movement duration, sway of adjusting and frequency of direction changes as well as higher APS values (15.4° vs. 8.6°, P < 0.001) with respect to controls due to alterations in trunk flexion-extension, shoulder abduction-adduction, flexion-extension and rotation and elbow flexion-extension. Moderate-to-large correlations were found between APS and EDSS (rho = 0.609, P < 0.001), NHPT (rho = 0.468, P = 0.03) and HGS (rho = − 0.627 P < 0.001). Interpretation The kinematic analysis of HTM provides useful information in quantifying UL impairments in pwMS. The APS index appears suitable to represent UL movement deviations from the physiological pattern in pwMS and to assess disease progression or effectiveness of pharmacologic and rehabilitative treatments effectiveness

Efficacy of telerehabilitation with digital and robotic tools for the continuity of care of people with chronic neurological disorders: The TELENEURO@REHAB protocol for a randomized controlled trial

Context Chronic Neurological Disorders (CNDs) are among the leading causes of disability worldwide, and their contribution to the overall need for rehabilitation is increasing. Therefore, the identification of new digital solutions to ensure early and continuous care is mandatory. Objective This protocol proposes to test the usability, acceptability, safety, and efficacy of Telerehabilitation (TR) protocols with digital and robotic tools in reducing the perceived level of disability in CNDs including Parkinson's Disease (PD), Multiple Sclerosis (MS), and post-stroke patients. Design, Setting, and Subjects This single-blinded, multi-site, randomized, two-treatment arms controlled clinical trial will involve PD (N = 30), MS (N = 30), and post-stroke (N = 30). Each participant will be randomized (1:1) to the experimental group (20 sessions of motor telerehabilitation with digital and robotic tools) or the active control group (20 home-based motor rehabilitation sessions according to the usual care treatment). Primary and secondary outcome measures will be obtained at the baseline (T0), post-intervention (T1, 5 weeks after baseline), and at follow-up (T2, 2 months after treatment). Main Outcome Measures a multifaceted evaluation including quality of life, motor, and clinical/functional measures will be conducted at each time-point of assessment. The primary outcome measures will be the change in the perceived level of disability as measured by the World Health Organization Disability Assessment Schedule 2.0. Conclusion The implementation of TR protocols will enable a more targeted and effective response to the growing need for rehabilitation linked to CNDs, ensuring accessibility to rehabilitation services from the initial stages of the disease

A simple liquid chromatography-tandem mass spectrometry method for urinary free cortisol analysis: suitable for routine purpose

Background: The best index of adrenal dysfunction is urinary free cortisol (UFC) measurements performed using a 24-h urine collection. This measurement is also useful in the investigation of Cushing's syndrome. In this paper, we report a simple and selective method for the analysis of UFC by liquid chromatography-tandem mass spectrometry (LC-MS/MS) suitable for use in a high-volume clinical laboratory routine. The results were compared to those obtained using a commercial immunoassay method used in our laboratory. Methods: Urine samples containing 50 ng of internal standard (Cortisol-9,11,12,12-d(4)) were deproteinized using centrifugal filters with a molecular weight 10,000 Da cut-off and injected on a reversed phase column. Cortisol was analyzed in highly selective reaction monitoring in positive atmospheric pressure chemical ionization mode, at a resolution of 0.4 amu full width half maximum, and following the transitions related to the precursor 363.2 for cortisol and 367.2 for deuterated cortisol. The method validation included analysis of precision, linearity, sensitivity, recovery and interference from structurally similar steroids. UFC from 230 subjects was measured using LC-MS/MS and electrochemiluminescence immunoassay (ECLIA) methods. Results: The calibration curves exhibited linearity and reproducibility in the range 7-10,000 nmol/L. Total imprecision was lower than 10\%. The limit of detection and limit of quantification were 2 and 7 nmol/L, respectively. Mean recovery was higher than 90\%. Structurally similar steroids do not interfere in the proposed method, but cause a significant change in the ECLIA results. Cortisol values obtained using the ECLIA method were always higher than those obtained using the LC-MS/MS method, with the bias directly proportional to cortisol concentrations. The reference values calculated using 180 normal subjects were 11-70 mu g/day. Conclusions: The proposed method is sensitive, simple, free from interferences and reliable for routine use. Clin Chem Lab Med 2010;48:1433-7

Unusual presentation of Denys-Drash syndrome in a girl with undisclosed consumption of biotin

We describe a 46,XX girl with Denys-Drash syndrome (DDS), showing both kidney disease and genital abnormalities, in whom a misdiagnosis of hyperandrogenism was made. A 15 year-old girl was affected by neonatal nephrotic syndrome, progressing to end stage kidney failure. Hair loss and voice deepening were noted during puberty. Pelvic ultrasound and MRI showed utero-tubaric agenesis, vaginal atresia and urogenital sinus, with inguinal gonads. Gonadotrophin and estradiol levels were normal, but testosterone levels increased up to 285 ng/dL at Tanner stage 3. She underwent prophylactic gonadectomy and histopathology reported fibrotic ovarian cortex containing numerous follicles in different maturation stages and rudimental remnants of Fallopian tubes. No features of gonadoblastoma were detected. Unexpectedly, testosterone levels were found elevated 4 months after gonadectomy (157 ng/dL). Recent medical history revealed a chronic assumption of a high daily dose of biotin, as a therapeutic support for hair loss. Laboratory immunoassay instruments used streptavidin-biotin interaction to detect hormones and, in competitive immunoassays, high concentrations of biotin can result in false high results. Total testosterone, measured using liquid chromatography tandem mass spectrometry (LC-MS/MS), was found within reference intervals. Similar testosterone levels were detected repeating the immunoassay two weeks after biotin uptake interruption. Discordance between clinical presentation and biochemical results in patients taking biotin, should rise the suspicion of erroneous results. Improved communication among patients, health care providers, and laboratory professionals is required concerning the likelihood of biotin interference with immunoassays

Graphene Quantum Dots’ Surface Chemistry Modulates the Sensitivity of Glioblastoma Cells to Chemotherapeutics

Recent evidence has shown that graphene quantum dots (GQDs) are capable of crossing the blood&ndash;brain barrier, the barrier that reduces cancer therapy efficacy. Here, we tested three alternative GQDs&rsquo; surface chemistries on two neural lineages (glioblastoma cells and mouse cortical neurons). We showed that surface chemistry modulates GQDs&rsquo; biocompatibility. When used in combination with the chemotherapeutic drug doxorubicin, GDQs exerted a synergistic effect on tumor cells, but not on neurons. This appears to be mediated by the modification of membrane permeability induced by the surface of GQDs. Our findings highlight that GQDs can be adopted as a suitable delivery and therapeutic strategy for the treatment of glioblastoma, by both directly destabilizing the cell membrane and indirectly increasing the efficacy of chemotherapeutic drugs

Targeting the multifaceted neurotoxicity of Alzheimer's disease by tailored functionalisation of the curcumin scaffold

Simultaneous modulation of multifaceted toxicity arising from neuroinflammation, oxidative stress, and mitochondrial dysfunction represents a valuable therapeutic strategy to tackle Alzheimer's disease. Among the significant hallmarks of the disorder, Aβ protein and its aggregation products are well-recognised triggers of the neurotoxic cascade. In this study, by tailored modification of the curcumin-based lead compound 1, we aimed at developing a small library of hybrid compounds targeting Aβ protein oligomerisation and the consequent neurotoxic events. Interestingly, from in vitro studies, analogues 3 and 4, bearing a substituted triazole moiety, emerged as multifunctional agents able to counteract Aβ aggregation, neuroinflammation and oxidative stress. In vivo proof-of-concept evaluations, performed in a Drosophila oxidative stress model, allowed us to identify compound 4 as a promising lead candidate