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Alzheimer's disease (AD) is linked to the abnormal accumulation of amyloid ? peptide (A?) aggregates in the brain. Silybin B, a natural compound extracted from milk thistle (Silybum marianum), has been shown to significantly inhibit A? aggregation in vitro and to exert neuroprotective properties in vivo. However, further explorations of silybin B's clinical potential are currently limited by three main factors: (a) poor solubility, (b) instability in blood serum, and (c) only partial knowledge of silybin's mechanism of action. Here, we address these three limitations. We demonstrate that conjugation of a trehalose moiety to silybin significantly increases both water solubility and stability in blood serum without significantly compromising its antiaggregation properties. Furthermore, using a combination of biophysical techniques with different spatial resolution, that is, TEM, ThT fluorescence, CD, and NMR spectroscopy, we profile the interactions of the trehalose conjugate with both A? monomers and oligomers and evidence that silybin may shield the "toxic" surfaces formed by the N-terminal and central hydrophobic regions of A?. Finally, comparative analysis with silybin A, a less active diastereoisomer of silybin B, revealed how even subtle differences in chemical structure may entail different effects on amyloid inhibition. The resulting insight on the mechanism of action of silybins as aggregation inhibitors is anticipated to facilitate the future investigation of silybin's therapeutic potential.

Anoxic-epileptic seizures (AES) are rare outcomes of common childhood reflex anoxic syncope that trigger a true epileptic seizure. The term AES was coined by Stephenson in 1983, to differentiate these events from convulsive syncopes and the more common reflex anoxic syncopes. A genetic susceptibility for AES has been postulated; but, its molecular basis has up to now been elusive. We report here two illustrative cases and show the association of de novo SCN8A variants and AES. One of them had focal or generalized seizures and autonomic symptoms triggered by orthostatism; the second had breath-holding spells triggered by pain or exercise leading to tonic-clonic seizures; both had repeatedly normal EEGs and a family history of reflex syncope. The data of three additional AES patients further suggest, for the first time, a link between SCN8A pathogenic variants and AES. The neurodevelopment of four patients was abnormal. Four of the five SCN8A mutations observed here were previously described in patients with seizure disorders. Seizures responded particularly well to sodium channel blockers. Our observation enriches the spectrum of seizures linked with SCN8A pathogenic variants.

Background: The birth of a child with a major congenital anomaly may create chronic caregiving stress for mothers, yet little is known about their psychiatric outcomes. Aims: To evaluate the association of the birth of a child with a major congenital anomaly with subsequent maternal psychiatric risk. Methods: This Danish nationwide cohort study included mothers who gave birth to an infant with a major congenital anomaly (n = 19 220) between 1997 and 2015. Comparators were randomly selected mothers, matched on maternal age, year of delivery and parity (n = 195 399). The primary outcome was any new-onset psychiatric diagnosis. Secondary outcomes included specific psychiatric diagnoses, psychiatric in-patient admissions and redeemed psychoactive medicines. Cox models were used to estimate hazard ratios (HRs), adjusted for socioeconomic and medical variables. Results: Mothers of affected infants had an elevated risk for a new-onset psychiatric disorder vs. the comparison group (adjusted HR, 1.16, 95% CI 1.11–1.22). The adjusted HR was particularly elevated during the first postpartum year (1.65, 95% CI 1.42–1.90), but remained high for years, especially among mothers of children with multiorgan anomalies (1.37, 95% CI 1.18–1.57). The risk was also elevated for most specific psychiatric diagnoses, admissions and medicines. Conclusions: Mothers who give birth to a child with a major congenital anomaly are at increased risk of new-onset psychiatric disorders, especially shortly after birth and for mothers of children with more severe anomalies. Our study highlights the need to screen for mental illness in this high-risk population, as well as to integrate adult mental health services and paediatric care.

Compensatory stepping is an important protective mechanism to prevent falling. To recover from sideways perturbations side steps are generally more advantageous than cross-over steps. However, there is lack of understanding of the characteristics of compensatory side steps following sideways perturbations that separate successful recoveries (i.e., no falls) from falls, the most clinically relevant outcome following a balance perturbation. We aimed to identify the critical determinants for successful side stepping after large sideways balance perturbations. Twelve healthy young adults were subjected to large leftward perturbations at varying intensities on a translating sheet. For recovery attempts started with a side step, we determined body configuration variables (frontal-plane leg and trunk angle) at first step contact, as well as spatiotemporal step variables (onset, length, duration, velocity). A logistic regression analysis was conducted to determine the predictive ability of body configuration and spatiotemporal variables on the probability of success (no fall vs. fall); perturbation intensity (peak jerk of translating sheet) and a random effect for individual were also included in the model. In the final model, leg angle and peak jerk were retained as predictors of successful balance recovery and these variables correctly classified the recovery outcome in 86% of the trials. This final 'body configuration' model yielded a -2 log likelihood of -36.3, whereas the best fitting model with only spatiotemporal variables yielded a -2 log likelihood of -45.8 (indicating a poorer fit). The leg angle at a given perturbation intensity appears to be a valid measure of reactive side step quality. The relative ease of measuring this leg angle at step contact makes it a candidate outcome for reactive stepping assessments in clinical practice.

ATP8A2 is a P4-ATPase (adenosine triphosphate) that actively flips phosphatidylserine and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflet of cell membranes to generate and maintain phospholipid asymmetry. Mutations in the ATP8A2 gene have been reported to cause severe autosomal recessive neurological diseases in humans characterized by intellectual disability, hypotonia, chorea, and hyperkinetic movement disorders with or without optic and cerebellar atrophy. To determine the effect of disease-associated missense mutations on ATP8A2, we expressed six variants with the accessory subunit CDC50A in HEK293T cells. The level of expression, cellular localization, and functional activity were analyzed by western blot analysis, immunofluorescence microscopy, and ATPase activity assays. Two variants (p.Ile376Met and p.Lys429Met) expressed at normal ATP8A2 levels and preferentially localized to the Golgi-recycling endosomes, but were devoid of ATPase activity. Four variants (p.Lys429Asn, pAla544Pro, p.Arg625Trp, and p.Trp702Arg) expressed poorly, localized to the endoplasmic reticulum, and lacked ATPase activity. The expression of these variants was increased twofold by the addition of the proteasome inhibitor MG132. We conclude that the p.Ile376Met and p.Lys429Met variants fold in a native-like conformation, but lack key amino acid residues required for ATP-dependent lipid transport. In contrast, the p.Lys429Asn, pAla544Pro, p.Arg625Trp, and p.Trp702Arg variants are highly misfolded and undergo rapid proteosomal degradation.

Pregnancy is a period of increased cardiovascular risk in a woman's life. In the setting of an inherited arrhythmia syndrome (IAS), cardiologists and obstetricians may be unfamiliar with cardiovascular optimization and risk stratification in pregnancy. Historically, there were little data addressing the safety of pregnancy in these rare disorders. Recent advances suggest that no type of IAS represents an absolute contraindication to pregnancy. However, it is imperative that obstetric and cardiovascular clinicians understand the major forms of IAS and how they affect the risks and course of pregnancy. This includes any disease-specific proarrhythmic triggers unique to pregnancy, such as the postpartum period in long QT syndrome (especially type 2), which poses the greatest risk of arrhythmias, and the adrenergic nature of labor and delivery, which is relevant to catecholaminergic polymorphic ventricular tachycardia. Fortunately, several effective antiarrhythmic options exist that pose little fetal risk. IAS-specific optimization of implantable cardioverter-defibrillator algorithms, drug therapy, and a maternal cardiac plan addressing the antepartum, labor, and delivery and postpartum periods reduces the risk. Where evidence does not exist, there are plausible mechanistic considerations to guide clinicians. To achieve optimal outcomes, early involvement of an expert pregnancy heart team comprising obstetrics, genetics, cardiology, and anesthesiology team members and a shared decision-making approach to IAS issues in pregnancy are needed.

To assess associations between neonatal intensive care unit (NICU)-level patent ductus arteriosus (PDA) treatment rates (pharmacologic or surgical) and neonatal outcomes.This cohort study included infants born at 24-28 weeks of gestation and birth weight1500 g in 2007-2015 in NICUs caring for ≥100 eligible infants in 6 countries. The ratio of observed/expected (O/E) PDA treatment rates was derived for each NICU by estimating the expected rate using a logistic regression model adjusted for potential confounders and network. The primary composite outcome was death or severe neurologic injury (grades III-IV intraventricular hemorrhage or periventricular leukomalacia). The associations between the NICU-level O/E PDA treatment ratio and neonatal outcomes were assessed using linear regression analyses including a quadratic effect (a square term) of the O/E PDA treatment ratio.From 139 NICUs, 39 096 infants were included. The overall PDA treatment rate was 45% in the cohort (13%-77% by NICU) and the O/E PDA treatment ratio ranged from 0.30 to 2.14. The relationship between the O/E PDA treatment ratio and primary composite outcome was U-shaped, with the nadir at a ratio of 1.13 and a significant quadratic effect (P.001). U-shaped relationships were also identified with death, severe neurologic injury, and necrotizing enterocolitis.Both low and high PDA treatment rates were associated with death or severe neurologic injury, whereas a moderate approach was associated with optimal outcomes.

Muscle-invasive bladder cancer (MIBC) is an aggressive form of urothelial bladder carcinoma (UBC) with poorer outcomes compared to the non-muscle invasive form (NMIBC). Higher recurrent rates and rapid progression after relapse in UBC is known to be linked with chronic inflammation. Here, the preclinical murine models of NMIBC (MB49) and MIBC (MB49-I) were used to assess the antitumor effects of DAB-1, an anti-inflammatory aminobenzoic acid derivative we have developed in order to target cancer-related inflammation. A subchronic toxicity study on cancer-free mice shown that DAB-1 treatment did not affect normal mouse development or normal function of vital organs. In mice bearing MB49-I tumors, whole body accumulation of the radioconjugate [ 131I]DAB-1 was higher than in control mice, the main sites of [131I]DAB-1 accumulation being the liver (34%), the intestines (21%), and the tumors (18%). In vivo molecular therapy of ectopic and orthotopic tumors indicated that treatment with DAB-1 efficiently inhibited tumor growth, metastasis formation, and mortality rate. The antitumor efficacy of DAB-1 was associated with strong decreased tumor cell proliferation and iNOS expression in tumor tissues and deactivation of macrophages from tumor-bearing mice. Mechanistic investigations revealed that DAB-1 efficiently inhibited i) TNFα/NFΚB and IL6/STAT3 signaling pathways activation; ii) TNFα-induced NO production by decreasing NFΚB transcriptional activation and functional iNOS expression; and iii) cellular proliferation with minimal or no effects on cell mortality or apoptosis. In conclusion, this study provides preclinical and biological/mechanistic data highlighting the potential of DAB-1 as a safe and efficient therapeutic agent for the treatment of patients with NMIBC and MIBC. Fil: Girouard, Julie. Université du Québec a Montreal; Canadá Fil: Belgorosky, Denise. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Hamelin Morrissette , Jovane. Université du Québec a Montreal; Canadá Fil: Boulanger, Valerie. Université du Québec a Montreal; Canadá Fil: D'Orio, Ernesto. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Ramla, Djamel. Université du Québec a Montreal; Canadá Fil: Perron, Robert. Université du Québec a Montreal; Canadá Fil: Charpentier, Lucie. Université du Québec a Montreal; Canadá Fil: Van Themsche, Celine. Université du Québec a Montreal; Canadá Fil: Eijan, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Bérubé, Gervais. Université du Québec a Montreal; Canadá Fil: Reyes Moreno, Carlos. Université du Québec a Montreal; Canadá