Acuna M.,University of Santiago de Chile |
Acuna M.,Center for Genome Regulation |
Gonzalez-Hodar L.,University of Santiago de Chile |
Amigo L.,University of Santiago de Chile |
And 8 more authors.
Journal of Hepatology | Year: 2016
Background & Aims Niemann-Pick C2 (NPC2) is a lysosomal protein involved in the egress of low-density lipoprotein-derived cholesterol from lysosomes to other intracellular compartments. NPC2 has been detected in several tissues and is also secreted from the liver into bile. We have previously shown that NPC2-deficient mice fed a lithogenic diet showed reduced biliary cholesterol secretion as well as cholesterol crystal and gallstone formation. This study aimed to investigate the consequences of NPC2 hepatic overexpression on liver cholesterol metabolism, biliary lipid secretion, gallstone formation and the effect of NPC2 on cholesterol crystallization in model bile. Methods We generated NPC2 transgenic mice (Npc2.Tg) and fed them either chow or lithogenic diets. We studied liver cholesterol metabolism, biliary lipid secretion, bile acid composition and gallstone formation. We performed cholesterol crystallization studies in model bile using a recombinant NPC2 protein. Results No differences were observed in biliary cholesterol content or secretion between wild-type and Npc2.Tg mice fed the chow or lithogenic diets. Interestingly, Npc2.Tg mice showed an increased susceptibility to the lithogenic diet, developing more cholesterol gallstones at early times, but did not show differences in the bile acid hydrophobicity and gallbladder cholesterol saturation indices compared to wild-type mice. Finally, recombinant NPC2 decreased nucleation time in model bile. Conclusions These results suggest that NPC2 promotes cholesterol gallstone formation by decreasing the cholesterol nucleation time, indicating a pro-nucleating function of NPC2 in bile.
Lischinsky J.E.,George Washington University |
Lischinsky J.E.,Center for Neuroscience Research |
Skocic J.,Neuroscience and Mental Health Program |
Clairman H.,Neuroscience and Mental Health Program |
And 2 more authors.
Frontiers in Endocrinology | Year: 2016
In rodents, insufficient thyroid hormone (TH) gestationally has adverse effects on cerebral cortex development. Comparable studies of humans examining how TH insufficiency affects cortical morphology are limited to children with congenital hypothyroidism or offspring of hypothyroxinemic women; effects on cortex of children born to women with clinically diagnosed hypothyroidism are not known. We studied archived MRI scans from 22 children aged 10-12 years born to women treated for preexisting or de novo hypothyroidism in pregnancy (HYPO) and 24 similar age and sex controls from euthyroid women. FreeSurfer Image Analysis Suite software was used to measure cortical thickness (CT) and a vertex-based approach served to compare HYPO versus control groups and Severe versus Mild HYPO subgroups as well as to perform regression analyses examining effects of trimester-specific maternal TSH on CT. Results showed that relative to controls, HYPO had multiple regions of both cortical thinning and thickening, which differed for left and right hemispheres. In HYPO, thinning was confined to medial and mid-lateral regions of each hemisphere and thickening to superior regions (primarily frontal) of the left hemisphere and inferior regions (particularly occipital and temporal) of the right. The Severe HYPO subgroup showed more thinning than Mild in frontal and temporal regions and more thickening in bilateral posterior and frontal regions. Maternal TSH values predicted degree of thinning and thickening within multiple brain regions, with the pattern and direction of correlations differing by trimester. Notably, some correlations remained when cases born to women with severe hypothyroidism were removed from the analyses, suggesting that mild variations of maternal TH may permanently affect offspring cortex. We conclude that maternal hypothyroidism during pregnancy has long-lasting manifestations on the cortical morphology of their offspring with specific effects reflecting both severity and timing of maternal TH insufficiency. © 2016 Lischinsky, Skocic, Clairman and Rovet.
Asztalos E.V.,University of Toronto |
Asztalos E.V.,Sunnybrook Research Institute |
Murphy K.E.,University of Toronto |
Willan A.R.,University of Toronto |
And 14 more authors.
JAMA Pediatrics | Year: 2013
ImportanceA single course of antenatal corticosteroid therapy is recommended for pregnant women at risk of preterm birth between 24 and 33 weeks' gestational age. However, 50% of women remain pregnant 7 to 14 days later, leading to the question of whether additional courses should be given to women remaining at risk for preterm birth. The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study (MACS) was an international randomized clinical trial that compared multiple courses of antenatal corticosteroids with a single course in women at risk of preterm birth. OBJECTIVE To determine the effects of single vs multiple courses of antenatal corticosteroid therapy on death or neurodevelopmental disability (neuromotor, neurosensory, or neurocognitive/neurobehavioral function) at 5 years of age in children whose mothers participated in MACS. Our secondary aims were to determine the effect on height, weight, head circumference, blood pressure, intelligence, and specific cognitive (visual, spatial, and language) skills. DESIGN, SETTING, AND PARTICIPANTS Cohort follow-up study of children seen between June 2006 and May 2012 at 55 centers. In total, 1724 women (2141 children) were eligible for the study, of whom 1728 children (80.7%of the 2141 eligible children) participated and 1719 children contributed to the primary outcome. INTERVENTION Single and multiple courses of antenatal corticosteroid therapy. MAIN OUTCOMES AND MEASURES The primary outcomewas death or survival with a neurodevelopmental disability in 1 of the following domains: neuromotor (nonambulatory cerebral palsy), neurosensory (blindness, deafness, or need for visual/hearing aids), or neurocognitive/neurobehavioral function (abnormal attention, memory, or behavior). RESULTS There was no significant difference between the groups in the risk of death or neurodevelopmental disability: 217 of 871 children (24.9%) in the multiple-courses group vs 210 of 848 children (24.8%) in the single-course group (odds ratio, 1.02 [95%CI, 0.81 to 1.29]; P = .84). CONCLUSIONS AND RELEVANCE Multiple courses, compared with a single course, of antenatal corticosteroid therapy did not increase or decrease the risk of death or disability at 5 years of age. Because of a lack of strong conclusive evidence of short-term or long-term benefits, it remains our opinion that multiple courses not be recommended in women with ongoing risk of preterm birth. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00187382 and International Standard Randomized Controlled Trial Number Register identifier ISRCTN2654148. Copyright 2013 American Medical Association.
Asrar S.,Neuroscience and Mental Health Program |
Kaneko K.,Okazaki Institute for Integrative Bioscience |
Takao K.,National Institute for Physiological science |
Negandhi J.,Neuroscience and Mental Health Program |
And 11 more authors.
Molecular Brain | Year: 2011
Background: DIP (diaphanous interacting protein)/WISH (WASP interacting SH3 protein) is a protein involved in cytoskeletal signaling which regulates actin cytoskeleton dynamics and/or microtubules mainly through the activity of Rho-related proteins. Although it is well established that: 1) spine-head volumes change dynamically and reflect the strength of the synapse accompanying long-term functional plasticity of glutamatergic synaptic transmission and 2) actin organization is critically involved in spine formation, the involvement of DIP/WISH in these processes is unknown. Results: We found that DIP/WISH-deficient hippocampal CA1 neurons exhibit enhanced long-term potentiation via modulation of both pre- and post-synaptic events. Consistent with these electrophysiological findings, DIP/WISH-deficient mice, particularly at a relatively young age, found the escape hole more rapidly in the Barnes maze test. Conclusions: We conclude that DIP/WISH deletion improves performance in the Barnes maze test in mice probably through increased hippocampal long-term potentiation. © 2011Asrar et al; licensee BioMed Central Ltd.
Wheeler S.M.,Neuroscience and Mental Health Program |
Wheeler S.M.,University of Toronto |
Stevens S.A.,Neuroscience and Mental Health Program |
Stevens S.A.,University of Toronto |
And 3 more authors.
Child Neuropsychology | Year: 2012
Prenatal exposure to alcohol may lead to a range of neurobehavioral effects, including impaired learning and memory. Although children with fetal alcohol spectrum disorders (FASD) exhibit both verbal and nonverbal memory impairments, their memory for faces has not been as thoroughly investigated and the extent literature provides inconsistent results. The aim of the current study was to determine whether difficulties in face memory exist in children with FASD and whether the difficulties are mediated by task demands. To address this, we used two measures of immediate and delayed facial recognition memory, the Children's Memory Scale (CMS) and Test of Memory and Learning (TOMAL). Compared to typically developing controls, children with FASD showed memory deficits on all tests and were more likely to perform in a clinically significant range. As well, children performed more poorly on the CMS compared to TOMAL, a finding consistent with the greater difficulty of the CMS task. Our results are consistent with our hypothesis that children with FASD show impairment in facial memory, particularly on demanding memory tasks. © 2012 Copyright Psychology Press, an imprint of the Taylor & Francis Group, an Informa business.