Zonisamide is an anticonvulsant used as an adjunctive treatment for partial seizures. It has also been used off-label for treatment of mania. Abdoh et al recently reported a very interesting case of ...psychosis induced by zonisamide. We too observed a case of psychosis induced by zonisamide in a 34-year-old female with bipolar disorder and narcolepsy.
In recent years, the journal has carried several papers on parental consent (assent) for participation of their babies in clinical trials. 1, 2 This is important because Archives is read by many of ...those who organise neonatal research projects. Readers of the Journal of Medical Ethics would find little of direct use when confronted by the clinical realities and research questions of neonatal care-although this journal once published a neonatal study on the variability of ethics committee views.
Clinical manifestations of Niemann-Pick type C1 (NP-C1) disease include neonatal hepatosplenomegaly and in some patients progressive liver dysfunction and failure. This study involved a
H NMR-linked ...metabolomics analysis of liver samples collected from a NP-C1 disease mutant mouse model in order to explore time-dependent imbalances in metabolic pathways associated with NP-C1 liver dysfunction, including fibrosis. NP-C1 mutant (Npc1
; NP-C1), control (Npc1
; WT), and NP-C1 heterozygous mice (Npc1
; HET) were generated from heterozygote matings. Aqueous extracts of these liver samples collected at time points of 3, 6, 9, and 11 weeks were subjected to high-resolution NMR analysis, and multivariate (MV) metabolomics analyses of data sets acquired were performed. A MV random forests (RFs) model effectively discriminated between NP-C1 and a combined WT/HET hepatic NMR profiles with very high predictive accuracy and reliability. Key distinguishing features included significant upregulations in the hepatic concentrations of phenylalanine, tyrosine, glutamate, lysine/ornithine, valine, threonine, and hypotaurine/methionine, and diminished levels of nicotinate/niacinamide, inosine, phosphoenolpyruvate, and 3-hydroxyphenylacetate. Quantitative pathway topological analysis confirmed that imbalances in tyrosine biosynthesis, and hepatic phenylalanine, tyrosine, glutamate/glutamine, and nicotinate/niacinamide metabolism were involved in the pathogenesis of NP-C1 disease-associated liver dysfunction/damage.
H NMR-linked metabolomics analysis provides valuable biomarker information regarding hepatic dysfunction or damage in NP-C1 disease.
Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease caused by mutations in either the
or
genes. Mutations in the
gene lead to the majority of clinical cases (95%); however, the ...function of NPC1 remains unknown. To gain further insights into the biology of NPC1, we took advantage of the homology between the human NPC1 protein and its yeast orthologue, Niemann-Pick C-related protein 1 (Ncr1). We recreated the
mutant in yeast and performed screens to identify compensatory or redundant pathways that may be involved in NPC pathology, as well as proteins that were mislocalized in
-deficient yeast. We also identified binding partners of the yeast Ncr1 orthologue. These screens identified several processes and pathways that may contribute to NPC pathogenesis. These included alterations in mitochondrial function, cytoskeleton organization, metal ion homeostasis, lipid trafficking, calcium signalling, and nutrient sensing. The mitochondrial and cytoskeletal abnormalities were validated in patient cells carrying mutations in
, confirming their dysfunction in NPC disease.
Background
The Galα(1,3)Gal epitope (α‐GAL), created by α‐1,3‐glycosyltransferase‐1 (GGTA1), is a major xenoantigen causing hyperacute rejection in pig‐to‐primate and pig‐to‐human ...xenotransplantation. In response, GGTA1 gene‐deleted pigs have been generated. However, it is unclear whether there is a residual small amount of α‐Gal epitope expressed in GGTA1−/− pigs. Isoglobotrihexosylceramide synthase (iGb3s), another member of the glycosyltransferase family, catalyzes the synthesis of isoglobo‐series glycosphingolipids with an α‐GAL‐terminal disaccharide (iGb3), creating the possibility that iGb3s may be a source of α‐GAL epitopes in GGTA1−/− animals. The objective of this study was to examine the impact of silencing the iGb3s gene (A3GalT2) on pig‐to‐primate and pig‐to‐human immune cross‐reactivity by creating and comparing GGTA1−/− pigs to GGTA1−/−‐ and A3GalT2−/−‐double‐knockout pigs.
Methods
We used the CRISPR/Cas 9 system to target the GGTA1 and A3GalT2 genes in pigs. Both GGTA1 and A3GalT2 genes are functionally inactive in humans and baboons. CRISPR‐treated cells used directly for somatic cell nuclear transfer produced single‐ and double‐gene‐knockout piglets in a single pregnancy. Once grown to maturity, the glycosphingolipid profile (including iGb3) was assayed in renal tissue by normal‐phase liquid chromatography. In addition, peripheral blood mononuclear cells (PBMCs) were subjected to (i) comparative cross‐match cytotoxicity analysis against human and baboon serum and (ii) IB4 staining for α‐GAL/iGb3.
Results
Silencing of the iGb3s gene significantly modulated the renal glycosphingolipid profile and iGb3 was not detected. Moreover, the human and baboon serum PBMC cytotoxicity and α‐GAL/iGb3 staining were unchanged by iGb3s silencing.
Conclusions
Our data suggest that iGb3s is not a contributor to antibody‐mediated rejection in pig‐to‐primate or pig‐to‐human xenotransplantation. Although iGb3s gene silencing significantly changed the renal glycosphingolipid profile, the effect on Galα3Gal levels, antibody binding, and cytotoxic profiles of baboon and human sera on porcine PBMCs was neutral.
Endocytosis leads to the internalisation of both lipids and proteins and their delivery to specific subcellular locations. This involves sorting processes that are not completely understood, but may ...involve interactions between lipids and proteins as well as pH and calcium gradients. This article discusses the importance of endocytosis in glycosphingolipid (GSL) synthesis as well as the potential roles of GSLs in endocytic membrane transport. Although the accumulation of GSLs in storage diseases clearly disrupts endocytic transport, increasing evidence also supports a role for GSLs in endocytosis in normal cells.
We document the ability of the new-generation Oslo chemistry-transport model, Oslo CTM3, to accurately simulate present-day aerosol distributions. The model is then used with the new Community ...Emission Data System (CEDS) historical emission inventory to provide updated time series of anthropogenic aerosol concentrations and consequent direct radiative forcing (RFari) from 1750 to 2014.
The GM2 gangliosidoses, Tay–Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme β-N-acetylhexosaminidase (Hex). Due ...to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were largely normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated SD patients and those in future clinical trials.
•Clinically relevant biomarkers objectively evaluate feline Sandhoff disease.•Blood, CSF, liver, MRI and electro-diagnostics are utilized to track disease.•Intracranial AAV mediated gene therapy normalizes many of these objective measures.•Minimally invasive biomarkers will inform future human clinical trials.
Humans with histories of prolonged heavy alcohol use exhibit poorer performance on cognitive tasks associated with problem solving, short-term memory, and visuospatial reasoning, even following the ...cessation of drinking, when compared with healthy controls. It is unclear, however, whether the cognitive problems are a consequence of alcohol exposure or a contributing factor to alcohol-use disorders. Here, we examined the relationship between performance on a novel object recognition (NOR) task and total alcohol consumption (TAC) in adult male rhesus macaques (n = 12; ETH group; trained to self-administer alcohol). NOR performance in this group was assessed prior to induction of alcohol drinking (“pre”) and, again, after a 1-year abstinence period (“post”) and was compared to the performance of a second group (n = 6; Control group), which was alcohol-naïve. In the NOR task, difficulty was manipulated across three phases by varying specific object features and/or by varying duration of access to objects. For each monkey, we measured aspects of novelty-related behavior including novelty detection, novelty reactivity, and perseverative behavior. TAC during induction and a “free” access period in which the monkey could choose between water and a 4% w/v ethanol solution also was determined. We found that performance deficits in the NOR task were a consequence of high total alcohol intake instead of a predictor of subsequent high intake. Poor NOR performance in drinkers with the highest intakes was characterized by increased perseverative behavior rather than an inability to detect or react to novelty. Finally, the observed deficits are long-lasting – persisting even after a year of abstinence. Given the prevalent and persistent nature of alcohol-induced cognitive deficits in patients in treatment settings, understanding the nature of the deficit and its neural basis could ultimately offer novel treatment approaches based on the reversal of alcohol-induced impairment.
•Deficits on a novel object recognition task do not predict alcohol intake.•Deficits on a novel object recognition task are a consequence of alcohol intake.•Deficits on a novel object recognition task are long-lasting.•Deficits manifest as increased perseverative behavior to the incorrect stimuli.
Almost one-quarter of school-age children in the United States meet criteria for serious mental illness. School nurses can identify children at risk or suffering from undetected mental illness ...through observation, consultation with teachers and parents, interview techniques, and simple written tools. Valid and reliable tools that are in the public domain and can be accessed via the Internet are included. Referral to mental health providers within the school system or community is necessary for students at risk.
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