February 2024
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7 Reads
Sleep Medicine
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February 2024
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7 Reads
Sleep Medicine
February 2024
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14 Reads
Sleep Medicine
February 2024
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7 Reads
Sleep Medicine
May 2020
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63 Reads
Sleep
Introduction The 2009 Pandemrix influenza A pH1N1 vaccine has been linked to an increased number of Narcolepsy type I onsets in children across Europe whereas administration of a very similar adjuvanted vaccine, Arepanrix, had little effects in Canada. One possible explanation for the difference may be vaccine composition differences that could modify peptide binding to narcolepsy associated HLA-DQ0602 allele, as viral extracts for these two vaccines used distinct processes in different factories. Other explanations may involve differences in vaccination timing in relation to the pandemic H1N1 infection wave, or other environmental factors. We have previously compared the amino acid sequence of the Hemagglutinin (HA) component of the Pandemrix and the 2010 Arepanrix vaccine, finding possible contributors, but excluding most of these after DQ0602-tetramer analysis of T cell reactivity in narcolepsy versus controls. Methods Mass spectrometric characterization of multiple additional batches of Pandemrix and Arepanrix used during 2009 influenza pandemic vaccination campaign was performed. Results In addition to confirming previously published results such as increased deamidation of hemagglutinin (HA) (146N>D) in Pandemrix (p=2.1e-9), we identified novel differences, including a significant 2-fold post-translation deamidation increase in 277N in Arepanrix versus Pandemrix (p=0.032), together with increased 2-fold glycosylation in the 286-323 positions in Arepanrix (p=0.00036). The 277 N to D/isoD substitution is located in pocket 1 of the binding core of a strong binder NAGSGIIIS, (< 10% rank) for HLA-DQ0602 allele and abolishes epitope binding. The increased glycosylation in Arepanrix occurs in the immediate flanking area of the same 277N epitope and could also reduce DQ0602 presentation of the same epitope through differential binding and/or proteolysis of HA in this region of the molecules. As CD4 T cells recognizing this epitope have been reported to be significantly increased in narcolepsy versus DQ0602 controls, with possible mimicry with homologous hypocretin sequence. Conclusion These changes could explain why Arepanrix was less narcolepsy inducing. Confirmatory studies, as well as studies of all novel changes observed, are ongoing, but this is a promising result. Support Wake Up Narcolepsy
May 2020
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32 Reads
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2 Citations
Sleep
Introduction Kleine-Levin Syndrome (KLS) is a rare disorder affecting adolescents and characterized by relapsing-remitting episodes of severe hypersomnia, cognitive impairment, and behavioral disturbances such as hyperphagia and sexual disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas and in cortical areas during episodes. Familial occurrence is increased, and risk is associated with reports of complicated birth. Methods A worldwide Genome wide association (GWA) study was conducted in 673 KLS patients and ethnically matched 15,341 control individuals. Results We found a strong genome-wide significant association (OR=1.48 at rs150168018, p=8.6x10-9) with 24 single nucleotide polymorphisms (SNPs) encompassing a 35kb region located in the 5’ region of TRANK1 gene previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with TRANK1 had statistically increased reports of difficult birth. As perinatal outcomes have dramatically improved over the last 40 years, we further stratified our sample by birth years, and found that recent cases had a significantly reduced TRANK1 association. These findings were confirmed in an independent replication cohort of 171 new patients where polygenic risk scores constructed on the discovery cohort replicated (r2=0.15; p<2.7x10-22 at p=0.1 threshold) and the TRANK1 association was found to be dependent on reports of birth difficulties (OR=1.54, p=0.01 versus OR=1.12, p=0.4). Pathway analysis of the overall GWAS association revealed significant association (p=0.02) with 19 genes in a pathway modulating rhythmic behaviors. Conclusion Our results demonstrate links between hypersomnia, behavioral rhythmicity and bipolar disorder and indicate that a polymorphism in the TRANK1 region affect brain development in the presence of a perinatal injury, with pathophysiological consequences such as KLS, bipolar disorder and schizophrenia. Support NIH NIMH 1R01MH080957 to EM PHRC 070138 to IA
April 2018
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233 Reads
Sleep
Introduction Kleine-Levin syndrome (KLS) is neurological disorder characterized by recurrent but reversible episodes of hypersomnia, accompanied by behavioral and cognitive abnormalities. Underlying pathophysiology remains unknown and any associated biomarkers have not been described consistently. We employed a high throughput aptamer approach to profile in parallel hundreds of cerebrospinal fluid (CSF) proteins in KLS cases and controls. Methods A high throughout Aptamer array was used to profile 1123 CSF proteins. CSF from 22 KLS patients (in-episode) and 41 control individuals, matched for age and sex were used in this study. Raw data was normalized to remove any technical artifacts and a z-score transformation was applied. A linear model with an empirical Bayes approach was used to probe differentially expressed proteins in KLS cases and controls. Resulting statistical guarantees were subjected to a 5% FDR control. Results A set of 26 CSF proteins were identified as differentially expressed in KLS cases versus controls. Among these proteins, KLS cases had significantly higher levels (BH p value<0.005) of IGF-1, IL-34, SPARC, SPARCL1, caspase-10, JAM-B and LY86. Intriguingly, these proteins are tightly linked to monocyte/macrophage innate immune axis. For instance, IGF-1, SPARCL1 and JAM-B drive migration and homing of monocytes/macrophages, IL-34 is vital to survival and proliferation of monocytes, while, SPARC and LY86 promote inflammatory responses associated with macrophages and monocytes. Finally, caspase-10 promotes apoptosis via extrinsic death receptor pathway. Conclusion KLS cases tended to harbour increased CSF levels of proteins/cytokines implicated in innate immune responses. Support (If Any) KLS Foundation.
December 2017
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12 Reads
Sleep Medicine
April 2017
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35 Reads
Sleep
Introduction Chronic sleep disturbance is known to impair dietary metabolisms. Altered dietary metabolisms, such as amino acid level changes, may conversely affect sleep. In accordance with this hypothesis, we reported altered amino acid metabolisms in severe sleep disorders breathing (SDB) patients at Sleep 2016.We have extended the analysis and found that disease specific amino acid changes may exist in SBD and insomnia. Methods 981 participants with insomnia and SBD were recruited randomly from 1999 to 2010 at the Stanford Sleep Medicine Center. and had undergone Polysomnography to calculate respiratory disturbance index (RDI). We divided the patients into two groups; SDB defined as RDI≥5 (n=833) and non-SDB (n=148) defined as RDI<5. SDB patients were further divided into mild (RDI<15) and moderate/severe cases (RDI≥15). Non-SDB patients were also dichotomized at their median total sleep time (TST) (i.e., TST<369mins vs. ≥369mins). Results We applied multivariate logistic regression models with stepwise selection to select final confounding variables chosen at p<0.25 in univariable logistic models, with sex, age, and BMI forcedly included. The variables significant in the final model for SDB were sex, age, BMI, 2-aminoadipic acid [a 1mg increase had 0.83 odds ratio (OR) to be moderate/severe cases compared to mild cases; the average value was 2.89 ± 1.90mg in moderate/severe cases vs. 3.43 ± 1.92mg in mild cases], glutamine (1.00 OR; 603.0 ± 92.1mg vs. 590.6 ± 91.4mg), and phenylalanine (1.02 OR; 59.78 ± 10.06mg vs. 56.19 ± 8.06mg). The variables significant in the final model for short sleep time were sex, age, race, β-alanine (a 1mg increase had 2.46 OR to be a shorter sleep cases compared to longer sleep cases; the average value was 4.68 ± 1.93mg in shorter sleep time cases vs. 4.07 ± 2.10mg in longer sleep time cases), hydroxyproline (1.06 OR; 19.04 ± 8.92mg vs. 16.24 ± 10.18mg), and citrulline (0.90 OR; 36.31 ± 7.10mg vs. 34.78 ± 8.57mg). Conclusion Our findings suggest that specific amino acid changes may occur depending on the sleep and sleep/breathing disorders. Interestingly, plasma 2-aminoadipic acid was recently shown to be tightly associated with glucose tolerance and the risk for diabetes. Studies on functional significances of the findings are warranted. Support (If Any) This study was supported by Ajinomoto Co., Inc.
April 2017
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24 Reads
Sleep
Introduction To evaluate familial risk of narcolepsy in parents of children with Type 1 narcolepsy using objective sleep recording studies. Methods From a total of 5,462 patient visiting the Sleep Center of Peking University People’s Hospital from 09/01/2012 to 12/03/2014, 496 narcolepsy cases were identified, including 307 children meeting inclusion criteria (<18 y, HLA-DQB1*0602 positive, typical cataplexy, or measured CSF Hcrt ≤ 110 pg/ml). One hundred and six families refused further evaluation or had parent(s) unavailable, leaving 201 families (66%) with at least one parent available. The resulting 378 parents underwent HLA typing, nocturnal polysomnography, multiple sleep latency tests(MSLT), interviews and questionnaire evaluation. CSF hypocretin-1 was tested in 4 subjects. Three subjects with a positive MSLT had a second MSLT for confirmation. ICSD3 criteria were used to diagnose Type 1 and Type 2 narcolepsy. Symptoms in parents with versus without DQB1*06:02 were also compared. Results We found 3 parents (0.7%) with narcolepsy- cataplexy (100% DQB1*06:02) and 9 with a positive MSLT but no cataplexy (78% DQB1*06:02). In the four parents tested for CSF hypocretin-1 level, one with and one without cataplexy had low CSF Hcrt (≤110) one without cataplexy had intermediary level(153 pg/ml), and normal in the last relative. Repeat PSG-MSLT was positive in 3 relatives retested. Analysis of individual patients suggests that between 3 (0.7%) and 6 (1.4%) of the 9 subjects with narcolepsy-cataplexy have hypocretin deficiency. Conclusion This study is the first to confirm the existence of a genuine narcolepsy/hypocretin deficiency spectrum using systematic MSLT testing, HLA typing and CSF hypocretin-1 measurements in a very large number of relatives of patients with Type 1 narcolepsy. These findings illustrate the urgent need to find biologically measurable immune markers for the disease autoimmune process, as this would greatly facilitate large population based studies and a better understanding of its spectrum. Support (If Any) Supported by NSFC (81300061,81420108002, 81670087),Ministry of Science and Technology (2015CB856405, 2014DFA31500)Corresponding to: hanfang1@hotmail.com;mignot@stanford.edu
April 2017
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142 Reads
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8 Citations
Sleep
Introduction Kleine-Levin syndrome (KLS) is a rare sleep disorder that affects ~ 1 person in a million and has been suggested to be more frequent in Ashkenazi Jewish. The disorder typically strikes adolescent males and improves with age, often resolving by age 30. KLS, patients have recurrent episodes sometimes lasting up to several weeks where they sleep nearly 24 hours per day. While awake, patients during episodes experience apathy, cognitive disturbances and occasionally hyperphagia and/or hypersexuality. Between episodes, patients are totally asymptomatic. Our aim was to identify genetic variants that contribute to KLS predisposition. Methods We performed GWAS on 650 KLS cases and 15,000 controls as a part of an international collaboration. The sample contained KLS cases and matched controls from United States, Europe and Asia plus additional controls from the GERA consortium. Genotyping was done using Affy 6.0 and Affymetrix Axiom World Array with ethnicity specific platforms that were imputed to 1000 genomes. Analyses were controlled for population stratification and ethnicity (Caucasian, Ashkenazi Jewish, Asians, other). We also have pursued other approaches in understanding KLS by using Whole Exome Sequencing (WES) data and have identified 14 family pedigrees to pursue family association studies. Furthermore, we are also looking into any shared genetic architectures with other neuropsychiatric disorders. Results So far we have identified a Genome-wide significant loci near TRANK1. Most interestingly, the leading TRANK1 variant is also reported in other GWAS for bipolar disorder (BD). With this new insight we are looking into identifying any other shared genetic characteristics with BD. Conclusion The findings give the first biological evidence for disease mechanisms in KLS. Importantly, these results suggest a partially overlapping genetic composition for schizophrenia and KLS. That these patients are not primarily depressed or psychotic during episodes and completely reverse to normality between episodes could suggest important pathophysiological clues linking sleep and episodic psychiatric conditions. Support (If Any) none.
... Karyotyping was normal in 112 patients [92]. Exome sequencing in familial cases did not yield any specific gene [93]. Genome-wide association in more than 400 patients suggests that a polymorphism in Trank1 gene is more frequent in affected patients (mostly those with birth defect) than in controls (Mignot, personal communication). ...
May 2020
Sleep
... A study by Islam et al. found CCR8 to bind MIP-4 and to activate downstream G-protein-coupled signaling and activation of cell chemotaxis [10]. Another study by Chen et al. identifed PIRPNM3 as a receptor for MIP-4 that mediated the invasion and metastasis of breast cancer xenografts [11]. Although MIP-4 is a chemokine produced by M2 macrophages, lung fbroblasts as well as other several types of cancer cells produce MIP-4 [9,12,13]. ...
June 2011
Cancer Cell
... Trakada et al. 38 developing this condition, suggesting a founder effect [281,311,[319][320][321][322][323]. A genome wide association study has identified a TRANK1 variant associated with KLS [324]. More recently, another study has identified an association between LMOD3 variants and familial, as well as sporadic KLS [325]. ...
April 2017
Sleep
... Ida et al. [14] reported that short-time immobilization or cold stresses increase mRNA expression, but 48 h of cold (a longer stress procedure) does not affect mRNA hypocretin level. To date, there is no study verifying the effects of stress on CSF hypocretin levels, except for our own data showing that cold stress does not affect hypocretin CSF levels and that immobilization decreases Hctr CSF levels [19]. These stress effects are opposite to what we observed with sleep deprivation in the present study. ...
May 2003
Sleep
... Seventy-eight percent of the population were men. Special consideration of this test is needed for women [5] . Sixty-three of the 283 patients had prior angioplasty (n=43) and/or coronary artery bypass graft surgery (n=24). ...
March 1998
Journal of Investigative Medicine
... Further research is required to fully understand the impact of altered methylation on human health and to utilize this knowledge for the development of effective therapeutics. Autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN, OMIM 604121) is a degenerative disease caused by mutations in the DNA-targeting domain of the maintenance methyltransferase DNMT1 [7][8][9]. This adult-onset condition (onset in the second to fourth decade) is characterized by hearing loss, narcolepsy/ cataplexy, and cerebellar ataxia; there are also reports of sensory neuropathy and psychiatric and behavioural manifestations. ...
January 2012
Sleep
... Immunological research to evaluate the CD4 + T-cell etiology hypothesis Several publications that emerged over the last decade have begun to shed light on the potential role of T-cell responses in the context of NT1 (31,(64)(65)(66)(67)(68)(69)(70)(71). These studies demonstrated amongst others that HCRT can be a target for both CD4 + and CD8 + T cells, and provided some indications for cross-reactivity. ...
July 2014
Science Translational Medicine
... Так, например, показано, что у ряда пациентов наблюдается фрагментированный ночной сон, а во время приступов катаплексии сохраняется сознание [36]. Кроме того, в орек-син-содержащих нейронах синтезируется ряд биологически активных веществ, нейромедиаторов и нейрогормонов, участвующих в поддержании жизненно важных функций, нарушение синтеза которых меняет клиническую картину заболевания, что затрудняет диагностику [37]. ...
January 2007
... [8b] Additionally, 1 H NMR analysis of mixtures of NIS and TsNH 2 or of NBS and TsNH 2 con- firmed the existence of TsNHI (see the Supporting Informa- tion) or TsNHBr. [5g] A proposed possible reaction process for the haloamina- tion reaction, based on the above results and on previous mechanistic studies on the chloroamination and bromoami- nation reactions, [8] is shown in Scheme 5. Initially, TsNHX (X = I, Br, Cl) could be generated through the reaction of TsNH 2 and the halo source, such as DIH, NIS, NBS, or TsNCl 2 . Then, in the presence of the chiral N,N'-dioxide/Sc III complex, TsNHX could stereoselectively attack the enones [a] Unless specified, the reactions were performed with ...
November 2010
Synfacts
... However, there is a high rate of cisplatin resistance among patients [101]. It was observed that EMT process is involved in drug resistance of tumor cells [102,103]. MiR-206 reduced EMT process and CDDP resistance via MET targeting that inhibited PI3K/AKT/mTOR axis in lung adenocarcinoma cells. EMT gene profile was significantly associated with MDR1 up regulation and CDDP resistance [104]. ...
July 2011
Oncogene