Publications by authors named "Stine Knudsen"

47 Publications

Emergency drug kits at the Danish hospital pharmacies: varying management and challenges.

Eur J Hosp Pharm 2020 07 26;27(4):232-236. Epub 2018 Nov 26.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.

Objectives: Access to emergency drug kits (EDK) during medical emergencies can be life-saving; however, recent doubts about the quality of the kits have been expressed. Procurements of pharmaceuticals to the five regional authorities in Denmark are serviced by Amgros, a public sector organisation owned by the regions and established to create economies of scale and achieve administrative savings by centralisation. This means that Amgros calls for tenders for the supply of pharmaceuticals to the hospital pharmacies. The Hospital Pharmacy in the North Denmark Region does not currently have an effective method to manage Amgros procurements in relation to EDKs. Thus, the objectives were to explore how quality in the management and packing of EDKs is assured and maintained at different hospital pharmacies in Denmark and how this is affected by Amgros procurements.

Methods: The hospital pharmacies in Denmark were enrolled in a cross-sectional study. Information about the management and challenges of the EDKs was inquired by means of a questionnaire. Responses were analysed by simple statistics.

Results: All eight hospital pharmacies in Denmark completed the questionnaire, and the distribution between single-use and reusable packaging was nearly equal. The hospital pharmacies comply with a variation of regulations of which good distribution practice is the most common. Six hospital pharmacies experience challenges with drug replacements in the EDKs and only one hospital pharmacy complies completely with the Amgros procurement. The majority of the hospital pharmacies use parameters such as and in their decision of whether to comply with the Amgros procurement.

Conclusion: The management of the EDKs varies greatly among the hospital pharmacies in Denmark, and national requirements are therefore encouraged to ensure the quality. The challenges experienced with drug replacements reflect that complying with the Amgros procurement can be troublesome.
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http://dx.doi.org/10.1136/ejhpharm-2018-001740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335624PMC
July 2020

Hypocretin-deficient narcolepsy patients have abnormal brain activation during humor processing.

Sleep 2019 07;42(7)

Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom), Department of Rare Disorders, Oslo University Hospital, Ullevål, Norway.

Study Objectives: To assess brain activation patterns in response to fun-rated and neutral-rated movies we performed functional magnetic resonance imaging (fMRI) during a humor-paradigm in narcolepsy type 1 (NT1) patients with cataplexy (muscle atonia triggered by emotions) and controls.

Methods: The fMRI-humor-paradigm consisted of short movies (25/30 with a humorous punchline; 5/30 without a humorous punchline [but with similar build-up/anticipation]) rated by participants based on their humor experience. We included 41 NT1 patients and 44 controls. Group-level inferences were made using permutation testing.

Results: Permutation testing revealed no group differences in average movie ratings. fMRI analysis found no group differences in brain activations to fun-rated movies. Patients showed significantly higher activations compared to controls during neutral-rated movies; including bilaterally in the thalamus, pallidum, putamen, amygdala, hippocampus, middle temporal gyrus, cerebellum, brainstem and in the left precuneus, supramarginal gyrus, and caudate. We found no brain overactivation for patients during movies without a humorous punchline (89.0% neutral-rated). Group analyses revealed significantly stronger differentiation between fun-rated and neutral-rated movies in controls compared with patients (patients showed no significant differentiation), including bilaterally in the inferior frontal gyrus, thalamus, putamen, precentral gyrus, lingual gyrus, supramarginal gyrus, occipital areas, temporal areas, cerebellum and in the right hippocampus, postcentral gyrus, pallidum, and insula.

Conclusion: Patients showed significantly higher activations in several cortical and subcortical regions during neutral-rated movies, with no differentiation from activations during fun-rated movies. This lower threshold for activating the humor response (even during neutral-rated movies), might represent insight into the mechanisms associated with cataplexy.
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http://dx.doi.org/10.1093/sleep/zsz082DOI Listing
July 2019

CD8 T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens.

Nat Commun 2019 02 19;10(1):837. Epub 2019 Feb 19.

Department of Clinical Biochemistry, Molecular Sleep Laboratory, Rigshospitalet, 2600 Glostrup, Denmark.

Narcolepsy Type 1 (NT1) is a neurological sleep disorder, characterized by the loss of hypocretin/orexin signaling in the brain. Genetic, epidemiological and experimental data support the hypothesis that NT1 is a T-cell-mediated autoimmune disease targeting the hypocretin producing neurons. While autoreactive CD4 T cells have been detected in patients, CD8 T cells have only been examined to a minor extent. Here we detect CD8 T cells specific toward narcolepsy-relevant peptides presented primarily by NT1-associated HLA types in the blood of 20 patients with NT1 as well as in 52 healthy controls, using peptide-MHC-I multimers labeled with DNA barcodes. In healthy controls carrying the disease-predisposing HLA-DQB1*06:02 allele, the frequency of autoreactive CD8 T cells was lower as compared with both NT1 patients and HLA-DQB1*06:02-negative healthy individuals. These findings suggest that a certain level of CD8 T-cell reactivity combined with HLA-DQB1*06:02 expression is important for NT1 development.
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http://dx.doi.org/10.1038/s41467-019-08774-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381094PMC
February 2019

Psychiatric symptoms in patients with post-H1N1 narcolepsy type 1 in Norway.

Sleep 2019 04;42(4)

Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias, Department of Rare Disorders, Oslo University Hospital, Oslo, Norway.

Study Objectives: Several studies have reported psychiatric comorbidity in patients with narcolepsy type 1 (NC1). The primary aim of this study was to explore the extent of psychiatric symptoms in a cohort of Norwegian NC1 patients, most of whom were H1N1-vaccinated. We also wanted to explore possible causes of the psychiatric symptoms seen in NC1.

Methods: Cross-sectional study. Psychiatric symptoms were assessed by the Achenbach System of Empirically Based Assessment (ASEBA) Child Behavior Check List (CBCL) in children and by Adult Self Report (ASR) in adults.

Results: The mean (SD) total T-scores were 58.6 (9.2) for children and 57.0 (9.8) for adults, these being mainly driven by internalizing problems. Internalizing symptom T-scores showed that 37.5% of the children and 33.3% of the adults were in the clinical range of concern. T-scores were lower when the questionnaire's sleep-related items were excluded. However, 27.5% of children and 22.2% of adults still remained within the total psychiatric symptoms clinical range. Psychiatric symptoms and excessive daytime sleepiness were not associated. However, in children fragmented sleep, measured by sleep-stage shift index was significantly negatively associated with all the psychiatric summary scores (all p ≤ 0.020), and awakening index was negatively associated with externalizing (p = 0.042) and total summary scores (p = 0.042). In adults, awakening index, but not sleep-stage shift index, was positively associated with internalizing score (p = 0.015). Hypocretin-1 levels showed no association with psychiatric symptoms.

Conclusions: We found a high prevalence of psychiatric symptoms in NC1 patients. Fragmented sleep was significantly associated with psychiatric symptoms.
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http://dx.doi.org/10.1093/sleep/zsz008DOI Listing
April 2019

Comparison of subjective and objective measures of constipation - Employing a new method for categorizing gastrointestinal symptoms.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 2):23-28. Epub 2018 Aug 24.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Mølleparkvej 4, Aalborg 9000, Denmark; Department of Clinical Medicine, Aalborg University, Søndre Skovvej 15, Aalborg 9000, Denmark; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160/162, Copenhagen 2100, Denmark. Electronic address:

Introduction: Correlations between subjective and objective measures of constipation have seldom been demonstrated. This could be due to multiple confounding factors in clinical studies and the broad span of symptoms represented in questionnaires used to assess constipation. We developed a new method for categorizing gastrointestinal (GI) symptoms into relevant symptom groups, and used this in a controlled experimental study aimed to investigate whether GI transit times and colonic volumes were correlated to self-reported GI symptoms.

Methods: Twenty-five healthy male participants were enrolled in a randomized, double-blinded, placebo-controlled, five-day crossover study with the treatments oxycodone and placebo. Objective measures of GI transit times and colonic volumes were obtained by the means of the 3D-Transit System and magnetic resonance colonography, whereas subjective GI symptoms were measures via three validated questionnaires. The symptoms were then categorized into five groups; "abdominal symptoms", "defecation difficulties", "incomplete bowel evacuation", "reduced bowel movement frequency", and "stool symptoms". Spearman's rank order correlation was used to determine correlations between the five groups of symptoms and the objective measures.

Results: No correlations between the GI symptoms and transit times or colonic volumes were found (all P > 0.05).

Discussion: GI transit times and colonic volumes were not correlated to self-reported GI symptoms even in a controlled experimental study and when symptoms were categorized into relevant symptom groups. Thus, both subjective and objective measures must be considered relevant when assessing constipation in clinical and research settings, ensuring that both physiological aspects as well as the severity and impact of symptoms experienced by patients can be assessed.
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http://dx.doi.org/10.1016/j.vascn.2018.08.002DOI Listing
March 2019

Changes in quality of life in individuals with narcolepsy type 1 after the H1N1-influenza epidemic and vaccination campaign in Norway: a two-year prospective cohort study.

Sleep Med 2018 10 27;50:175-180. Epub 2018 Jun 27.

Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias, Department of Rare Disorders, Oslo University Hospital, Norway.

Objective: Cross-sectional studies show a lower health-related quality of life (HRQoL) in individuals with narcolepsy. We aimed to describe changes in HRQoL after two years of multidisciplinary follow-up in a cohort of mainly post-H1N1 vaccination narcolepsy type-1 (NT1) patients in Norway.

Methods: Prospective-cohort study. Narcolepsy diagnosis was based on the International Classification of Sleep Disorders (third edition). Psychiatric comorbidity was assessed using the Achenbach System of Empirically Based Assessment (ASEBA). HRQoL was evaluated with the Pediatric Quality of Life Inventory (PedsQL™ Generic Core Scales 4.0) at baseline and follow-up. Mean follow-up time was 20.7 (2.7) months.

Results: Thirty one patients (18 females) with NT1, mean age 14.6 (SD = 4.8) years answered questionnaires at baseline and follow-up. On a group level, the PedsQL Total Health Summary score significantly improved by a mean of 5.9 (95%CI = 0.4, 11.9), p = 0.038; this was mainly driven by improvements in the Physical Health Summary score by 9.8 (3.0, 16.5) points, p = 0.006 and the School Functioning Scale score by 7.5 (1.0, 13.9) points p = 0.025. The Total ASEBA score was correlated with PedsQL Total Health Summary score at baseline, but not with changes in HRQoL. Sodium oxybate (Xyrem®) treatment at follow up was positively associated with changes in PedsQL Total Health Summary score, after adjusting for age and gender, p = 0.027.

Conclusion: HRQoL in NT1 patients improved after two years of follow-up. The use of sodium oxybate (Xyrem®) at follow-up was associated with increases in HRQoL. Psychiatric comorbidity was correlated with HRQoL at baseline but did not predict changes in HRQoL at follow-up.
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http://dx.doi.org/10.1016/j.sleep.2018.05.037DOI Listing
October 2018

Widespread white matter changes in post-H1N1 patients with narcolepsy type 1 and first-degree relatives.

Sleep 2018 10;41(10)

Department of Rare Disorders, Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom), Oslo University Hospital, Ullevål, Norway.

Study Objectives: To assess white matter involvement in H1N1-vaccinated hypocretin deficient patients with narcolepsy type 1 (NT1) compared with first-degree relatives (a potential risk group) and healthy controls.

Methods: We compared four diffusion tensor imaging-based microstructural indices (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], and axial diffusivity [AD]) in 57 patients with NT1 (39 females, mean age 21.8 years, 51/57 H1N1-vaccinated, 57/57 HLA-DQB1*06:02-positive, 54/54 hypocretin-deficient), 54 first-degree relatives (29 females, mean age 19.1 years, 37/54 H1N1-vaccinated, 32/54 HLA-DQB1*06:02-positive), and 55 healthy controls (38 females, mean age 22.3 years). We tested for differences between these groups, for parametric effects (controls > first-degree relatives > patients) and associations in patients (cerebrospinal fluid [CSF] hypocretin-1 and disease duration) and first-degree relatives (HLA-DQB1*06:02 and H1N1-vaccination). We employed tract-based spatial statistics and used permutation testing and threshold-free cluster enhancement for inference.

Results: Patients with NT1 had a widespread, bilateral pattern of significantly lower FA compared with first-degree relatives and healthy controls. Additionally, patients with NT1 also exhibited significantly higher RD and lower AD in several focal white matter clusters. The parametric model showed that first-degree relatives had intermediate values. Full sample of patients with NT1 showed no significant associations with disease duration or CSF hypocretin-1.

Conclusions: Our study suggests widespread abnormal white matter involvement far beyond the already known focal hypothalamic pathology in NT1, possibly reflecting the combined effects of the loss of the widely projecting hypothalamic hypocretin neurons, and/or secondary effects of wake/sleep dysregulation. These findings demonstrate the importance of white matter pathology in NT1.
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http://dx.doi.org/10.1093/sleep/zsy145DOI Listing
October 2018

Long-term improvement after combined immunomodulation in early post-H1N1 vaccination narcolepsy.

Neurol Neuroimmunol Neuroinflamm 2017 Sep 7;4(5):e389. Epub 2017 Aug 7.

Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom), Department of Rare Disorders (R.V., S.K.), Department of Neurology, Section for Clinical Neurophysiology (R.V., K.B.N.), Department of Child Neurology (J.S., T.V.), Oslo University Hospital, Ullevål, Norway; Hormone Laboratory, Department of Medical Biochemistry (P.M.T.), Oslo University Hospital, Aker, Norway; Department of Neuromedicine and Movement Science (K.B.N.), Norwegian University of Science and Technology, Trondheim, Norway; and Medical Faculty (R.V.), University of Oslo, Norway.

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http://dx.doi.org/10.1212/NXI.0000000000000389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567175PMC
September 2017

Absence of autoreactive CD4 T-cells targeting HLA-DQA1*01:02/DQB1*06:02 restricted hypocretin/orexin epitopes in narcolepsy type 1 when detected by EliSpot.

J Neuroimmunol 2017 08 4;309:7-11. Epub 2017 May 4.

Danish Center for Sleep Medicine, Department of Neurophysiology, Rigshospitalet, Glostrup, Denmark; Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias, Oslo University Hospital, Ullevål, Norway. Electronic address:

Narcolepsy type 1, a neurological sleep disorder strongly associated with Human Leukocyte Antigen (HLA-)DQB1*06:02, is caused by the loss of hypothalamic neurons producing the wake-promoting neuropeptide hypocretin (hcrt, also known as orexin). This loss is believed to be caused by an autoimmune reaction. To test whether hcrt itself could be a possible target in the autoimmune attack, CD4 T-cell reactivity towards six different 15-mer peptides from prepro-hypocretin with high predicted affinity to the DQA1*01:02/DQB1*06:02 MHC class II dimer was tested using EliSpot in a cohort of 22 narcolepsy patients with low CSF hcrt levels, and 23 DQB1*06:02 positive healthy controls. Our ELISpot assay had a detection limit of 1:10,000 cells. We present data showing that autoreactive CD4 T-cells targeting epitopes from the hcrt precursor in the context of MHC-DQA1*01:02/DQB1*06:02 are either not present or present in a frequency is <1:10,000 among peripheral CD4 T-cells from narcolepsy type 1 patients.
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http://dx.doi.org/10.1016/j.jneuroim.2017.05.001DOI Listing
August 2017

Narcolepsy.

Nat Rev Dis Primers 2017 Feb 9;3:16100. Epub 2017 Feb 9.

Sleep Medicine Center Kempenhaeghe, Heeze, The Netherlands.

Narcolepsy is a chronic sleep disorder that has a typical onset in adolescence and is characterized by excessive daytime sleepiness, which can have severe consequences for the patient. Problems faced by patients with narcolepsy include social stigma associated with this disease, difficulties in obtaining an education and keeping a job, a reduced quality of life and socioeconomic consequences. Two subtypes of narcolepsy have been described (narcolepsy type 1 and narcolepsy type 2), both of which have similar clinical profiles, except for the presence of cataplexy, which occurs only in patients with narcolepsy type 1. The pathogenesis of narcolepsy type 1 is hypothesized to be the autoimmune destruction of the hypocretin-producing neurons in the hypothalamus; this hypothesis is supported by immune-related genetic and environmental factors associated with the disease. However, direct evidence in support of the autoimmune hypothesis is currently unavailable. Diagnosis of narcolepsy encompasses clinical, electrophysiological and biological evaluations, but simpler and faster procedures are needed. Several medications are available for the symptomatic treatment of narcolepsy, all of which have quite good efficacy and safety profiles. However, to date, no treatment hinders or slows disease development. Improved diagnostic tools and increased understanding of the pathogenesis of narcolepsy type 1 are needed and might lead to therapeutic or even preventative interventions.
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http://dx.doi.org/10.1038/nrdp.2016.100DOI Listing
February 2017

Normal Morning Melanin-Concentrating Hormone Levels and No Association with Rapid Eye Movement or Non-Rapid Eye Movement Sleep Parameters in Narcolepsy Type 1 and Type 2.

J Clin Sleep Med 2017 Feb 15;13(2):235-243. Epub 2017 Feb 15.

Danish Center for Sleep Medicine, University of Copenhagen, Rigshospitalet, Glostrup, Denmark.

Study Objectives: Other than hypocretin-1 (HCRT-1) deficiency in narcolepsy type 1 (NT1), the neurochemical imbalance of NT1 and narcolepsy type 2 (NT2) with normal HCRT-1 levels is largely unknown. The neuropeptide melanin-concentrating hormone (MCH) is mainly secreted during sleep and is involved in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep regulation. Hypocretin neurons reciprocally interact with MCH neurons. We hypothesized that altered MCH secretion contributes to the symptoms and sleep abnormalities of narcolepsy and that this is reflected in morning cerebrospinal fluid (CSF) MCH levels, in contrast to previously reported normal evening/afternoon levels.

Methods: Lumbar CSF and plasma were collected from 07:00 to 10:00 from 57 patients with narcolepsy (subtypes: 47 NT1; 10 NT2) diagnosed according to International Classification of Sleep Disorders, Third Edition (ICSD-3) and 20 healthy controls. HCRT-1 and MCH levels were quantified by radioimmunoassay and correlated with clinical symptoms, polysomnography (PSG), and Multiple Sleep Latency Test (MSLT) parameters.

Results: CSF and plasma MCH levels were not significantly different between narcolepsy patients regardless of ICSD-3 subtype, HCRT-1 levels, or compared to controls. CSF MCH and HCRT-1 levels were not significantly correlated. Multivariate regression models of CSF MCH levels, age, sex, and body mass index predicting clinical, PSG, and MSLT parameters did not reveal any significant associations to CSF MCH levels.

Conclusions: Our study shows that MCH levels in CSF collected in the morning are normal in narcolepsy and not associated with the clinical symptoms, REM sleep abnormalities, nor number of muscle movements during REM or NREM sleep of the patients. We conclude that morning lumbar CSF MCH measurement is not an informative diagnostic marker for narcolepsy.
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http://dx.doi.org/10.5664/jcsm.6454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5263079PMC
February 2017

Monozygotic twins discordant for narcolepsy type 1 and multiple sclerosis.

Neurol Neuroimmunol Neuroinflamm 2016 Aug 16;3(4):e249. Epub 2016 Jun 16.

Danish Center for Sleep Medicine (P.J.J., S.K.) and Molecular Sleep Laboratory, Department of Clinical Biochemistry (B.R.K., S.G.), University of Copenhagen, Rigshospitalet, Glostrup, Denmark; Norwegian Centre of Expertise for Neurodevelopmental Disorders and Hypersomnias (NevSom) (S.K.), Oslo University Hospital, Ullevål, Norway; Department of Neurology (N.M.I.), University of Copenhagen, Hillerød Hospital; Department of Cellular and Molecular Medicine, Panum Institute (N.T.), and Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Science (N.M.), University of Copenhagen; Applied Human Molecular Genetics (Z.T.), Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.

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http://dx.doi.org/10.1212/NXI.0000000000000249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911794PMC
August 2016

Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset.

Brain Behav Immun 2015 Oct 11;49:54-8. Epub 2015 Mar 11.

Center for Sleep Sciences and Medicine, Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA, USA.

Type 1 narcolepsy is caused by a loss of hypocretin (orexin) signaling in the brain. Genetic data suggests the disorder is caused by an autoimmune attack on hypocretin producing neurons in hypothalamus. This hypothesis has however not yet been confirmed by consistent findings of autoreactive antibodies or T-cells in patient samples. One explanation for these negative results may be that the autoimmune process is no longer active when patients present to the clinic. With increasing awareness in recent years, more and more patients have been diagnosed closer and closer to disease onset. In this study, we tested whether an active immune process in the brain could be detected in these patients, as reflected by increased cytokine levels in the cerebrospinal fluid (CSF). Using multiplex analysis, we measured the levels of 51 cytokines and chemokines in the CSF of 40 type 1 narcolepsy patients having varying disease duration. For comparison, we used samples from 9 healthy controls and 9 patients with other central hypersomnia. Cytokine levels did not differ significantly between controls and patients, even in 5 patients with disease onset less than a month prior to CSF sampling.
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http://dx.doi.org/10.1016/j.bbi.2015.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567452PMC
October 2015

HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy.

Am J Hum Genet 2015 Jan;96(1):136-46

Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur and Department of Neurosciences, University of Montreal, Montreal, QC H3T 1J4, Canada.

Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.
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http://dx.doi.org/10.1016/j.ajhg.2014.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289679PMC
January 2015

Reduced CSF hypocretin-1 levels are associated with cluster headache.

Cephalalgia 2015 Sep 9;35(10):869-76. Epub 2014 Dec 9.

Danish Headache Center, Dept. of Neurology, Glostrup Hospital, University of Copenhagen, Denmark

Background: Cluster headache (CH) is a debilitating disorder characterized by unilateral, severe pain attacks with accompanying autonomic symptoms, often waking the patient from sleep. As it exhibits strong chronobiological traits and genetic studies have suggested a link with the hypocretin (HCRT) system, the objective of this study was to investigate HCRT-1 in CH patients.

Methods: Cerebrospinal fluid HCRT-1 concentration was measured in 12 chronic and 14 episodic CH patients during an active bout, and in 27 healthy controls. The patients were well characterized and clinical features compared to the HCRT concentration.

Results: We found significantly lower HCRT levels both in chronic (p = 0.0221) and episodic CH (p = 0.0005) patients compared with controls. No significant relationship was found with other clinical features.

Conclusions: This is the first report of significantly reduced HCRT concentrations in CH patients. We speculate that decreased HCRT may reflect insufficient antinociceptive activity of the hypothalamus. The mechanism of the antinociceptive effect of HCRT is not known and requires further investigation. This study supports the hypothesis of a connection between arousal regulation and CH.
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http://dx.doi.org/10.1177/0333102414562971DOI Listing
September 2015

MiRNA profiles in cerebrospinal fluid from patients with central hypersomnias.

J Neurol Sci 2014 Dec 2;347(1-2):199-204. Epub 2014 Oct 2.

Danish Center for Sleep Medicine, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark. Electronic address:

MicroRNAs (miRNAs) are involved in the pathogenesis of many human diseases, including some neurological disorders. Recently, we have reported dysregulated miRNAs in plasma from patients with central hypersomnias including type 1 and type 2 narcolepsy, and idiopathic hypersomnia. This study addressed whether miRNA levels are altered in the cerebrospinal fluid (CSF) of patients with central hypersomnias. We conducted high-throughput analyses of miRNAs in CSF from patients using quantitative real-time polymerase chain reaction panels. We identified 13, 9, and 11 miRNAs with a more than two-fold change in concentration in CSF from patients with type 1 and type 2 narcolepsy and idiopathic hypersomnia, respectively, compared with matched healthy controls. Most miRNAs differed in more than one of the sleep disorders. However, all miRNAs were detected at low levels in CSF and varied between individuals. None of them showed significant differences in concentrations between groups after correcting for multiple testing, and none could be validated in an independent cohort. Nevertheless, approximately 60% of the most abundant miRNAs in the profile reported here have previously been identified in the CSF of healthy individuals, showing consistency with previous miRNA profiles found in CSF. In conclusion, we were not able to demonstrate distinct levels or patterns of miRNAs in CSF from central hypersomnia patients.
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http://dx.doi.org/10.1016/j.jns.2014.09.047DOI Listing
December 2014

Sleep-wake transition in narcolepsy and healthy controls using a support vector machine.

J Clin Neurophysiol 2014 Oct;31(5):397-401

*Department of Electrical Engineering, Technical University of Denmark, Kongens Lyngby, Denmark; and †Danish Center for Sleep Medicine, Glostrup University Hospital, Glostrup, Denmark.

Narcolepsy is characterized by abnormal sleep-wake regulation, causing sleep episodes during the day and nocturnal sleep disruptions. The transitions between sleep and wakefulness can be identified by manual scorings of a polysomnographic recording. The aim of this study was to develop an automatic classifier capable of separating sleep epochs from epochs of wakefulness by using EEG measurements from one channel. Features from frequency bands α (0-4 Hz), β (4-8 Hz), δ (8-12 Hz), θ (12-16 Hz), 16 to 24 Hz, 24 to 32 Hz, 32 to 40 Hz, and 40 to 48 Hz were extracted from data by use of a wavelet packet transformation and were given as input to a support vector machine classifier. The classification algorithm was assessed by hold-out validation and 10-fold cross-validation. The data used to validate the classifier were derived from polysomnographic recordings of 47 narcoleptic patients (33 with cataplexy and 14 without cataplexy) and 15 healthy controls. Compared with manual scorings, an accuracy of 90% was achieved in the hold-out validation, and the area under the receiver operating characteristic curve was 95%. Sensitivity and specificity were 90% and 88%, respectively. The 10-fold cross-validation procedure yielded an accuracy of 88%, an area under the receiver operating characteristic curve of 92%, a sensitivity of 87%, and a specificity of 87%. Narcolepsy with cataplexy patients experienced significantly more sleep-wake transitions during night than did narcolepsy without cataplexy patients (P = 0.0199) and healthy subjects (P = 0.0265). In addition, the sleep-wake transitions were elevated in hypocretin-deficient patients. It is concluded that the classifier shows high validity for identifying the sleep-wake transition. Narcolepsy with cataplexy patients have more sleep-wake transitions during night, suggesting instability in the sleep-wake regulatory system.
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http://dx.doi.org/10.1097/WNP.0000000000000074DOI Listing
October 2014

EGFR signaling patterns are regulated by its different ligands.

Growth Factors 2014 Oct;32(5):155-63

Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen , Denmark .

EGF receptor (EGFR) and its signaling have been investigated for many years, but how its different ligands regulate signaling has not been thoroughly explored. When investigating EGFR activation and downstream signaling in HeLa cells using a panel of ligands, we found a ligand-dependent differential activation of EGFR and the signaling pathways Akt, PLCγ and STAT with HB-EGF and BTC being the most potent ligands. All the tested ligands induced full activation of Erk signaling at 1 nM, whereas only HB-EGF and partly BTC and EGF induced strong activation of Akt, STAT3 and PLCγ at this concentration. Interestingly, we also found that the high activation potencies of HB-EGF and BTC could only partially be explained by their binding affinities, and are therefore likely to be regulated by other mechanisms. We thus suggest that the signaling pathways initiated from the EGFR vary depending on the ligands bound in a cell specific manner.
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http://dx.doi.org/10.3109/08977194.2014.952410DOI Listing
October 2014

HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency.

Sleep 2014 Oct 1;37(10):1601-8. Epub 2014 Oct 1.

Center for Sleep Sciences and Medicine, and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA.

Study Objectives: To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02.

Settings: China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University).

Design: CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes.

Measurements And Results: Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing.

Conclusions: Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.
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http://dx.doi.org/10.5665/sleep.4066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173917PMC
October 2014

miRNA profiles in plasma from patients with sleep disorders reveal dysregulation of miRNAs in narcolepsy and other central hypersomnias.

Sleep 2014 Sep 1;37(9):1525-33. Epub 2014 Sep 1.

Study Objectives: MicroRNAs (miRNAs) have been implicated in the pathogenesis of human diseases including neurological disorders. The aim is to address the involvement of miRNAs in the pathophysiology of central hypersomnias including autoimmune narcolepsy with cataplexy and hypocretin deficiency (type 1 narcolepsy), narcolepsy without cataplexy (type 2 narcolepsy), and idiopathic hypersomnia.

Design: We conducted high-throughput analysis of miRNA in plasma from three groups of patients-with type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia, respectively-in comparison with healthy controls using quantitative real-time polymerase chain reaction (qPCR) panels.

Setting: University hospital based sleep clinic and research laboratories.

Patients: Twelve patients with type 1 narcolepsy, 12 patients with type 2 narcolepsy, 12 patients with idiopathic hypersomnia, and 12 healthy controls.

Measurements And Results: By analyzing miRNA in plasma with qPCR we identified 50, 24, and 6 miRNAs that were different in patients with type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia, respectively, compared with healthy controls. Twenty miRNA candidates who fulfilled the criteria of at least two-fold difference and p-value < 0.05 were selected to validate the miRNA changes in an independent cohort of patients. Four miRNAs differed significantly between type 1 narcolepsy patients and healthy controls. Levels of miR-30c, let-7f, and miR-26a were higher, whereas the level of miR-130a was lower in type 1 narcolepsy than healthy controls. The miRNA differences were not specific for type 1 narcolepsy, since the levels of the four miRNAs were also altered in patients with type 2 narcolepsy and idiopathic hypersomnia compared with healthy controls.

Conclusion: The levels of four miRNAs differed in plasma from patients with type 1 narcolepsy, type 2 narcolepsy and idiopathic hypersomnia suggesting that alterations of miRNAs may be involved in the pathophysiology of central hypersomnias.
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http://dx.doi.org/10.5665/sleep.4004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153051PMC
September 2014

[Travel and venous thromboembolism].

Ugeskr Laeger 2013 Oct;175(44):2628-31

Schønbergsgade 7, 2. tv., 1906 Frederiksberg C.

A literature study on the association between travel and venous thromboembolism (VTE) is conducted. Studies examining the risk of travel-associated VTE, predisposing factors and prophylactic measures are presented. It is concluded that the absolute risk of travel-associated VTE is low and holds a 2-4 fold increase after travel. The risk increases with duration, presence of other risk factors for VTE and extremes of height. Stockings reduces the risk of asymptomatic VTE. Heparin is presumed to constitute protection whereas there is no evidence of a prophylactic effect of acetylsalicylic acid.
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October 2013

Sleep transitions in hypocretin-deficient narcolepsy.

Sleep 2013 Aug 1;36(8):1173-7. Epub 2013 Aug 1.

Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Glostrup Hospital, Copenhagen, Denmark.

Study Objectives: Narcolepsy is characterized by instability of sleep-wake, tonus, and rapid eye movement (REM) sleep regulation. It is associated with severe hypothalamic hypocretin deficiency, especially in patients with cataplexy (loss of tonus). As the hypocretin neurons coordinate and stabilize the brain's sleep-wake pattern, tonus, and REM flip-flop neuronal centers in animal models, we set out to determine whether hypocretin deficiency and/or cataplexy predicts the unstable sleep-wake and REM sleep pattern of the human phenotype.

Design: We measured the frequency of transitions in patients with narcolepsy between sleep-wake states and to/from REM and NREM sleep stages. Patients were subdivided by the presence of +/- cataplexy and +/- hypocretin-1 deficiency.

Setting: Sleep laboratory studies conducted from 2001-2011.

Patients: In total 63 narcolepsy patients were included in the study. Cataplexy was present in 43 of 63 patients and hypocretin-1 deficiency was present in 37 of 57 patients.

Measurements And Results: Hypocretin-deficient patients with narcolepsy had a significantly higher frequency of sleep-wake transitions (P = 0.014) and of transitions to/from REM sleep (P = 0.044) than patients with normal levels of hypocretin-1. Patients with cataplexy had a significantly higher frequency of sleep-wake transitions (P = 0.002) than those without cataplexy. A multivariate analysis showed that transitions to/from REM sleep were predicted mainly by hypocretin-1 deficiency (P = 0.011), whereas sleep-wake transitions were predicted mainly by cataplexy (P = 0.001).

Conclusions: In human narcolepsy, hypocretin deficiency and cataplexy are both associated with signs of destabilized sleep-wake and REM sleep control, indicating that the disorder may serve as a human model for the sleep-wake and REM sleep flip-flop switches.
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http://dx.doi.org/10.5665/sleep.2880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700714PMC
August 2013

[New knowledge about narcolepsy in children].

Tidsskr Nor Laegeforen 2013 Jun;133(12-13):1326-8

Nasjonalt kompetansesenter for AD/HD, Tourettes syndrom og narkolepsi, Norway.

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http://dx.doi.org/10.4045/tidsskr.13.0414DOI Listing
June 2013

Comorbidity and mortality of narcolepsy: a controlled retro- and prospective national study.

Sleep 2013 Jun 1;36(6):835-40. Epub 2013 Jun 1.

Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Glostrup Hospital, Copenhagen, Denmark.

Study Objectives: To identify the factual morbidity and mortality of narcolepsy in a controlled design.

Setting: National Patient Registry.

Patients: All national diagnosed patients (757) with health information at least 3 years prior to and after diagnose of narcolepsy.

Controls: Randomly selected four citizens (3,013) matched for age, sex, and socioeconomic status from the Danish Civil Registration System Statistics.

Results: Increased morbidity prior to narcolepsy diagnosis included (odds ratio, 95% confidence interval):- diseases of the endocrine, nutritional, and metabolic systems (2.10, 1.32-3.33); nervous system (5.27, 3.65-7.60); musculoskeletal system (1.59, 1.23-2.05); and other abnormal symptoms and laboratory findings (1.66, 1.25-2.22). After the diagnosis, narcolepsy patients experienced diseases of the endocrine, nutritional, and metabolic (2.31, 1.51-3.54), nervous (9.19, 6.80-12.41), musculoskeletal (1.70, 1.28-2.26), eye (1.67, 1.03-2.71), and respiratory systems (1.84, 1.21-2.81). Specific diagnoses were diabetes (2.4, 1,2-4.7, P < 0.01), obesity (13.4, 3.1-57.6, P < 0.001), sleep apnea (19.2, 7.7-48.3, P < 0.001), other sleep disorders (78.5, 11.8-523.3, P < 0.001), chronic obstructive pulmonary disease (2.8, 1.4-5.8, P < 0.01), lower back pain (2.5, 1.4-4.2, P < 0.001), arthrosis/arthritis (2.5, 1.3-4.8, P < 0.01), observation of neurological diseases (3.5, 1.9-6.5, P < 0.001), observation of other diseases (1.7, 1.2-2.5, P < 0.01), and rehabilitation (5.0, 1.5-16.5, P < 0.005). There was a trend towards greater mortality in narcolepsy (P = 0.07).

Conclusions: Patients with narcolepsy present higher morbidity several years prior to diagnose and even higher thereafter. The mortality rate due to narcolepsy was slightly but not significantly higher.
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http://dx.doi.org/10.5665/sleep.2706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649826PMC
June 2013

[The association between narcolepsy and H1N1 influenza].

Ugeskr Laeger 2013 Mar;175(12):815

Dansk Selskab for Søvnmedicin, Denmark.

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March 2013

Increased serum brain-derived neurotrophic factor (BDNF) levels in patients with narcolepsy.

Neurosci Lett 2013 Jun 6;544:31-5. Epub 2013 Apr 6.

Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Denmark.

Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness, sudden loss of muscle tone (cataplexy), fragmentation of nocturnal sleep and sleep paralysis. The symptoms of the disease strongly correlate with a reduction in hypocretin levels in CSF and a reduction in hypocretin neurons in hypothalamus in post-mortem tissue. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are important for activity-dependent neuronal function and synaptic modulation and it is considered that these mechanisms are important in sleep regulation. We hypothesized that serum levels of these factors are altered in patients with narcolepsy compared to healthy controls without sleep disturbances. Polysomnography data was obtained and serum BDNF and NGF levels measured using ELISA, while hypocretin was measured using RIA. Serum BDNF levels were significantly higher in narcolepsy patients than in healthy controls (64.2±3.9 ng/ml vs. 47.3±2.6 ng/ml, P<0.01), while there were no significant differences in NGF levels. As expected, narcolepsy patients had higher BMI compared to controls, but BMI did not correlate with the serum BDNF levels. The change in BDNF levels was not related to disease duration and sleep parameters did not correlate with BDNF in narcolepsy patients. The mechanisms behind the marked increase in BDNF levels in narcolepsy patients remain unknown.
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http://dx.doi.org/10.1016/j.neulet.2013.03.031DOI Listing
June 2013

Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study.

J Sleep Res 2013 Oct 18;22(5):482-95. Epub 2013 Mar 18.

Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Switzerland.

The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E-07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.
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http://dx.doi.org/10.1111/jsr.12044DOI Listing
October 2013

Internalization mechanisms of the epidermal growth factor receptor after activation with different ligands.

PLoS One 2013 5;8(3):e58148. Epub 2013 Mar 5.

Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

The epidermal growth factor receptor (EGFR) regulates normal growth and differentiation, but dysregulation of the receptor or one of the EGFR ligands is involved in the pathogenesis of many cancers. There are eight ligands for EGFR, however most of the research into trafficking of the receptor after ligand activation focuses on the effect of epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). For a long time it was believed that clathrin-mediated endocytosis was the major pathway for internalization of the receptor, but recent work suggests that different pathways exist. Here we show that clathrin ablation completely inhibits internalization of EGF- and TGF-α-stimulated receptor, however the inhibition of receptor internalization in cells treated with heparin-binding EGF-like growth factor (HB-EGF) or betacellulin (BTC) was only partial. In contrast, clathrin knockdown fully inhibits EGFR degradation after all ligands tested. Furthermore, inhibition of dynamin function blocked EGFR internalization after stimulation with all ligands. Knocking out a number of clathrin-independent dynamin-dependent pathways of internalization had no effect on the ligand-induced endocytosis of the EGFR. We suggest that EGF and TGF-α lead to EGFR endocytosis mainly via the clathrin-mediated pathway. Furthermore, we suggest that HB-EGF and BTC also lead to EGFR endocytosis via a clathrin-mediated pathway, but can additionally use an unidentified internalization pathway or better recruit the small amount of clathrin remaining after clathrin knockdown.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058148PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589378PMC
December 2013

Hypocretin deficiency develops during onset of human narcolepsy with cataplexy.

Sleep 2013 Jan 1;36(1):147-8. Epub 2013 Jan 1.

Paediatric Department, Blekinge Hospital, Karlskrona, Sweden.

Study Objectives: Although hypothesized through animal studies, a temporal and causal association between hypocretin deficiency and the onset of narcolepsy with cataplexy (NC) has never been proven in humans.

Setting: Paediatric Department, Blekinge Hospital, Sweden, and Danish Center for Sleep Medicine, Glostrup Hospital, Denmark.

Patient And Results: Two weeks after his second Pandemrix-vaccination, a 10 year old HLA-DQB1*0602-positive boy developed NC. The CSF hypocretin-1 level was 10 pg/ml. However, CSF saved from a pre-narcolepsy episode of Lyme disease revealed a normal hypocretin-1 level (318 pg/ml).

Conclusions: We confirm that hypocretin deficiency develops in parallel to the onset of human narcolepsy with cataplexy.
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http://dx.doi.org/10.5665/sleep.2320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524537PMC
January 2013
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