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- Strømme, P., et al.
(författare)
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Mutated thyroid hormone transporter OATP1C1 associates with severe brain hypometabolism and juvenile neurodegeneration
- 2018
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 28:11, s. 1406-1415
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Tidskriftsartikel (refereegranskat)abstract
- Background: Thyroid hormones (TH) are essential for brain development and function. The TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporter1 C1 (OATP1C1) facilitate the transport of TH across the blood-brain barrier and into glia and neuronal cells in the brain. Loss of MCT8 function causes Allan-Herndon-Dudley syndrome (AHDS, OMIM 300523) characterized by severe intellectual and motor disability due to cerebral hypothyroidism. Here, the first patient with loss of OATP1C1 function is described. The patient is a 15.5-year-old girl with normal development in the first year of life, who gradually developed dementia with spasticity and intolerance to cold. Brain imaging demonstrated gray and white matter degeneration and severe glucose hypometabolism. Methods: Exome sequencing of the patient and parents was performed to identify the disease-causing mutation, and the effect of the mutation was studied through a panel of in vitro experiments, including thyroxine uptake studies, immunoblotting, and immunocytochemistry. Furthermore, the clinical effects of treatment with the triiodothyronine analogue triiodothyroacetic acid (Triac) are described. Results: Exome sequencing identified a homozygous missense mutation in OATP1C1, changing the highly conserved aspartic acid 252 to asparagine (D252N). In vitro, the mutated OATP1C1 displays impaired plasma membrane localization and decreased cellular thyroxine uptake. After treatment with Triac, the clinical condition improved in several domains. Conclusions: This is the first report of human OATP1C1 deficiency compatible with brain-specific hypothyroidism and neurodegeneration. © Copyright 2018, Mary Ann Liebert, Inc., publishers 2018.
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| 2. |
- Hermanussen, M, et al.
(författare)
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Adolescent growth: genes, hormones and the peer group.
- 2014
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Ingår i: Pediatric endocrinology reviews : PER. Proceedings of the 20th Aschauer Soiree, held at Glücksburg castle, Germany, 15th to 17th November 2013.. - 1565-4753. ; 11:3, s. 341-53
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Konferensbidrag (refereegranskat)abstract
- The association between poverty, malnutrition, illness and poor socioeconomic conditions on the one side, and poor growth and short adult stature on the other side, is well recognized. Yet, the simple assumption by implication that poor growth and short stature result from poor living conditions, should be questioned. Recent evidence on the impact of the social network on adolescent growth and adult height further challenges the traditional concept of growth being a mirror of health. Twenty-nine scientists met at Glücksburg castle, Northern Germany, November 15th - 17th 2013, to discuss genetic, endocrine, mathematical and psychological aspects and related issues, of child and adolescent growth and final height.
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| 5. |
- Hughes, T., et al.
(författare)
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Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder
- 2018
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Ankyrin-3 (ANK3) is one of the few genes that have been consistently identified as associated with bipolar disorder by multiple genome-wide association studies. However, the exact molecular basis of the association remains unknown. A rare loss-of-function splice-site SNP (rs41283526*G) in a minor isoform of ANK3 (incorporating exon ENSE00001786716) was recently identified as protective of bipolar disorder and schizophrenia. This suggests that an elevated expression of this isoform may be involved in the etiology of the disorders. In this study, we used novel approaches and data sets to test this hypothesis. First, we strengthen the statistical evidence supporting the allelic association by replicating the protective effect of the minor allele of rs41283526 in three additional large independent samples (meta-analysis pvalues: 6.8E-05 for bipolar disorder and 8.2E-04 for schizophrenia). Second, we confirm the hypothesis that both bipolar and schizophrenia patients have a significantly higher expression of this isoform than controls (p-values: 3.3E-05 for schizophrenia and 9.8E-04 for bipolar type I). Third, we determine the transcription start site for this minor isoform by Pacific Biosciences sequencing of full-length cDNA and show that it is primarily expressed in the corpus callosum. Finally, we combine genotype and expression data from a large Norwegian sample of psychiatric patients and controls, and show that the risk alleles in ANK3 identified by bipolar disorder GWAS are located near the transcription start site of this isoform and are significantly associated with its elevated expression. Together, these results point to the likely molecular mechanism underlying ANK3's association with bipolar disorder.
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| 6. |
- Prigge, Justin R., et al.
(författare)
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Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase
- 2017
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Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 19:13, s. 2771-2781
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Tidskriftsartikel (refereegranskat)abstract
- Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP(+) ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed. Here, we show that liver-specific co-disruption of the genes encoding Trx1, TrxR1, and Gsr (triplenull) causes dramatic hepatocyte hyperproliferation. Thus, even in the absence of Trx1, methionine-fueled glutathione production supports hepatocyte S phase deoxyribonucleotide production. Also, Trx1 in the absence of TrxR1 provides a survival advantage to cells under hyperglycemic stress, suggesting that glutathione, likely via glutaredoxins, can reduce Trx1 disulfide in vivo. In triple-null livers like in many cancers, deoxyribonucleotide synthesis places a critical yet relatively low-volume demand on these reductase systems, thereby favoring high hepatocyte turnover over sustained hepatocyte integrity.
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| 9. |
- Holmgren, Kristina, 1955, et al.
(författare)
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Early identification in primary health care of people at risk for sick leave due to work-related stress - Study protocol of a randomized controlled trial (RCT)
- 2016
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Ingår i: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- © 2016 The Author(s).Background: Early identification of persons at risk of sickness absence due to work-related stress is a crucial problem for society in general, and primary health care in particular. Tho date, no established method to do this exists. This project's aim is to evaluate whether systematic early identification of work-related stress can prevent sickness absence. This paper presents the study design, procedure and outcome measurements, as well as allocation and baseline characteristics of the study population. Method/design: The study is a two-armed randomized controlled trial with follow-up at 3, 6 and 12 months. Non-sick-listed employed women and men, aged 18 to 64 years, who had mental and physical health complaints and sought care at primary health care centers (PHCC) were eligible to participate. At baseline work-related stress was measured by the Work Stress Questionnaire (WSQ), combined with feedback at consultation, at PHCC. The preventive intervention included early identification of work-related stress by the WSQ, GP training in the use of WSQ, GP feedback at consultation and finding suitable preventive measures. A process evaluation was used to explore how to facilitate future implementation and structural use of the WSQ at the PHCC. The primary outcome to compare the preventive sick leave intervention by the general practitioner (GP) versus treatment as usual is sick leave data obtained from the Swedish Social Insurance Agency register. Discussion: Early screening for sick leave due to work-related stress makes it possible not only to identify those at risk for sick leave, but also to put focus on the patient's specific work-related stress problems, which can be helpful in finding suitable preventive measures. This study investigates if use of the WSQ by GPs at PHCCs, combined with feedback at consultation, prevents future sickness absence. Trial registration: ClinicalTrials.gov. Identifier: NCT02480855. Registered 20 May 2015
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| 10. |
- Larsson, Maria E H, 1969, et al.
(författare)
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Prevention of sickness absence through early identification and rehabilitation of at-risk patients with musculoskeletal pain (PREVSAM): a randomised controlled trial protocol
- 2020
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Ingår i: BMC Musculoskeletal Disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMusculoskeletal pain is globally a leading cause of physical disability. Many musculoskeletal-related pain conditions, such as low back pain, often resolve spontaneously. In some individuals, pain may recur or persist, leading to ong-term physical disability, reduced work capacity, and sickness absence. Early identification of individuals in which this may occur, is essential for preventing or reducing the risk of developing persistent musculoskeletal pain and long-term sickness absence. The aim of the trial described in this protocol is to evaluate effects of an early intervention, the PREVSAM model, on the prevention of sickness absence and development of persistent pain in at-risk patients with musculoskeletal pain.MethodsEligible participants are adults who seek health care for musculoskeletal pain and who are at risk of developing persistent pain, physical disability, and sickness absence. Participants may be recruited from primary care rehabilitation centres or primary care healthcare centres in Region Vastra Gotaland. Participants will be randomised to treatment according to the PREVSAM model (intervention group) or treatment as usual (control group). The PREVSAM model comprises an interdisciplinary, person-centred rehabilitation programme, including coordinated measures within primary health care, and may include collaboration with participants' employers. The primary outcome sickness absence is operationalised as the number and proportion of individuals who remain in full- or part-time work, the number of gross and net days of sickness absence during the intervention and follow-up period, and time to first sickness absence spell. Secondary outcomes are patient-reported short-term sickness absence, work ability, pain, self-efficacy, health-related quality of life, risk for sickness absence, anxiety and depression symptoms and physical disability at 1 and 3months after inclusion (short-term follow-up), and at 6 and 12months (long-term follow-up). A cost-effectiveness analysis is planned and drug consumption will be investigated.DiscussionThe study is expected to provide new knowledge on the effectiveness of a comprehensive rehabilitation model that incorporates early identification of patients with musculoskeletal pain at risk for development of sickness absence and persistent pain. The study findings may contribute to more effective rehabilitation processes of this large patient population, and potentially reduce sickness absence and costs.Trial registrationClinicalTrials.gov Protocol ID: NCT03913325, Registered April 12, 2019.Version 2, 10 July 2020.Version 2 changes: Clarifications regarding trial aim and inclusion process.
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