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- Jersin, R. A., et al.
(författare)
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Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 70:3, s. 680-695
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Tidskriftsartikel (refereegranskat)abstract
- Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.
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| 3. |
- Scott, J., et al.
(författare)
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Prospective cohort study of early biosignatures of response to lithium in bipolar-I-disorders: overview of the H2020-funded R-LiNK initiative
- 2019
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Ingår i: International Journal of Bipolar Disorders. - : Springer Science and Business Media LLC. - 2194-7511. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need. Structure The H2020-funded Response to Lithium Network (R-LiNK; ) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants' response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence. Conclusions The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.
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- Hokken-Koelega, A. C. S., et al.
(författare)
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International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood
- 2023
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Ingår i: Endocrine Reviews. - : The Endocrine Society. - 0163-769X .- 1945-7189. ; 44:3, s. 539-565
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Tidskriftsartikel (refereegranskat)abstract
- This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.
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| 5. |
- Zalm, P. W. V., et al.
(författare)
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Article Meta-analysis of published cerebrospinal fluid proteomics data identifies and validates metabolic enzyme panel as Alzheimer's disease biomarkers
- 2023
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Ingår i: Cell Reports Medicine. - 2666-3791. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- To develop therapies for Alzheimer's disease, we need accurate in vivo diagnostics. Multiple proteomic studies mapping biomarker candidates in cerebrospinal fluid (CSF) resulted in little overlap. To overcome this shortcoming, we apply the rarely used concept of proteomics meta-analysis to identify an effective biomarker panel. We combine ten independent datasets for biomarker identification: seven datasets from 150 patients/controls for discovery, one dataset with 20 patients/controls for down-selection, and two data -sets with 494 patients/controls for validation. The discovery results in 21 biomarker candidates and down -selection in three, to be validated in the two additional large-scale proteomics datasets with 228 diseased and 266 control samples. This resulting 3-protein biomarker panel differentiates Alzheimer's disease (AD) from controls in the two validation cohorts with areas under the receiver operating characteristic curve (AUROCs) of 0.83 and 0.87, respectively. This study highlights the value of systematically re-analyzing pre-viously published proteomics data and the need for more stringent data deposition.
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| 6. |
- Athanasiu, L., et al.
(författare)
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A genetic association study of CSMD1 and CSMD2 with cognitive function
- 2017
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Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 61, s. 209-216
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Tidskriftsartikel (refereegranskat)abstract
- The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n = 670). Replication testing of SNPs with p-value < 0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n =1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n = 1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMDI SNP rs2740931 and performance in immediate episodic memory (p-value = 5 Chi 10(-6), minor allele A, MAF 0.48-0.49, negative direction of effect). This association reached the study-wide significance level (p <= 1.2 Chi 10(-5)). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n = 3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease. (C) 2016 The Authors. Published by Elsevier Inc.
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| 9. |
- Langhelle, A., et al.
(författare)
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Recommended guidelines for reviewing, reporting, and conducting research on post-resuscitation care: the Utstein style
- 2005
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Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 66:3, s. 271-83
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this report is to establish recommendations for reviewing, reporting, and conducting research during the post-resuscitation period in hospital. It defines data that are needed for research and more specialised registries and therefore supplements the recently updated Utstein template for resuscitation registries. The updated Utstein template and the out-of-hospital "Chain of Survival" describe factors of importance for successful resuscitation up until return of spontaneous circulation (ROSC). Several factors in the in-hospital phase after ROSC are also likely to affect the ultimate outcome of the patient. Large differences in survival to hospital discharge for patients admitted alive are reported between hospitals. Therapeutic hypothermia has been demonstrated to improve the outcome, and other factors such as blood glucose, haemodynamics, ventilatory support, etc., might also influence the result. No generally accepted, scientifically based protocol exists for the post-resuscitation period in hospital, other than general brain-oriented intensive care. There is little published information on this in-hospital phase. This statement is the result of a scientific consensus development process started as a symposium by a task force at the Utstein Abbey, Norway, in September 2003. Suggested data are defined as core and supplementary and include the following categories: pre-arrest co-morbidity and functional status, cause of death, patients' quality of life, in-hospital system factors, investigations and treatment, and physiological data at various time points during the first three days after admission. It is hoped that the publication of these recommendations will encourage research into the in-hospital post-resuscitation phase, which we propose should be included in the chain-of-survival as a fifth ring. Following these recommendations should enable better understanding of the impact of different in-hospital treatment strategies on outcome.
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| 10. |
- Nichol, G., et al.
(författare)
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International Resuscitation Network Registry: design, rationale and preliminary results
- 2005
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Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 65:3, s. 265-77
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Tidskriftsartikel (refereegranskat)abstract
- There is a lack of high-quality information about the effectiveness of resuscitation interventions and international differences in structure, process and outcome after out-of-hospital cardiac arrest and cardiopulmonary resuscitation because data are not collected uniformly. An internet-based international registry could make such evaluations possible, and enable the conduct of large randomized controlled trials of resuscitation therapies. A prospective international cohort study was performed that included 571 infants, children and adults (a) who experienced cardiac arrest requiring chest compressions or external defibrillation, (b) outside the hospital in the study communities and (c) upon whom resuscitation was attempted by EMS personnel. Cardiac arrest was defined as lack of responsiveness, breathing or movement in individuals for whom the EMS system is activated for whom an arrest record is completed. All data were collated via a secure and confidential web-based method by using automated forms processing software with appropriate variable range checks, logic checks and skip rules. Median number of missing responses for each variable was 0 (interquartile range 0, 0). Twenty-seven percent of the patients had a first recorded rhythm of ventricular fibrillation or ventricular tachycardia, 60% had a witnessed arrest, and 34% received bystander CPR. Mean time from call to arrival on scene was 7.1+/-5.1 min. Six percent of the patients survived to hospital discharge. The resuscitation process was highly variable across centers, and survival and neurological outcome were also significantly and independently different across centers. This study shows that it is possible to collect data prospectively describing the structure, process and outcome associated with cardiac arrest in multiple international sites via the internet. Therefore, it is feasible to conduct adequately powered randomized trials of resuscitation therapies in international settings.
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