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- Bhandage, Amol K., 1988-, et al.
(författare)
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GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes
- 2018
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 30, s. 283-294
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Tidskriftsartikel (refereegranskat)abstract
- The neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100nM, 500nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion.
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- Diaz Heijtz, Rochellys, et al.
(författare)
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Genetic Variation in the Dopamine System Influences Intervention Outcome in Children with Cerebral Palsy
- 2018
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 28, s. 162-167
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is large variation in treatment responses in children with cerebral palsy. Experimental and clinical results suggest that dopamine neurotransmission and brain-derived neurotrophic factor (BDNF) signalling are involved in motor learning and plasticity, which are key factors in modern habilitation success. We examined whether naturally occurring variations in dopamine and BDNF genes influenced the treatment outcomes.METHODS: Thirty-three children (18-60months of age) with spastic unilateral cerebral palsy were enrolled in the study. Each child had participated in a training programme consisting of active training of the involved hand for 2h every day during a 2-month training period. The training outcome was measured using Assisting Hand Assessment before and after the training period. Saliva was collected for genotyping of COMT, DAT, DRD1, DRD2, DRD3, and BDNF. Regression analyses were used to examine associations between genetic variation and training outcome.FINDINGS: There was a statistically significant association between variation in dopamine genes and treatment outcome. Children with a high polygenic dopamine gene score including polymorphisms of five dopamine genes (COMT, DAT, DRD1, DRD2, and DRD3), and reflecting higher endogenous dopaminergic neurotransmission, had the greatest functional outcome gains after intervention.INTERPRETATION: Naturally occurring genetic variation in the dopamine system can influence treatment outcomes in children with cerebral palsy. A polygenic dopamine score might be valid for treatment outcome prediction and for designing individually tailored interventions for children with cerebral palsy.
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- Genga, Kelly Roveran, et al.
(författare)
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Impact of PCSK9 loss-of-function genotype on 1-year mortality and recurrent infection in sepsis survivors
- 2018
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 38, s. 257-264
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Tidskriftsartikel (refereegranskat)abstract
- Background: Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown. Methods: We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 days after a sepsis admission in a tertiary hospital (Vancouver/Canada, 2004–2014), while an independent Validation cohort included 1079 septic shock patients admitted at the same hospital (2000–2006). All patients were genotyped for three common missense PCSK9 LOF variants rs11591147, rs11583680, rs562556 and were classified in 3 groups: Wildtype, single PCSK9 LOF, and multiple PCSK9 LOF, according to the number of LOF alleles per patient. We also performed a meta-analysis using both cohorts to investigate the effects of PCSK9 genotype on 90-day survival. Findings: In the Derivation cohort, patients carrying multiple PCSK9 LOF alleles showed lower risk for the composite outcome 1-year death or IRR (HR: 0.40, P = 0.006), accelerated reduction on neutrophil counts (P = 0.010), and decreased levels of PCSK9 (P = 0.037) compared with WT/single LOF groups. Our meta-analysis revealed that the presence of multiple LOF alleles was associated with lower 90-day mortality risk (OR = 0.69, P = 0.020). Interpretation: The presence of multiple PCSK9 LOF alleles decreased the risk of 1-year death or IRR in sepsis survivors. Biological measures suggest this may be related to an enhanced resolution of the initial infection. Funding: Canadian Institutes of Health Research (PJT-156056).
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- Huttner, Hagen B., et al.
(författare)
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Meningioma growth dynamics assessed by radiocarbon retrospective birth dating
- 2018
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 27, s. 176-181
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Tidskriftsartikel (refereegranskat)abstract
- It is not known how long it takes from the initial neoplastic transformation of a cell to the detection of a tumor, which would be valuable for understanding tumor growth dynamics. Meningiomas show a broad histological, genetic and clinical spectrum, are usually benign and considered slowly growing. There is an intense debate regarding their age and growth pattern and when meningiomas should be resected. We have assessed the age and growth dynamics of 14 patients with meningiomas (WHO grade I: n = 6 with meningothelial and n = 6 with fibrous subtype, as well as n = 2 atypical WHO grade II meningiomas) by combining retrospective birth-dating of cells by analyzing incorporation of nuclear-bomb-test-derived 14C, analysis of cell proliferation, cell density, MRI imaging and mathematical modeling. We provide an integrated model of the growth dynamics of benign meningiomas. The mean age of WHO grade I meningiomas was 22.1 ± 6.5 years, whereas atypical WHO grade II meningiomas originated 1.5 ± 0.1 years prior to surgery (p < 0.01). We conclude that WHO grade I meningiomas are very slowly growing brain tumors, which are resected in average two decades after time of origination.
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- Jokinen, Jussi, et al.
(författare)
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Epigenetic changes in the CRH gene are related to severity of suicide attempt and a general psychiatric risk score in adolescents
- 2018
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 27, s. 123-133
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study, comprising 88 suicide attempters, was to identify hypothalamic-pituitary-adrenal (HPA) -axis coupled CpG-sites showing methylation shifts linked to severity of the suicide attempt. Candidate methylation loci were further investigated as risk loci for a general psychiatric risk score in two cohorts of adolescents (cohort 1 and 2). The genome-wide methylation pattern was measured in whole blood using the Illumina Infinium Methylation EPIC BeadChip. Subjects were stratified into high-risk and low-risk groups based on the severity of the suicidal behavior. We included CpG sites located within 2000 basepairs away from transcriptional start site of the following HPA-axis coupled genes: corticotropin releasing hormone (CRH), corticotropin releasing hormone binding protein (CRHBP), corticotropin releasing hormone receptor 1 (CRHR1), corticotropin releasing hormone receptor 2 (CRHR2), FK506-binding protein 51 (FKBP5) and the glucocorticoid receptor (NR3C1). Themethylation state of two corticotropin releasing hormone (CRH)-associated CpG siteswere significantly hypomethylated in the high-risk group of suicide attempters (n=31) (cg19035496 and cg23409074) (p < 0.001). Adolescent cohort 1 and 2 consisted of 129 and 93 subjects, respectively, and were stratified by the in silico generated DAWBA measurements of a general psychiatric risk score into high-risk group (>similar to 50% risk) or controls. In adolescent cohort 2, cg19035496 was hypermethylated in subjects with a high general psychiatric risk score. Our results show epigenetic changes in the CRH gene related to severity of suicide attempt in adults and a general psychiatric risk score in adolescents.
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