| 1. |
- Abé, Christoph, et al.
(författare)
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Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group.
- 2022
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Ingår i: Biological psychiatry. - : Elsevier BV. - 1873-2402 .- 0006-3223. ; 91:6, s. 582-592
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD.Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables.Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18
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| 2. |
- Aidoukovitch, Alexandra, et al.
(författare)
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Antimicrobial peptide LL-37 and its pro-form, hCAP18, in desquamated epithelial cells of human whole saliva
- 2020
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Ingår i: European Journal of Oral Sciences. - : Wiley. - 0909-8836 .- 1600-0722. ; 128:1, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- The antimicrobial peptide LL-37 is active against oral bacteria and has been demonstrated to be present in human saliva, but its distribution in different fractions of saliva is not known. LL-37 is formed from its intracellular pro-form, hCAP18, in an extracellular enzymatic reaction catalyzed by proteinase 3 and kallikrein 5. Here, we prepared cell-containing and cell-free fractions of unstimulated human whole saliva by centrifugation after depolymerization of mucins with dithiothreitol, and measured the levels of hCAP18/LL-37 in these fractions using ELISA. Cellular expression of hCAP18/LL-37 was determined by western blotting and immunocytochemistry. The ELISA analyses demonstrated that both cells and cell-free saliva contained hCAP18/LL-37. Western blot analysis of cell-pellet homogenates showed a strong band corresponding to hCAP18 at the correct molecular weight and a weak band corresponding to LL-37. Phase-contrast and light microscopy revealed that the cells consisted of desquamated epithelial cells. These cells expressed cytoplasmic immunoreactivity for hCAP18/LL-37. The peripheral part of the cytoplasm, corresponding to the plasma membrane, was particularly rich in hCAP18/LL-37 immunoreactivity. No immunoreactivity was observed after omission of the primary antibody. We conclude that desquamated epithelial cells of human whole saliva contain antimicrobial hCAP18/LL-37, suggesting that these cells may take part in the innate immune system by harboring and releasing these peptides.
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| 3. |
- Aidoukovitch, Alexandra, et al.
(författare)
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The host defense peptide LL-37 is internalized by human periodontal ligament cells and prevents LPS-induced MCP-1 production
- 2019
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Ingår i: Journal of Periodontal Research. - : Wiley. - 0022-3484 .- 1600-0765. ; 54:6, s. 662-670
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The human host defense peptide LL-37 both shows antimicrobial effects and modulates host cell properties. Here, we assess the effects of synthesized LL-37 on lipopolysaccharide (LPS)-induced inflammation in human periodontal ligament (PDL) cells and investigates underlying mechanisms. Background: LL-37 has been detected in the periodontal tissues, but its functional importance for PDL cell innate immune responses is not known. Methods: Human PDL cells were obtained from premolars extracted on orthodontic indications. Cellular pro-inflammatory monocyte chemoattractant protein-1 (MCP-1) mRNA expression was determined using quantitative real-time RT-PCR. MCP-1 protein production was assessed by western blot and ELISA. Internalization of LL-37 by PDL cells was visualized by immunocytochemistry. Nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) activity was assessed by western blot of phosphorylated p65, phosphorylated p105, and IκBα proteins. Binding of LL-37 to PDL cell DNA was determined by isolation and purification of DNA and dot blot for LL-37 immunoreactivity. Results: Treatment with LL-37 (1 µmol/L) for 24 hours prevented LPS-induced stimulation of MCP-1 expression analyzed both on transcript and on protein levels. Stimulation with LL-37 (1 µmol/L) for 24 hours had no effect on toll-like receptor (TLR)2 and TLR4 transcript expression, suggesting that LL-37 acts downstream of the TLRs. Preincubation with LL-37 for 60 minutes followed by stimulation with LPS for 24 hours in the absence of LL-37 completely prevented LPS-evoked MCP-1 transcript expression, implying that LL-37 acts intracellularly and not via binding and neutralization of LPS. In PDL cells stimulated with LL-37 for 60 minutes, the peptide was internalized as demonstrated by immunocytochemistry, suggesting an intracellular mechanism of action. LL-37 immunoreactivity was observed both in the cytosol and in the nucleus. Downregulation of LPS-induced MCP-1 by LL-37 was not mediated by reduction in NF-κB activity as shown by unaltered expression of phosphorylated p65, phosphorylated p105, and IκBα NF-κB proteins in the presence of LL-37. Immunoreactivity for LL-37 was observed in PDL cell DNA treated with but not without 0.1 and 1 µmol/L LL-37 for 60 minutes in vitro. Conclusion: LL-37 abolishes LPS-induced MCP-1 production in human PDL cells through an intracellular, NF-κB-independent mechanism which probably involves direct interaction between LL-37 and DNA.
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| 4. |
- Bai, Ge, et al.
(författare)
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Frailty trajectories in three longitudinal studies of aging : Is the level or the rate of change more predictive of mortality?
- 2021
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Ingår i: Age and Ageing. - : Oxford University Press. - 0002-0729 .- 1468-2834. ; 50:6, s. 2174-2182
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: frailty shows an upward trajectory with age, and higher levels increase the risk of mortality. However, it is less known whether the shape of frailty trajectories differs by age at death or whether the rate of change in frailty is associated with mortality.OBJECTIVES: to assess population frailty trajectories by age at death and to analyse whether the current level of the frailty index (FI) i.e. the most recent measurement or the person-specific rate of change is more predictive of mortality.METHODS: 3,689 individuals from three population-based cohorts with up to 15 repeated measurements of the Rockwood frailty index were analysed. The FI trajectories were assessed by stratifying the sample into four age-at-death groups: <70, 70-80, 80-90 and >90 years. Generalised survival models were used in the survival analysis.RESULTS: the FI trajectories by age at death showed that those who died at <70 years had a steadily increasing trajectory throughout the 40 years before death, whereas those who died at the oldest ages only accrued deficits from age ~75 onwards. Higher level of FI was independently associated with increased risk of mortality (hazard ratio 1.68, 95% confidence interval 1.47-1.91), whereas the rate of change was no longer significant after accounting for the current FI level. The effect of the FI level did not weaken with time elapsed since the last measurement.CONCLUSIONS: Frailty trajectories differ as a function of age-at-death category. The current level of FI is a stronger marker for risk stratification than the rate of change.
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| 5. |
- Bankell, Elisabeth, et al.
(författare)
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LL-37-induced caspase-independent apoptosis is associated with plasma membrane permeabilization in human osteoblast-like cells
- 2021
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 135
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Tidskriftsartikel (refereegranskat)abstract
- The host defense peptide LL-37 is active against both gram-positive and gram-negative bacteria, but it has also been shown to reduce human host cell viability. However, the mechanisms behind LL-37-induced human host cell cytotoxicity are not yet fully understood. Here, we assess if LL-37-evoked attenuation of human osteoblast-like MG63 cell viability is associated with apoptosis, and if the underlying mechanism may involve LL-37-induced plasma membrane permeabilization. MG63 cell viability and plasma membrane permeabilization were investigated by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and by measuring lactate dehydrogenase (LDH) release, respectively. Apoptosis was assessed by the terminal deoxynucleotidyl dUTP nick end labeling (TUNEL) assay and Annexin V flow cytometry, and caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage were determined by Western blot. LL-37 (4 and 10 μM) reduced both cell number and cell viability, and these effects were associated with a pro-apoptotic effect demonstrated by positive TUNEL staining and Annexin V flow cytometry. LL-37-induced apoptosis was not coupled to either caspase-3 or PARP cleavage, suggesting that LL-37 causes caspase-independent apoptosis in MG63 cells. Both LL-37 and the well-known plasma membrane permeabilizer Triton X-100 reduced cell viability and stimulated LDH release. Triton X-100-treated cells showed positive TUNEL staining, and the detergent accumulated cells in late apoptosis/necrosis. Similar to LL-37, Triton X-100 caused no PARP cleavage. We conclude that LL-37 promotes caspase-independent apoptosis, and that this effect seems coupled to plasma membrane permeabilization in human MG63 cells.
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| 6. |
- Dahl, Sara, et al.
(författare)
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Human host defense peptide LL-37 facilitates double-stranded RNA pro-inflammatory signaling through up-regulation of TLR3 expression in vascular smooth muscle cells
- 2020
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 69:6, s. 579-588
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The importance of human host defense peptide LL-37 in vascular innate immunity is not understood. Here, we assess the impact of LL-37 on double-stranded RNA (dsRNA) signaling in human vascular smooth muscle cells.MATERIALS AND METHODS: Cellular import of LL-37 and synthetic dsRNA (poly I:C) were investigated by immunocytochemistry and fluorescence imaging. Transcript and protein expression were determined by qPCR, ELISA and Western blot. Knockdown of TLR3 was performed by siRNA.RESULTS: LL-37 was rapidly internalized, suggesting that it has intracellular actions. Co-stimulation with poly I:C and LL-37 enhanced pro-inflammatory IL-6 and MCP-1 transcripts several fold compared to treatment with poly I:C or LL-37 alone. Poly I:C increased IL-6 and MCP-1 protein production, and this effect was potentiated by LL-37. LL-37-induced stimulation of poly I:C signaling was not associated with enhanced import of poly I:C. Treatment with poly I:C and LL-37 in combination increased expression of dsRNA receptor TLR3 compared to stimulation with poly I:C or LL-37 alone. In TLR3 knockdown cells, treatment with poly I:C and LL-37 in combination had no effect on IL-6 and MCP-1 expression, showing loss of function.CONCLUSIONS: LL-37 potentiates dsRNA-induced cytokine production through up-regulation of TLR3 expression representing a novel pro-inflammatory mechanism.
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| 7. |
- Dahl, Sara
(författare)
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Optic nerve hypoplasia in children : prevalence, associated disorders and genetic causes
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Optic nerve hypoplasia (ONH) is a congenital ocular malformation with a thin optic nerve in one or both eyes. ONH has been associated with neurodevelopmental disorders and pituitary dysfunction, but the prevalence of these comorbidities are still unknown, especially in children with less severe visual impairment and unilateral disease. The aims of this thesis were to examine the prevalence of ONH in children, to determine the prevalence of intellectual disability, autism spectrum disorder, motor impairment, and pituitary dysfunction in unilateral and bilateral disease, as well as to identify genetic variants underlying ONH. Methods: In study I, a population-based cohort of patients with ONH was established including patients who were diagnosed with ONH, below 20 years of age, and living in Stockholm in December 2009. Ophthalmological assessments were performed, and the Five to Fifteen parent questionnaire (FTF) was used to screen for developmental problems. Subsequently, study II and study III were population-based cross-sectional cohort studies. In study II, neurodevelopmental disorders were confirmed by the FTF, neurological assessments, reviewing previous neuropsychological investigations, or conducting neuropsychological tests. In study III, motor impairments were assessed using a specific protocol and previous neuroradiology was reviewed. Blood sampling was performed to screen for pituitary dysfunction together with analysis of growth curves and medical history. Study IV included 29 patients with ONH who were analysed with array comparative genomic hybridization followed by whole genome sequencing and in silico filtering of single nucleotide variants in 42 candidate genes. Rare variants were verified by Sanger sequencing. Results: The prevalence of ONH in children in Stockholm was 17.3/100 000. Unilateral ONH was almost as common as bilateral (45%). Intellectual disability was more common in bilateral ONH than in unilateral ONH (56% vs 9%, p< 0.001). Autism spectrum disorders were diagnosed in 17%, without correlation to laterality. Motor impairments were identified in 47% of the patients and were significantly more prevalent in bilateral ONH. In contrast, pituitary hormone deficiency (PHD) was confirmed in 29% of the cohort and 19% had multiple PHD, without correlation to laterality. Furthermore, presence of structural pituitary abnormalities had a very high sensitivity for PHD. Finally, we identified three rare variants in COL4A1 and three rare variants in COL4A2, of which two were assessed as likely pathogenic. In addition, we found an interesting rare variant in OPA1 and two other likely pathogenic variants in SOX5 and PAX6. Conclusions: ONH is a common ocular malformation in children, with a prevalence of 17.3/100 000 in Stockholm. Unilateral ONH seems to be as common as bilateral. Children with both unilateral and bilateral ONH have a high risk of neurodevelopmental disorders and PHD, but bilateral ONH increases the risk of intellectual disability, motor impairment, and brain abnormalities. These findings need to be considered when designing screening, care, and follow-up programs. Our genetic study suggests that a genetic cause of ONH is more common than previously reported and highlights COL4A1 and COL4A2 as candidate genes.
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| 8. |
- Dahl, Sara, et al.
(författare)
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The host defense peptide LL-37 triggers release of nucleic acids from human mast cells
- 2018
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 109, s. 39-45
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Tidskriftsartikel (refereegranskat)abstract
- The human host defense peptide LL-37 possesses antimicrobial activity but also affects host cell function and viability. Mast cells are involved in innate immunity but no data have been presented on effects of LL-37 on human mast cell viability and export of nucleic acids. Here, we demonstrated by immunofluorescence microscopy that synthesized LL-37 was internalized by human LAD2 mast cells and detected both in cytoplasm and nucleus. Treatment with high (4 and 10 μM) but not low (1 μM) concentrations of LL-37 for 4 h reduced cell viability assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Stimulation with 10 μM LL-37 for 4 h enhanced export of nucleic acids, total protein and lactate dehydrogenase (LDH), suggesting that both nuclear and plasma membranes are permeabilized by LL-37. Although LL-37 triggered release of nucleic acids, no extracellular trap-like structures were observed by laser scanning confocal microscopy of cells incubated with the plasma membrane impermeable nucleic acid fluorophore SYTOX-Green, indicating that LL-37 promotes export of nucleic acids but not formation of extracellular traps. On the other hand, phorbol-12-myristate-13-acetate (PMA), which is a well-known inducer of extracellular traps, stimulated export of nucleic acids and also formation of extracellular trap-like structures. However, PMA had no effect on export of either total protein or LDH. Hence, LL-37 and PMA seem to stimulate export of nucleic acids from LAD2 mast cells through different pathways. In conclusion, we demonstrate that LL-37 triggers release of nucleic acids from human mast cells but not the formation of extracellular trap-like structures.
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| 9. |
- Fahnehjelm, Kristina, et al.
(författare)
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Optic nerve hypoplasia in children and adolescents; prevalence, ocular characteristics and behavioural problems
- 2014
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 92:6, s. 563-570
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To report prevalence, ocular characteristics and coexisting behavioural problems in children and adolescents with optic nerve hypoplasia (ONH), which is a common cause of visual impairment in children in western countries, often associated with neurological or endocrinological problems and where autism has been reported in severe cases with blindness. Methods: This is a population-based cross-sectional study of patients <20 years of age who had been diagnosed with ONH and lived in the county of Stockholm in December 2009. Ophthalmological assessments including fundus photographs with optic disc analyses were made. A questionnaire was used to screen for behaviour and development. Results: The prevalence of ONH in all living children <18 years of age in Stockholm was 17.3/100 000 with a prevalence of visual impairment (<0.3) of 3.9/100 000. In total, 66 patients, median age 9.3 years (0.6-19.4), 36 with bilateral and 30 with unilateral ONH, were included in the current study; 53 were re-examined clinically, group A, and 13 agreed to retrospective analyses of existing medical records, group B. Analyses of the optic discs were made in fundus photographs from 53 patients comparing a semi-automated (Retinal Size Tool) and a manual method (Zeki). There was a strong curvilinear correlation (rS = -0.91 p < 0.0001 for both eyes). Behavioural problems were more common (p < 0.05) in bilateral ONH. Conclusion: Opticnerve hypoplasia is a common ocular malformation with a prevalence of 17.3/100 000 children and adolescents <18 years of age in Stockholm. Unilateral ONH seems as common as bilateral.
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| 10. |
- Karlsson, Ida K., et al.
(författare)
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Adiposity and the risk of dementia : mediating effects from inflammation and lipid levels
- 2022
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Ingår i: European Journal of Epidemiology. - : Springer Nature Switzerland AG.. - 0393-2990 .- 1573-7284. ; 37:12, s. 1261-1271
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Tidskriftsartikel (refereegranskat)abstract
- While midlife adiposity is a risk factor for dementia, adiposity in late-life appears to be associated with lower risk. What drives the associations is poorly understood, especially the inverse association in late-life. Using results from genome-wide association studies, we identified inflammation and lipid metabolism as biological pathways involved in both adiposity and dementia. To test if these factors mediate the effect of midlife and/or late-life adiposity on dementia, we then used cohort data from the Swedish Twin Registry, with measures of adiposity and potential mediators taken in midlife (age 40–64, n = 5999) or late-life (age 65–90, n = 7257). Associations between body-mass index (BMI), waist-hip ratio (WHR), C-reactive protein (CRP), lipid levels, and dementia were tested in survival and mediation analyses. Age was used as the underlying time scale, and sex and education included as covariates in all models. Fasting status was included as a covariate in models of lipids. One standard deviation (SD) higher WHR in midlife was associated with 25% (95% CI 2–52%) higher dementia risk, with slight attenuation when adjusting for BMI. No evidence of mediation through CRP or lipid levels was present. After age 65, one SD higher BMI, but not WHR, was associated with 8% (95% CI 1–14%) lower dementia risk. The association was partly mediated by higher CRP, and suppressed when high-density lipoprotein levels were low. In conclusion, the negative effects of midlife adiposity on dementia risk were driven directly by factors associated with body fat distribution, with no evidence of mediation through inflammation or lipid levels. There was an inverse association between late-life adiposity and dementia risk, especially where the body’s inflammatory response and lipid homeostasis is intact.
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