| 1. |
- Ahlgren, Erika, et al.
(författare)
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Association between Plasma Homocysteine Levels and Neuronal Injury in HIV Infection
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate the role of homocysteine in neuronal injury in HIV infection. Methods Using a cross-sectional design and archived samples, we compared concentrations of plasma homocysteine and cerebrospinal fluid (CSF) neurofilament light protein (NFL), a sensitive marker of neuronal injury, in 83 HIV-1-infected subjects without antiretroviral treatment. We also analyzed plasma vitamin B12, serum folate, CSF, and plasma HIV RNA, the immune activation marker neopterin in CSF and serum, and albumin ratio as a marker of blood-brain barrier integrity. Twenty-two subjects provided a second sample median of 12.5 months after antiretroviral treatment initiation. Results A significant correlation was found between plasma homocysteine and CSF NFL concentrations in untreated individuals (r = 0.52, p < 0.0001). As expected, there was a significant inverse correlation between homocysteine and B12 (r = -0.41, p < 0.001) and folate (r = -0.40, p = < 0.001) levels. In a multiple linear regression analysis homocysteine stood out as an independent predictor of CSF NFL in HIV-1-infected individuals. The correlation of plasma homocysteine and CSF NFL was also present in the group receiving antiretroviral therapy (r = 0.51, p = 0.016). Conclusion A correlation between plasma homocysteine and axonal injury, as measured by CSF NFL, was found in both untreated and treated HIV. While this study is not able to prove a causal link, homocysteine and functional B12/folate deficiency appear to play a role in neural injury in HIV-infected individuals.
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| 2. |
- Bacelis, Jonas, 1984, et al.
(författare)
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Literature-Informed Analysis of a Genome-Wide Association Study of Gestational Age in Norwegian Women and Children Suggests Involvement of Inflammatory Pathways
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Background Five-to-eighteen percent of pregnancies worldwide end in preterm birth, which is the major cause of neonatal death and morbidity. Approximately 30% of the variation in gestational age at birth can be attributed to genetic factors. Genome-wide association studies (GWAS) have not shown robust evidence of association with genomic loci yet. We separately investigated 1921 Norwegian mothers and 1199 children from pregnancies with spontaneous onset of delivery. Individuals were further divided based on the onset of delivery: initiated by labor or prelabor rupture of membranes. Genetic association with ultrasound- dated gestational age was evaluated using three genetic models and adaptive permutations. The top-ranked loci were tested for enrichment in 12 candidate gene-sets generated by text-mining PubMed abstracts containing pregnancy-related keywords. The six GWAS did not reveal significant associations, with the most extreme empirical p = 5.1 x 10(-7). The top loci from maternal GWAS with deliveries initiated by labor showed significant enrichment in 10 PubMed gene-sets, e.g., p = 0.001 and 0.005 for keywords "uterus" and "preterm" respectively. Enrichment signals were mainly caused by infection/inflammation-related genes TLR4, NFKB1, ABCA1, MMP9. Literature-informed analysis of top loci revealed further immunity genes: IL1A, IL1B, CAMP, TREM1, TFRC, NFKBIA, MEFV, IRF8, WNT5A. Our analyses support the role of inflammatory pathways in determining pregnancy duration and provide a list of 32 candidate genes for a follow-up work. We observed that the top regions from GWAS in mothers with labor-initiated deliveries significantly more often overlap with pregnancy-related genes than would be expected by chance, suggesting that increased sample size would benefit similar studies.
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| 3. |
- Edén, Arvid, 1975, et al.
(författare)
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Increased Intrathecal Immune Activation in Virally Suppressed HIV-1 Infected Patients with Neurocognitive Impairment
- 2016
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective Although milder forms of HIV-associated neurocognitive disorder (HAND) remain prevalent, a correlation to neuronal injury has not been established in patients on antiretroviral therapy (ART). We examined the relationship between mild HAND and CSF neurofilament light protein (NFL), a biomarker of neuronal injury; and CSF neopterin, a biomarker of CNS immunoactivation, in virally suppressed patients on antiretroviral therapy (ART). We selected 99 subjects on suppressive ART followed longitudinally from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Based on standardized comprehensive neurocognitive performance (NP) testing, subjects were classified as neurocognitively normal (NCN; n = 29) or impaired (NCI; n = 70). The NCI group included subjects with asymptomatic (ANI; n = 37) or mild (MND; n = 33) HAND. CSF biomarkers were analyzed on two occasions. Geometric mean CSF neopterin was 25% higher in the NCI group (p = 0.04) and NFL and neopterin were significantly correlated within the NCI group (r = 0.30; p<0.001) but not in the NCN group (r = -0.13; p = 0.3). Additionally, a trend towards higher NFL was seen in the NCI group (p = 0.06). Mild HAND was associated with increased intrathecal immune activation, and the correlation between neopterin and NFL found in NCI subjects indicates an association between neurocognitive impairment, CNS inflammation and neuronal damage. Together these findings suggest that NCI despite ART may represent an active pathological process within the CNS that needs further characterization in prospective studies.
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| 4. |
- Hallingström, Maria, et al.
(författare)
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Proteomic Analysis of Early Mid-Trimester Amniotic Fluid Does Not Predict Spontaneous Preterm Delivery
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- Objective The aim of this study was to identify early proteomic biomarkers of spontaneous preterm delivery (PTD) in mid-trimester amniotic fluid from asymptomatic women. This is a case-cohort study. Amniotic fluid from mid-trimester genetic amniocentesis (14-19 weeks of gestation) was collected from 2008 to 2011. The analysis was conducted in 24 healthy women with subsequent spontaneous PTD (cases) and 40 randomly selected healthy women delivering at term (controls). An exploratory phase with proteomics analysis of pooled samples was followed by a verification phase with ELISA of individual case and control samples. The median (interquartile range (IQR: 25th; 75th percentiles) gestational age at delivery was 35+5 (33+6-36+6) weeks in women with spontaneous PTD and 40+0 (39+1-40+5) weeks in women who delivered at term. In the exploratory phase, the most pronounced differences were found in C-reactive protein (CRP) levels, that were approximately two-fold higher in the pooled case samples than in the pooled control samples. However, we could not verify these differences with ELISA. The median (25th; 75th IQR) CRP level was 95.2 ng/mL (64.3; 163.5) in women with spontaneous PTD and 86.0 ng/mL (51.2; 145.8) in women delivering at term (p = 0.37; t-test). Proteomic analysis with mass spectrometry of mid-trimester amniotic fluid suggests CRP as a potential marker of spontaneous preterm delivery, but this prognostic potential was not verified with ELISA.
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| 5. |
- Hermansson, Linn, et al.
(författare)
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Plasma concentration of neurofilament light chain protein decreases after switching from tenofovir disoproxil fumarate to tenofovir alafenamide fumarate
- 2019
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 14:12
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Tidskriftsartikel (refereegranskat)abstract
- Background Because tenofovir alafenamide (TAF) leads to significantly lower plasma tenofovir concentrations than tenofovir disoproxil fumarate (TDF) and is a stronger substrate for P-glycoprotein (P-gp) than TDF, TAF could lead to decreased central nervous system (CNS) tenofovir exposure than TDF. We aimed to determine if switching from TDF to TAF increases the risk of neuronal injury, by quantifying plasma levels of neurofilament light protein (NfL), a sensitive marker of neuronal injury in HIV CNS infection. Methods Plasma NfL concentration was measured at baseline, week 24, and week 84 in stored plasma samples from 416 participants (272 switching to elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TAF and 144 continuing E/C/F/TDF) enrolled in the randomized, active-controlled, multicenter, open-label, noninferiority Gilead GS-US-292-0109 trial. Results While plasma NfL levels in both groups were within the normal range, we found a small but significant decrease in the E/C/F/TAF arm after 84 weeks from a geometric mean of 9.3 to 8.8 pg/mL (5.4% decline, 95% CI 2.0-8.4, p = 0.002). This change was significantly different (p = 0.001) from that of the E/C/F/TDF arm, in which plasma NfL concentration changed from 9.7 pg/mL at baseline to 10.2 pg/mL at week 84 (5.8% increase, 95% CI -0.8-12.9, p = 0.085). This increase is in line with what could be expected in normal ageing. Plasma NfL concentrations significantly correlated with age. No correlation was found between plasma NfL and serum creatinine. Conclusions We found no biomarker evidence of CNS injury when switching from TDF to TAF. It is unclear whether the small decrease in plasma NfL found after switch to TAF is of any clinical relevance, particularly with plasma NfL levels in both arms remaining within the limits found in HIV-negative controls. These results indicate that switching from TDF to TAF appears safe with regard to neuronal injury.
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| 6. |
- Mostowy, Johanna, et al.
(författare)
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Shared Genetic Factors Involved in Celiac Disease, Type 2 Diabetes and Anorexia Nervosa Suggest Common Molecular Pathways for Chronic Diseases
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Genome-wide association studies (GWAS) have identified several genetic regions involved in immune-regulatory mechanisms to be associated with celiac disease. Previous GWAS also revealed an over-representation of genes involved in type 2 diabetes and anorexia nervosa associated with celiac disease, suggesting involvement of common metabolic pathways for development of these chronic diseases. The aim of this study was to extend these previous analyses to study the gene expression in the gut from children with active celiac disease. Thirty six target genes involved in type 2 diabetes and four genes associated with anorexia nervosa were investigated for gene expression in small intestinal biopsies from 144 children with celiac disease at median (range) age of 7.4 years (1.6-17.8) and from 154 disease controls at a median (range) age 11.4. years (1.4-18.3). A total of eleven of genes were differently expressed in celiac patients compared with disease controls of which CD36, CD38, FOXP1, SELL, PPARA, PPARG, AGT previously associated with type 2 diabetes and AKAP6, NTNG1 with anorexia nervosa remained significant after correction for multiple testing. Shared genetic factors involved in celiac disease, type 2 diabetes and anorexia nervosa suggest common underlying molecular pathways for these diseases.
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| 7. |
- Sjökvist Ottsjö, Louise, 1986, et al.
(författare)
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Defining the Roles of IFN-gamma and IL-17A in Inflammation and Protection against Helicobacter pylori Infection
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- CD4(+) T cells have been shown to be essential for vaccine-induced protection against Helicobacter pylori infection. However, the effector mechanisms leading to reductions in the gastric bacterial loads of vaccinated mice remain unclear. We have investigated the function of IFN-gamma and IL-17A for vaccine-induced protection and inflammation (gastritis) using IFN-gamma-gene-knockout (IFN-gamma(-/-)) mice, after sublingual or intragastric immunization with H. pylori lysate antigens and cholera toxin. Bacteria were enumerated in the stomachs of mice and related to the gastritis score and cellular immune responses. We report that sublingually and intragastrically immunized IFN-gamma(-/-) mice had significantly reduced bacterial loads similar to immunized wild-type mice compared to respective unimmunized infection controls. The reduction in bacterial loads in sublingually and intragastrically immunized IFN-gamma(-/-) mice was associated with significantly higher levels of IL-17A in stomach extracts and lower gastritis scores compared with immunized wild-type mice. To study the role of IL-17A for vaccine-induced protection in sublingually immunized IFN-gamma(-/-) mice, IL-17A was neutralized in vivo at the time of infection. Remarkably, the neutralization of IL-17A in sublingually immunized IFN-gamma(-/-) mice completely abolished protection against H. pylori infection and the mild gastritis. In summary, our results suggest that IFN-gamma responses in the stomach of sublingually immunized mice promote vaccine-induced gastritis, after infection with H. pylori but that IL-17A primarily functions to reduce the bacterial load.
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| 8. |
- Studer, Erik, et al.
(författare)
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Serotonin Depletion-Induced Maladaptive Aggression Requires the Presence of Androgens
- 2015
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- The sex hormone testosterone and the neurotransmitter serotonin exert opposite effects on several aspects of behavior including territorial aggression. It is however not settled if testosterone exerts its pro-aggressive effects by reducing serotonin transmission and/or if the anti-aggressive effect of serotonin requires the presence of the androgen. Using the resident intruder test, we now show that administration of the serotonin synthesis inhibitor parachlorophenylalanine (300 mg/kg x 3 days) increases the total time of attack as well as the percentage amount of social behavior spent on attack but not that spent on threat - i.e. that it induces a pattern of unrestricted, maladaptive aggression - in gonadectomized C57Bl/6 male mice receiving testosterone replacement; in contrast, it failed to reinstate aggression in those not given testosterone. Whereas these results suggest the pro-aggressive effect of testosterone to be independent of serotonin, and not caused by an inhibition of serotonergic activity, the pCPA-induced induction of maladaptive aggression appears to require the presence of the hormone. In line with these findings, pCPA enhanced the total time of attack as well the relative time spent on attacks but not threats also in wild-type gonadally intact male C57Bl/6 mice, but failed to reinstate aggression in mice rendered hypo-aggressive by early knock-out of androgen receptors in the brain (AR(NesDel) mice). We conclude that androgenic deficiency does not dampen aggression by unleashing an anti-aggressive serotonergic influence; instead serotonin seems to modulate aggressive behavior by exerting a parallel-coupled inhibitory role on androgen-driven aggression, which is irrelevant in the absence of the hormone, and the arresting of which leads to enhanced maladaptive aggression.
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| 9. |
- Torinsson Naluai, Åsa, 1968, et al.
(författare)
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Altered peripheral amino acid profile indicate a systemic impact of active celiac disease and a possible role of amino acids in disease pathogenesis
- 2018
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: We have previously performed a Genome Wide Association and linkage study that indicated a new disease triggering mechanism involving amino acid metabolism and nutrient sensing signaling pathways. Objective: The aim of this study was to investigate if plasma amino acid levels differed among children with celiac disease compared with disease controls. Materials and methods: Fasting plasma samples from 141 children with celiac disease and 129 non-celiac disease controls, were analyzed for amino acid levels by liquid chromatography-tandem mass spectrometry (LC/MS). A general linear model using age and experimental effects as covariates was used to compare amino acid levels between children with a diagnosis of celiac disease and controls. Results: Seven out of twenty-three analyzed amino acids were elevated in children with celiac disease compared with controls (tryptophan, taurine, glutamic acid, proline, ornithine, alanine and methionine). The significance of the individual amino acids do not survive multiple correction, however, multivariate analyses of the amino acid profile showed significantly altered amino acid levels in children with celiac disease overall and after correction for age, sex and experimental effects (p = 8.4 × 10-8). Conclusion: These findings support the idea that amino acids could influence systemic inflammation and play a possible role in disease pathogenesis. © 2018 Torinsson Naluai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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| 10. |
- Ulleryd, Marcus A, et al.
(författare)
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The association between autonomic dysfunction, inflammation and atherosclerosis in men under investigation for carotid plaques
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 12:4, s. Artno e0174974-
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Tidskriftsartikel (refereegranskat)abstract
- Background Autonomic dysfunction is a risk factor for cardiovascular disease (CVD), however, the exact mechanism linking autonomic dysfunction to cardiovascular disease is not known. In this study we hypothesized that autonomic dysfunction increases inflammation, which subsequently accelerates atherosclerosis. The aim of the current study was to investigate the association between autonomic tone, inflammation and atherosclerosis. 124 men under investigation for carotid atherosclerosis were examined for autonomic function (heart rate variability; HRV and baroreflex sensitivity; BRS), inflammatory markers (white blood cell count; WBCC and C-reactive protein; CRP) and degree of carotid atherosclerosis. The direct or indirect associations between autonomic function, inflammatory parameters and carotid plaque area were investigated with multiple linear regressions. Male subjects with prevalent CVD showed larger carotid plaque area, higher WBCC, and reduced BRS compared to subjects with no history of CVD. Further, BRS was inversely associated with carotid plaque area (r = -0.21, p = 0.018) as well as inflammatory parameters WBCC and CRP (r = -0.29, p = 0.001, and r = -0.23, p = 0.009, respectively), whereas HRV only was inversely associated with WBCC (r = -0.22, p = 0.014). To investigate if inflammation could provide a link between autonomic function and carotid atherosclerosis we adjusted the associations accordingly. After adjusting for WBCC and CRP the inverse association between BRS and carotid plaque area was attenuated and did not remain significant, while both WBCC and CRP remained significantly associated with carotid plaque area, indicating that low-grade inflammation can possibly link BRS to atherosclerosis. Also, after adjusting for age, antihypertensive treatment and cardiovascular risk factors, BRS was independently inversely associated with both WBCC and CRP, and HRV independently inversely associated with WBCC. WBCC was the only inflammatory marker independently associated with carotid plaque area after adjustment. We demonstrate that autonomic dysfunction is associated with atherosclerosis and that inflammation could play an important role in mediating this relationship.
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