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| 4. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 5. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 6. |
- Kalman, L. V., et al.
(författare)
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Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting
- 2016
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Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY-BLACKWELL. - 0009-9236 .- 1532-6535. ; 99:2, s. 172-185
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Tidskriftsartikel (refereegranskat)abstract
- This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.
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| 7. |
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| 8. |
- Del Chiaro, M, et al.
(författare)
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European evidence-based guidelines on pancreatic cystic neoplasms
- 2018
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 67:5, s. 789-804
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Tidskriftsartikel (refereegranskat)abstract
- Evidence-based guidelines on the management of pancreatic cystic neoplasms (PCN) are lacking. This guideline is a joint initiative of the European Study Group on Cystic Tumours of the Pancreas, United European Gastroenterology, European Pancreatic Club, European-African Hepato-Pancreato-Biliary Association, European Digestive Surgery, and the European Society of Gastrointestinal Endoscopy. It replaces the 2013 European consensus statement guidelines on PCN. European and non-European experts performed systematic reviews and used GRADE methodology to answer relevant clinical questions on nine topics (biomarkers, radiology, endoscopy, intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm, rare cysts, (neo)adjuvant treatment, and pathology). Recommendations include conservative management, relative and absolute indications for surgery. A conservative approach is recommended for asymptomatic MCN and IPMN measuring <40 mm without an enhancing nodule. Relative indications for surgery in IPMN include a main pancreatic duct (MPD) diameter between 5 and 9.9 mm or a cyst diameter ≥40 mm. Absolute indications for surgery in IPMN, due to the high-risk of malignant transformation, include jaundice, an enhancing mural nodule >5 mm, and MPD diameter >10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery. The European evidence-based guidelines on PCN aim to improve the diagnosis and management of PCN.
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| 9. |
- Bernson, Elin, 1987, et al.
(författare)
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Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia
- 2018
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Ingår i: Cancer Immunology Research. - : American Association for Cancer Research (AACR). - 2326-6066 .- 2326-6074. ; 6:9, s. 1110-1119
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Tidskriftsartikel (refereegranskat)abstract
- Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML.
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| 10. |
- Blom, Kristin, et al.
(författare)
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Mebendazole-induced M1 polarisation of THP-1 macrophages may involve DYRK1B inhibition
- 2019
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Ingår i: BMC Research Notes. - : Springer Nature. - 1756-0500. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We recently showed that the anti-helminthic compound mebendazole (MBZ) has immunomodulating activity by inducing a M2 to M1 phenotype switch in monocyte/macrophage models. In the present study we investigated the potential role of protein kinases in mediating this effect.Results: MBZ potently binds and inhibits Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) with a Kd and an IC50 of 7 and 360 nM, respectively. The specific DYRK1B inhibitor AZ191 did not mimic the cytokine release profile of MBZ in untreated THP-1 monocytes. However, in THP-1 cells differentiated into macrophages, AZ191 strongly induced a pro-inflammatory cytokine release pattern similar to MBZ and LPS/IFNγ. Furthermore, like MBZ, AZ191 increased the expression of the M1 marker CD80 and decreased the M2 marker CD163 in THP-1 macrophages. In this model, AZ191 also increased phospho-ERK activity although to a lesser extent compared to MBZ. Taken together, the results demonstrate that DYRK1B inhibition could, at least partly, recapitulate immune responses induced by MBZ. Hence, DYRK1B inhibition induced by MBZ may be part of the mechanism of action to switch M2 to M1 macrophages.
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| 11. |
- Bloom, A. C., et al.
(författare)
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Deletion of the membrane complement inhibitor CD59a drives age and gender-dependent alterations to bone phenotype in mice
- 2016
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Ingår i: Bone. - : Elsevier BV. - 8756-3282. ; 84, s. 253-261
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Tidskriftsartikel (refereegranskat)abstract
- Degenerative joint diseases such as osteoarthritis are characterised by aberrant region-specific bone formation and abnormal bone mineral content. A recent study suggested a role for the complement membrane attack complex in experimental models of osteoarthritis. Since CD59a is the principal regulator of the membrane attack complex in mice, we evaluated the impact of CD59a gene deletion upon maintenance of bone architecture. In vivo bone morphology analysis revealed that male CD59a-deficient mice have increased femur length and cortical bone volume, albeit with reduced bone mineral density. However, this phenomenon was not observed in female mice. Histomorphometric analysis of the trabecular bone showed increased rates of bone homeostasis, with both increased bone resorption and mineral apposition rate in CD59a-deficient male mice. When bone cells were studied in isolation, in vitro osteoclastogenesis was significantly increased in male CD59a-deficient mice, although osteoblast formation was not altered. Our data reveal, for the first time, that CD59a is a regulator of bone growth and homeostasis. CD59a ablation in male mice results in longer and wider bones, but with less density, which is likely a major contributing factor for their susceptibility to osteoarthritis. These findings increase our understanding of the role of complement regulation in degenerative arthritis.
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| 12. |
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| 13. |
- Fogleman, Nicholas D., et al.
(författare)
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Regional variation in quality of life in patients with a Fontan circulation: A multinational perspective
- 2017
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 193, s. 55-62
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 Elsevier Inc. Background Impaired quality of life (QOL) is associated with congenital heart disease (CHD) and country of residence; however, few studies have compared QOL in patients with differing complexities of CHD across regional populations. The current study examined regional variation in QOL outcomes in a large multinational sample of patients with a Fontan relative to patients with atrial septal defects (ASDs) and ventricular septal defects (VSDs). Methods From the Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease—International Study (APPROACH-IS), 405 patients (163 Fontan and 242 ASD/VSD) across Asia, Europe, and North America provided consent for access to their medical records and completed a survey evaluating QOL (0 to 100 linear analog scale). Primary CHD diagnosis, disease complexity, surgical history, and documented history of mood and anxiety disorders were recorded. Differences in QOL, medical complications, and mood and anxiety disorders between Fontan and ASD/VSD patients, and across geographic regions, were examined using analysis of covariance. Hierarchical regression analyses were conducted to identify variables associated with the QOL ratings. Results Patients with a Fontan reported significantly lower QOL, and greater medical complications and mood and anxiety disorders relative to patients with ASD/VSD. Inpatient cardiac admissions, mood disorders, and anxiety disorders were associated with lower QOL among patients with a Fontan, and mood disorders were associated with lower QOL among patients with ASD/VSD. Regional differences for QOL were not observed in patients with a Fontan; however, significant differences were identified in patients with ASD/VSD. Conclusions Regional variation of QOL is commonplace in adults with CHD; however, it appears affected by greater disease burden. Among patients with a Fontan, regional variation of QOL is lost. Specific attempts to screen for QOL and mood and anxiety disorders among CHD patients may improve the care of patients with the greatest disease burden.
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| 14. |
- Gouveia-Figueira, Sandra, et al.
(författare)
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Cord blood eicosanoid signatures and newborn gestational age
- 2017
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Ingår i: Prostaglandins & other lipid mediators. - : Elsevier. - 1098-8823 .- 2212-196X. ; 133, s. 123-127
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Tidskriftsartikel (refereegranskat)abstract
- Beyond prostaglandins, the function of eicosanoids and other oxylipins in pregnancy and labor is poorly understood. In contrast to earlier work focusing on preterm infants, we investigated how oxylipin levels in newborns (measured in cord blood) vary during the last weeks of pregnancy in 190 mother-newborns (≥37 weeks of gestation) of the ENVIRONAGE birth cohort, Belgium. We found increased levels of PGE2 (p = 0.003), PGF2α (p = 0.042), 8,9-DHET (p = 0.037), 11-HETE (p = 0.034), and 15-HETrE (p = 0.008) associated with full term pregnancy compared to early term labor. Furthermore, late vs early term was associated with increased levels of PGE2 (p = 0.012) and TXB2 (p = 0.033), while late vs full term was associated with decreased levels of 14,15-DHET (p = 0.029), 11,12-DHET (p = 0.033), and 5-HETE (p = 0.045). To summarize, nine eicosanoids, derived via three enzymatic pathways, were significantly associated with gestational age. Eight of these were derived from arachidonic acid, and one from dihomo-γ-linolenic acid.
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| 17. |
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| 18. |
- Klevstig, Martina, et al.
(författare)
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Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia
- 2019
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Ingår i: Journal of Molecular and Cellular Cardiology. - : Elsevier BV. - 0022-2828 .- 1095-8584. ; 137, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression. Materials and methods: We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP. Results: Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart. Conclusions: Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events.
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| 19. |
- Ko, Jong Mi, et al.
(författare)
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Differential impact of physical activity type on depression in adults with congenital heart disease : A multi-center international study
- 2019
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Ingår i: Journal of Psychosomatic Research. - : Elsevier BV. - 0022-3999 .- 1879-1360. ; 124
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This study aimed to examine the association between physical activity (PA) and depression in a large international cohort of adults with congenital heart disease (ACHD) as data about the differential impact of PA type on depression in this population are lacking.METHODS: In 2018, we conducted a cross-sectional assessment of 3908 ACHD recruited from 24 ACHD-specialized centers in 15 countries between April 2013 to March 2015. The Hospital Anxiety and Depression Scale was used to assess self-reported depressive symptoms and the Health-Behavior Scale-Congenital Heart Disease was used to collect PA information. Cochran-Armitage tests were performed to assess trends between depressive symptom levels and PA participation. Chi-Square and Wilcoxon Rank Sum tests were utilized to examine relations between depressive symptom levels and patient characteristics. Stepwise multivariable models were then constructed to understand the independent impact of PA on depressive symptoms.RESULTS: The overall prevalence of elevated depressive symptoms in this sample was 12% with significant differences in rates between countries (p < .001). Physically active individuals were less likely to be depressed than those who were sedentary. Of the 2 PA domains examined, sport participation rather than active commute was significantly associated with reduced symptoms of depression. After adjustment in multivariable analysis, sport participation was still significantly associated with 38% decreased probability of depressive symptoms (p < .001).CONCLUSIONS: Sport participation is independently associated with reduced depressive symptoms. The development and promotion of sport-related exercise prescriptions uniquely designed for ACHD may improve depression status in this unique population.
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| 20. |
- Ko, Jong Mi, et al.
(författare)
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Physical Activity-Related Drivers of Perceived Health Status in Adults With Congenital Heart Disease
- 2018
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 122:8, s. 1437-1442
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Tidskriftsartikel (refereegranskat)abstract
- Data on the differential impact of physical activity on perceived health status (PHS) in a large adult congenital heart disease (ACHD) patient population are lacking. We conducted a cross-sectional assessment of 4,028 ACHD patients recruited from 24 ACHD-specialized centers in 15 countries across 5 continents to examine the association between physical activity and PHS in a large international cohort of ACHD patients. A linear analog scale of the EuroQol-5D 3 level version and the 12-item Short Form Health Survey-version 2 were used to assess self-reported health status and the Health-Behavior Scale-Congenital Heart Disease was used as a subjective measurement of physical activity type, participation, and level. Correlation analyses and Wilcoxon Rank Sum tests examined bivariate relations between sample characteristics and PHS scores. Then, multivariable models were constructed to understand the impact of physical activity on PHS. Only 30% of our sample achieved recommended physical activity levels. Physically active patients reported better PHS than sedentary patients; however, the amount of physical activity was not associated with PHS. Further statistical analyses demonstrated that specifically sport participation regardless of physical activity level was a predictor of PHS. In conclusion, the majority of ACHD patients across the world are physically inactive. Sport participation appears to be the primary physical activity-related driver of PHS. By promoting sport-related exercise ACHD specialists thus may improve PHS in ACHD patients.
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| 21. |
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| 22. |
- Martens, Dries S, et al.
(författare)
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Neonatal Cord Blood Oxylipins and Exposure to Particulate Matter in the Early-Life Environment : an ENVIRONAGE Birth Cohort Study
- 2017
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Ingår i: Journal of Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 125:4, s. 691-698
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: As part of the lipidome, oxylipins are bioactive lipid compounds originating from oxidation of different fatty acids. Oxylipins could provide a new target in the developmental origins model or the ability of early life exposure to change biology.OBJECTIVES: We studied the association between in utero PM2.5 (particulate matter with aerodynamic diameter <2.5µm) exposure and oxylipin profiles in newborns.METHODS: Thirty-seven oxylipins reflecting the cyclooxygenase (COX), lipoxygenase (5-LOX and 12/15-LOX) and cytochrome P450 (CYP) pathways were assayed in 197 cord blood plasma samples from the ENVIRONAGE birth cohort. Principal component (PC) analysis and multiple regression models were used to estimate associations of in utero PM2.5 exposure with oxylipin pathways and individual metabolites.RESULTS: A principal component representing the 5-LOX pathway (6 metabolites) was significantly positively associated with PM2.5 exposure during the entire (multiple testing-adjusted q-value = 0.05) and second trimester of pregnancy (q = 0.05). A principal component representing the 12/15-LOX pathway (11 metabolites) was positively associated with PM2.5 exposure during the second trimester of pregnancy (q = 0.05). PM2.5 was not significantly associated with the COX pathway during any time period. There was a positive but non-significant association between second trimester PM2.5 and the CYP pathway (q = 0.16).CONCLUSION: In utero exposure to particulate matter, particularly during the second trimester, was associated with differences in the cord blood levels of metabolites derived from the lipoxygenase pathways. These differences may indicate an effect of air pollution during in utero life on the inflammatory state of the newborn at birth. Oxylipins may be important mediators between early life exposures and health outcomes later in life.
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| 23. |
- Moons, Philip, 1968, et al.
(författare)
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Prevalence and Effects of Cigarette Smoking, Cannabis Consumption, and Co-use in Adults From 15 Countries With Congenital Heart Disease
- 2019
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Ingår i: Canadian Journal of Cardiology. - : Elsevier BV. - 0828-282X .- 1916-7075. ; 35:12, s. 1842-1850
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The prevalence and effects of cigarette smoking and cannabis use in persons with congenital heart disease (CHD) are poorly understood. We (1) described the prevalence of cigarette smoking, cannabis consumption, and co-use in adults with CHD; (2) investigated intercountry differences; (3) tested the relative effects on physical functioning, mental health, and quality of life (QOL); and (4) quantified the differential effect of cigarette smoking, cannabis use, or co-use on those outcomes.METHODS: APPROACH-IS was a cross-sectional study, including 4028 adults with CHD from 15 countries. Patients completed questionnaires to measure physical functioning, mental health, and QOL. Smoking status and cannabis use were assessed by means of the Health Behaviour Scale-Congenital Heart Disease. Linear models with doubly robust estimations were computed after groups were balanced with the use of propensity weighting.RESULTS: Overall, 14% of men and 11% of women smoked cigarettes only; 8% of men and 4% of women consumed cannabis only; and 4% of men and 1% of women used both substances. Large intercountry variations were observed, with Switzerland having the highest prevalence for smoking cigarettes (24% of men, 19% of women) and Canada the highest for cannabis use (19% of men, 4% of women). Cigarette smoking had a small negative effect on patient-reported outcomes, and the effect of cannabis was negligible. The effect of co-use was more prominent, with a moderate negative effect on mental health.CONCLUSIONS: We found significant intercountry variability in cigarette and cannabis use in adults with CHD. Co-use has the most detrimental effects on patient-reported outcomes.
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| 24. |
- Pang, M-F, et al.
(författare)
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TGF-beta 1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis
- 2016
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Ingår i: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 35:6, s. 748-760
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Tidskriftsartikel (refereegranskat)abstract
- Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial-mesenchymal transition (EMT) in response to transforming growth factor-beta (TGF-beta 1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-beta 1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-beta 1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-beta 1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-beta 1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.
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| 25. |
- Sluman, Maayke A., et al.
(författare)
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Education as important predictor for successful employment in adults with congenital heart disease worldwide
- 2019
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Ingår i: Congenital Heart Disease. - : Computers, Materials and Continua (Tech Science Press). - 1747-079X .- 1747-0803. ; 14:3, s. 362-371
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundConflicting results have been reported regarding employment status and work ability in adults with congenital heart disease (CHD). Since this is an important determinant for quality of life, we assessed this in a large international adult CHD cohort.MethodsData from 4028 adults with CHD (53% women) from 15 different countries were collected by a uniform survey in the cross-sectional APPROACH International Study. Predictors for employment and work limitations were studied using general linear mixed models.ResultsMedian age was 32 years (IQR 25-42) and 94% of patients had at least a high school degree. Overall employment rate was 69%, but varied substantially among countries. Higher education (OR 1.99-3.69) and having a partner (OR 1.72) were associated with more employment; female sex (OR 0.66, worse NYHA functional class (OR 0.67-0.13), and a history of congestive heart failure (OR 0.74) were associated with less employment. Limitations at work were reported in 34% and were associated with female sex (OR 1.36), increasing age (OR 1.03 per year), more severe CHD (OR 1.31-2.10), and a history of congestive heart failure (OR 1.57) or mental disorders (OR 2.26). Only a university degree was associated with fewer limitations at work (OR 0.62).ConclusionsThere are genuine differences in the impact of CHD on employment status in different countries. Although the majority of adult CHD patients are employed, limitations at work are common. Education appears to be the main predictor for successful employment and should therefore be encouraged in patients with CHD.
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| 26. |
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| 27. |
- Wulff, Angela, 1963, et al.
(författare)
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Ocean acidification and desalination: climate-driven change in a Baltic Sea summer microplanktonic community
- 2018
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Ingår i: Marine Biology. - : Springer Science and Business Media LLC. - 0025-3162 .- 1432-1793. ; 165:4
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Tidskriftsartikel (refereegranskat)abstract
- Helcom scenario modelling suggests that the Baltic Sea, one of the largest brackish-water bodies in the world, could expect increased precipitation (decreased salinity) and increased concentration of atmospheric CO2 over the next 100 years. These changes are expected to affect the microplanktonic food web, and thereby nutrient and carbon cycling, in a complex and possibly synergistic manner. In the Baltic Proper, the extensive summer blooms dominated by the filamentous cyanobacteria Aphanizomenon sp., Dolichospermum spp. and the toxic Nodularia spumigena contribute up to 30% of the yearly new nitrogen and carbon exported to the sediment. In a 12 days outdoor microcosm experiment, we tested the combined effects of decreased salinity (from 6 to 3) and elevated CO2 concentrations (380 and 960 µatm) on a natural summer microplanktonic community, focusing on diazotrophic filamentous cyanobacteria. Elevated pCO2 had no significant effects on the natural microplanktonic community except for higher biovolume of Dolichospermum spp. and lower biomass of heterotrophic bacteria. At the end of the experimental period, heterotrophic bacterial abundance was correlated to the biovolume of N. spumigena. Lower salinity significantly affected cyanobacteria together with biovolumes of dinoflagellates, diatoms, ciliates and heterotrophic bacteria, with higher biovolume of Dolichospermum spp. and lower biovolume of N. spumigena, dinoflagellates, diatoms, ciliates and heterotrophic bacteria in reduced salinity. Although the salinity effects on diatoms were apparent, they could not clearly be separated from the influence of inorganic nutrients. We found a clear diurnal cycle in photosynthetic activity and pH, but without significant treatment effects. The same diurnal pattern was also observed in situ (pCO2, pH). Thus, considering the Baltic Proper, we do not expect any dramatic effects of increased pCO2 in combination with decreased salinity on the microplanktonic food web. However, long-term effects of the experimental treatments need to be further studied, and indirect effects of the lower salinity treatments could not be ruled out. Our study adds one piece to the complicated puzzle to reveal the combined effects of increased pCO2 and reduced salinity levels on the Baltic microplanktonic community.
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| 28. |
- Zhang, Mingfeng, et al.
(författare)
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Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:41, s. 66328-66343
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10(-15)), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10(-9)) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10(-8)). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10(-8)). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10(-4)-2.0x10(-3)). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
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| 29. |
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| 30. |
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| 31. |
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| 32. |
- Anderson, Jenna, et al.
(författare)
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Molecular Signatures of a TLR4 Agonist-Adjuvanted HIV-1 Vaccine Candidate in Humans
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Systems biology approaches have recently provided new insights into the mechanisms of action of human vaccines and adjuvants. Here, we investigated early transcriptional signatures induced in whole blood of healthy subjects following vaccination with a recombinant HIV-1 envelope glycoprotein subunit CN54gp140 adjuvanted with the TLR4 agonist glucopyranosyl lipid adjuvant-aqueous formulation (GLA-AF) and correlated signatures to CN54gp140-specific serum antibody responses. Fourteen healthy volunteers aged 18-45 years were immunized intramuscularly three times at 1-month intervals and whole blood samples were collected at baseline, 6 h, and 1, 3, and 7 days post first immunization. Subtle changes in the transcriptomic profiles were observed following immunization, ranging from over 300 differentially expressed genes (DEGs) at day 1 to nearly 100 DEGs at day 7 following immunization. Functional pathway analysis revealed blood transcription modules (BTMs) related to general cell cycle activation, and innate immune cell activation at early time points, as well as BTMs related to T cells and B cell activation at the later time points post-immunization. Diverse CN54gp140-specific serum antibody responses of the subjects enabled their categorization into high or low responders, at early (< 1 month) and late (up to 6 months) time points post vaccination. BTM analyses revealed repression of modules enriched in NK cells, and the mitochondrial electron chain, in individuals with high or sustained antigen-specific antibody responses. However, low responders showed an enhancement of BTMs associated with enrichment in myeloid cells and monocytes as well as integrin cell surface interactions. Flow cytometry analysis of peripheral blood mononuclear cells obtained from the subjects revealed an enhanced frequency of CD56(dim) NK cells in the majority of vaccines 14 days after vaccination as compared with the baseline. These results emphasize the utility of a systems biology approach to enhance our understanding on the mechanisms of action of TLR4 adjuvanted human vaccines.
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| 33. |
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| 34. |
- Andersson, Håkan S., 1967-, et al.
(författare)
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Alpha-nemertides - a novel family of nemertean peptide neurotoxins
- 2018
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- We recently discovered a novel family of neuroactive peptides in nemerteans, which we have named alpha-nemertides (1). One of these peptides, nemertide alpha-1, has been the subject of detailed studies with regard to structure and effects. The peptide exhibits exceptional potency against a number of arthropod species. Moreover, in vitro experiments suggest that alpha-1 acts primarily on voltage-gated sodium channels, and that this action is selective for arthropods by two orders of magnitude over vertebrate species. Using transcriptomic and proteomic approaches, we have identified 10 alpha-nemertides, but this number is likely to increase. These peptides alongside with a series of mutants are currently under evaluation by our group, with the goal to improve our understanding of structure-function relationships. In addition, we are considering potential practical uses of alpha-nemertides. In this talk, I will describe the current status of this research project.1. E. Jacobsson et al., Peptide ion channel toxins from the bootlace worm, the longest animal on Earth. Scientific reports 8, 4596 (2018).
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| 35. |
- Andersson, Håkan S., 1967-, et al.
(författare)
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Discovery of novel ion-channel active peptide toxins in a North Sea Ribbon Worm
- 2016
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Ribbon worms (nemerteans) are marine predators, which capture their prey using a proboscis containing a mixture of toxins which brings on rapid paralysis [1]. In addition, their epidermis contains thick mucus of similar toxic constitution. One very potent toxin reported in ribbon worm mucus is tetrodotoxin (TTX). However, despite significant efforts, Strand et al. [2] were unable to detect any TTX, neither in the mucus of the ribbon worm Lineus longissimus, nor from Vibrio alginolyticus cultures isolated from and cultivated in the mucus. These observations challenged the notion of general presence of TTX in ribbon worm mucus, and prompted us to look for other toxins [3]. Using LC-MS analysis of mucus extracts, we identified three peptides present in significant amounts. The peptides were sequenced using a combination of MS/MS analysis and transcriptomics, and whereas one of them strongly resembles the only peptide toxin previously characterized from ribbon worms, Neurotoxin B-IV [4], the other two were found to represent a previously unknown class of peptide toxins. The most abundant of these was synthesized, and its 3D structure determined. Preliminary toxicity tests on shore crab (C. maenas) indicated toxicity (through paralysis) on par with that of TTX. Further analyses have indicated that its toxic effects are due to binding to voltage sensitive sodium channels. With L. longissimus as our primary target, we are now mapping the presence of peptide toxins in ribbon worms, with the objectives to establish routes for synthesis, and to characterize the biological activities and structures of these peptides. The number of peptides of this novel class is increasing, and synthesis and characterization is well underway. The striking potencies of these peptides make them potentially amenable as novel insecticidal or anthelmintic leads, pharmacological tools or in biotechnology applications. References1. Strand M, Sundberg P. Nationalnyckeln till Sveriges flora och fauna [DO-DP]. Stjärnmaskar-Slemmaskar: Sipuncula-Nemertea: Artdatabanken, SLU; 2010.2. Strand M, Hedstrom M, Seth H, McEvoy EG, Jacobsson E, Goransson U, Andersson HS, Sundberg P. The Bacterial (Vibrio alginolyticus) Production of Tetrodotoxin in the Ribbon Worm Lineus longissimus-Just a False Positive? Marine Drugs. 2016;14(4).3. Strand M, Andersson HS. Slemmaskens hemlighet. Forskning & Framsteg. 2016;(2):26-33.4. Blumenthal KM, Kem WR. Structure and action of heteronemertine polypeptide toxins. Primary structure of Cerebratulus lacteus toxin B-IV. The Journal of Biological Chemistry. 1976;251(19):6025-9.
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| 36. |
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| 37. |
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| 38. |
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| 39. |
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| 40. |
- Andersson, Håkan S., 1967-, et al.
(författare)
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The toxicity of ribbon worms: alpha-nemertides or tetrodotoxin, or both?
- 2016
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Ingår i: Planta Medica. - : Georg Thieme Verlag KG. - 0032-0943 .- 1439-0221. ; 82:Supplement 1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The marine ribbon worms (nemerteans) are predators which capture their prey by everting a proboscis carrying a mixture of toxins which brings on rapid paralysis [1]. Moreover, ribbon worms have a thick layer of epidermal mucus of similar constitution. Tetrodotoxin (TTX) has been identified as one of these toxins [2]. The extreme toxicity of TTX (lethal by ingestion of 0.5-2 mg) is due to its ability to block voltage-gated sodium channels. Although several bacterial species (among these Vibrio sp.) have been linked to its synthesis, the biogenic origin and biosynthesis is unclear. One hypothesis is that TTX production occurs in a symbiotic relationship with its host, in this case the ribbon worm [3]. We have made significant effort to identify TTX in a setup for production through the cultivation of Vibrio alginolyticus in nutrient broth infused with mucus from the ribbon worm Lineus longissimus. Toxicity was demonstrated by fraction injections into shore crabs, but no TTX was found, and it could be shown conclusively that toxicity was unrelated to TTX and the Vibrio culture itself, and rather a constituent of the ribbon worm mucus [4]. The following studies led us to the discovery of a new class of peptides, the alpha-nemertides, in the mucus of the ribbon worms, which could be directly linked to the toxic effects. A literature review of the available evidence for TTX in ribbon worms show that the evidence in most cases are indirect, although notable exceptions exist. This points to the necessity to further investigate the presence and roles of TTX and alpha-nemertides in ribbon worms.
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| 41. |
- Andersson, S-O, et al.
(författare)
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Consultation skills of last semester medical students in Sweden: : video-recorded real-patient consultations in primary health care assessed by Calgary-Cambridge Global Consultation Rating Scale, a pilot study
- 2019
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Ingår i: MedEdPublish. - : F1000 Research Ltd. - 2312-7996. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- This article was migrated. The article was marked as recommended. Introduction: Doctor-patient consultation is an essential element of high quality health care. Education and training of medical students in consultation skills is important. The aim of this study was to investigate the medical students' consultation skills before graduation by assessment of the students' video recordings of consultations with real patients at primary health care centres. Methods: All students had to make a video recording of a meeting with a real patient for formative examination. 26 students participated in the study and delivered a video recording and a self-assessment. Four general practitioners assessed the video recordings by Calgary-Cambridge Global Consultation Rating Scale (CC-GCRS). Statistical testing included comparisons between groups of students and assessors using non-parametric methods. Results: The average CC-GCRS-rating was higher for female students. The students' strengths were related to relation and problem exploration. Their limitations were related to patient's perspective, providing structure and providing information. The students assessed their consultation skills higher than the assessors did, while the relative levels were similar. The distribution of rating scores across the assessors was small. Conclusion:Consultation skills were acceptable for most medical students, although there was room for improvement regarding patient centeredness skills. CC-GCRS was feasible and might be a valuable instrument to assess consultation skills for medical students at the end of their medical education.
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| 42. |
- Andersson Shams Hakimi, Caroline, et al.
(författare)
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The Effect of Ex Vivo Factor XIII Supplementation on Clot Formation in Blood Samples From Cardiac and Scoliosis Surgery Patients.
- 2018
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Ingår i: Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. - : SAGE Publications. - 1938-2723. ; 24:4, s. 677-683
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Tidskriftsartikel (refereegranskat)abstract
- Excessive perioperative bleeding remains a substantial problem. Factor XIII (FXIII) contributes to clot stability, and it has therefore been suggested that supplementation with FXIII concentrate may improve perioperative hemostasis. We evaluated the effects of increasing doses of FXIII, alone or in combination with fibrinogen or platelet concentrate, in blood samples from 2 considerably different groups of surgical patients: cardiac and scoliosis surgery patients. Whole-blood samples were collected immediately after operation from cardiac and scoliosis surgery patients. The samples were supplemented with 3 clinically relevant doses of FXIII concentrate (+20%, +40%, and +60%), alone or in combination with a fixed dose of fibrinogen concentrate (+1.0 g/L) or fresh apheresis platelets (+92 × 10(9)/L). Clot formation was assessed with rotational thromboelastometry (ROTEM). When the highest dose of FXIII concentrate was added, EXTEM clotting time was shortened by 10% in both cardiac and scoliosis surgery patients (95% confidence intervals: 2.4%-17% and 3.3%-17%, respectively), and FIBTEM maximum clot firmness was increased by 25% (9.3%-41%) in cardiac patients, relative to baseline. When fibrinogen was added, the dose-dependent effect of FXIII on clot stability was maintained, but the total effect was markedly greater than with FXIII alone, +150% (100%-200%) and +160% (130%-200%) for the highest FXIII dose in cardiac and scoliosis patients, respectively. Ex vivo supplementation with clinically relevant doses of FXIII improved clot formation moderately in blood samples from cardiac and scoliosis surgery patients, both alone and when given in combination with fibrinogen or platelet concentrate.
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| 43. |
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| 44. |
- Arvhult, Carl-M, et al.
(författare)
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Thermodynamic assessment of the Fe-Te system. Part II : Thermodynamic modeling
- 2018
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Ingår i: Journal of Alloys and Compounds. - : Elsevier. - 0925-8388 .- 1873-4669. ; 767, s. 883-893
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Tidskriftsartikel (refereegranskat)abstract
- A thermodynamic description of the Fe-Te system modeled via the Calphad method is proposed, based on data published in a preceding publication Part I: Experimental study, and that available in literature. End-member formation energies for the phases beta, beta', delta, delta' and epsilon, as well as lattice stabilities of FCC and BCC tellurium, have been evaluated via DFT and used in the numerical optimization. The final Gibbs energy models fit thermodynamic and phase diagram data well, and inconsistencies are discussed. The thermodynamic description is then used to evaluate Gibbs energy of formation for selected Fe-Te compounds of interest for the modeling of internal corrosion of stainless steel fuel pin cladding during operation of Liquid Metal-cooled Fast Reactors (LMFR).
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| 45. |
- Arvhult, Carl, et al.
(författare)
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Thermodynamic assessment of the Fe–Ni–Te system
- 2019
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Ingår i: Calphad. - : Elsevier. - 0364-5916 .- 1873-2984. ; 67
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Tidskriftsartikel (refereegranskat)abstract
- For the purpose of modeling internal corrosion of the stainless steel fuel pins in fast nuclear reactors, the present work presents a thermodynamic description of the Fe–Ni–Te system modeled via the Calphad method. The liquid phase was modeled using the ionic 2-sublattice liquid model. Only binary parameters were optimized in the β2, δ and τ solid phases, to fit the isothermal section at 600 °C. The liquid did not require much adjustment from the extrapolation from the binary Fe–Te, Ni–Te and Fe–Ni systems. The paper presents a re-optimization of the Fe–Te liquid description in order to remove inverted liquid miscibility gaps at high temperatures. The resulting phase diagrams reproduce experimental isothermal sections well, and fits liquidus and solidus data very well. The description will be incorporated into the Thermodynamics of Advanced Fuels - International Database (TAF-ID). This will then be coupled with the Germinal system code to model the fission-product induced corrosion in nuclear fuel pins.
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| 46. |
- Bennet, Hedvig, et al.
(författare)
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Altered serotonin (5-HT) 1D and 2A receptor expression may contribute to defective insulin and glucagon secretion in human type 2 diabetes.
- 2015
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Ingår i: Peptides. - : Elsevier BV. - 1873-5169 .- 0196-9781. ; 71, s. 113-120
-
Tidskriftsartikel (refereegranskat)abstract
- Islet produced 5-hydroxy tryptamine (5-HT) is suggested to regulate islet hormone secretion in a paracrine and autocrine manner in rodents. Hitherto, no studies demonstrate a role for this amine in human islet function, nor is it known if 5-HT signaling is involved in the development of beta cell dysfunction in type 2 diabetes (T2D). To clarify this, we performed a complete transcriptional mapping of 5-HT receptors and processing enzymes in human islets and investigated differential expression of these genes in non-diabetic and T2D human islet donors. We show the expression of fourteen 5-HT receptors as well as processing enzymes involved in the biosynthesis of 5-HT at the mRNA level in human islets. Two 5-HT receptors (HTR1D and HTR2A) were over-expressed in T2D islet donors. Both receptors (5-HT1d and 5-HT2a) were localized to human alpha, beta and delta cells. 5-HT inhibited both insulin and glucagon secretion in non-diabetic islet donors. In islets isolated from T2D donors the amine significantly increased release of insulin in response to glucose. Our results suggest that 5-HT signaling participates in regulation of overall islet hormone secretion in non- diabetic individuals and over-expression of HTR1D and HTR2A may either contribute to islet dysfunction in T2D or arise as a consequence of an already dysfunctional islet.
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| 47. |
- Bergstrom, K, et al.
(författare)
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Core 1- and 3-derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice.
- 2017
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Ingår i: Mucosal immunology. - : Elsevier BV. - 1935-3456 .- 1933-0219. ; 10, s. 91-103
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Tidskriftsartikel (refereegranskat)abstract
- Core 1- and 3-derived mucin-type O-glycans are primary components of the mucus layer in the colon. Reduced mucus thickness and impaired O-glycosylation are observed in human ulcerative colitis. However, how both types of O-glycans maintain mucus barrier function in the colon is unclear. We found that C1galt1 expression, which synthesizes core 1 O-glycans, was detected throughout the colon, whereas C3GnT, which controls core 3 O-glycan formation, was most highly expressed in the proximal colon. Consistent with this, mice lacking intestinal core 1-derived O-glycans (IEC C1galt1(-/-)) developed spontaneous colitis primarily in the distal colon, whereas mice lacking both intestinal core 1- and 3-derived O-glycans (DKO) developed spontaneous colitis in both the distal and proximal colon. DKO mice showed an early onset and more severe colitis than IEC C1galt1(-/-) mice. Antibiotic treatment restored the mucus layer and attenuated colitis in DKO mice. Mucins from DKO mice were more susceptible to proteolysis than wild-type mucins. This study indicates that core 1- and 3-derived O-glycans collectively contribute to the mucus barrier by protecting it from bacterial protease degradation and suggests new therapeutic targets to promote mucus barrier function in colitis patients.Mucosal Immunology advance online publication, 4 May 2016; doi:10.1038/mi.2016.45.
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| 48. |
- Bernson, Elin, 1987, et al.
(författare)
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Downregulation of HLA Class I Renders Inflammatory Neutrophils More Susceptible to NK Cell-Induced Apoptosis
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Neutrophils are potent effector cells and contain a battery of harmful substances and degrading enzymes. A silent neutrophil death, i.e., apoptosis, is therefore of importance to avoid damage to the surrounding tissue and to enable termination of the acute inflammatory process. There is a pile of evidence supporting the role for pro-inflammatory cytokines in extending the life-span of neutrophils, but relatively few studies have been devoted to mechanisms actively driving apoptosis induction in neutrophils. We have previously demonstrated that natural killer (NK) cells can promote apoptosis in healthy neutrophils. In this study, we set out to investigate how neutrophil sensitivity to NK cell-mediated cytotoxicity is regulated under inflammatory conditions. Using in vitro-activated neutrophils and a human skin chamber model that allowed collection of in vivo-transmigrated neutrophils, we performed a comprehensive characterization of neutrophil expression of ligands to NK cell receptors. These studies revealed a dramatic downregulation of HLA class I molecules in inflammatory neutrophils, which was associated with an enhanced susceptibility to NK cell cytotoxicity. Collectively, our data shed light on the complex regulation of interactions between NK cells and neutrophils during an inflammatory response and provide further support for a role of NK cells in the resolution phase of inflammation.
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| 49. |
- Bever, Candace S., et al.
(författare)
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Effects of triclosan in breast milk on the infant fecal microbiome
- 2018
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Ingår i: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 203, s. 467-473
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Tidskriftsartikel (refereegranskat)abstract
- Triclosan is frequently used for its antimicrobial properties and has been detected in human serum, urine, and breast milk. Animal and molecular studies have shown that triclosan exerts a wide range of adverse health effects at both high (ppm) and low (ppb) concentrations. Since triclosan is of growing concern to human and environmental health, there is a need to improve extraction procedures and to study additional effects from triclosan exposure. In this study, we have improved triclosan extraction from breast milk by using salt (MgSO4) to reduce emulsion formation and increase water polarity and water (similar to 80%) to enhance the overall extraction efficiency (similar to 3.5 fold). This extraction method was applied to breast milk samples collected from donors who i) recorded their use of triclosan-containing personal care products and ii) provided matching infant stool samples. Of the participants who had detectable amounts of triclosan in their breast milk, nine (75%) of them reported daily use of triclosan-containing personal care products. Levels of triclosan in breast milk were compared to the donor's infant's fecal microbiome. We found that the bacterial diversity in the fecal microbiome of the infants exposed to breast milk with detectable triclosan levels differed compared to their peers exposed to milk containing non-detectable amounts. This finding implies that exogenous chemicals are impacting microbiome diversity.
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| 50. |
- Blacher, E., et al.
(författare)
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Potential roles of gut microbiome and metabolites in modulating ALS in mice
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 572:7770
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.
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