| 1. |
- Gehlen, J., et al.
(författare)
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First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B
- 2022
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Ingår i: Human Genetics and Genomics Advances. - : Elsevier BV. - 2666-2477. ; 3:2
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Tidskriftsartikel (refereegranskat)abstract
- Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10−8; odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10–5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10−10; OR = 1.47; 95% CI, 1.38–1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10−16; OR = 1.75; 95% CI, 1.64–1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes. © 2022 The Authors
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| 2. |
- Soda, T., et al.
(författare)
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International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic)
- 2020
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Ingår i: European Archives of Psychiatry and Clinical Neuroscience. - : Springer Science and Business Media LLC. - 0940-1334 .- 1433-8491. ; 270:7, s. 921-932
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Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.
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| 3. |
- Nilsson, D., et al.
(författare)
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Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation
- 2017
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 38:2, s. 180-192
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Tidskriftsartikel (refereegranskat)abstract
- Most balanced translocations are thought to result mechanistically from nonhomologous end joining or, in rare cases of recurrent events, by nonallelic homologous recombination. Here, we use low-coverage mate pair whole-genome sequencing to fine map rearrangement breakpoint junctions in both phenotypically normal and affected translocation carriers. In total, 46 junctions from 22 carriers of balanced translocations were characterized. Genes were disrupted in 48% of the breakpoints; recessive genes in four normal carriers and known dominant intellectual disability genes in three affected carriers. Finally, seven candidate disease genes were disrupted in five carriers with neurocognitive disabilities (SVOPL, SUSD1, TOX, NCALD, SLC4A10) and one XX-male carrier with Tourette syndrome (LYPD6, GPC5). Breakpoint junction analyses revealed microhomology and small templated insertions in a substantive fraction of the analyzed translocations (17.4%; n = 4); an observation that was substantiated by reanalysis of 37 previously published translocation junctions. Microhomology associated with templated insertions is a characteristic seen in the breakpoint junctions of rearrangements mediated by error-prone replication-based repair mechanisms. Our data implicate that a mechanism involving template switching might contribute to the formation of at least 15% of the interchromosomal translocation events.
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| 4. |
- Oakman, C, et al.
(författare)
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Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer-8-year results of the Breast International Group 02-98 phase III trial
- 2013
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Ingår i: Annals of Oncology. - : Oxford University Press (OUP): Policy A1. - 0923-7534 .- 1569-8041. ; 24:5, s. 1203-1211
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Tidskriftsartikel (refereegranskat)abstract
- Background: In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. less thanbrgreater than less thanbrgreater thanMethods: Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) x 4 -andgt; classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) x 4 -andgt; CMF; (iii) sequential docetaxel: A (75 mg/m(2)) x3 -andgt; docetaxel (T) (100 mg/m(2)) x3. CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) x 4 -andgt; CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. less thanbrgreater than less thanbrgreater thanResults: Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. less thanbrgreater than less thanbrgreater thanConclusion: With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.
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| 5. |
- Carlsson, G, et al.
(författare)
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Central nervous system involvement in severe congenital neutropenia : neurological and neuropsychological abnormalities associated with specific HAX1 mutations
- 2008
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 264:4, s. 388-400
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Homozygous mutations in the HAX1 gene were recently identified in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden. Our observations suggested that these patients also develop neurological and neuropsychological symptoms. METHODS: Detailed clinical studies and mutation analyses were performed in the surviving patients belonging to the Kostmann kindred and in two patients not related to this family, along with studies of HAX1 splice variant expression in normal human tissues. RESULTS: Five of six Kostmann family patients and one other patient from northern Sweden harboured homozygous HAX1 mutations (568C-->T, Q190X) and one carried a heterozygous ELA2 gene mutation. One Swedish patient of Kurdish extraction carried alternative homozygous HAX1 mutations (131G-->A, W44X). All the three patients with Q190X mutations who were alive and available for evaluation developed neurological disease with decreased cognitive function, and three of four patients who reached 10 years developed epilepsy. In contrast, the patients with the ELA2 and W44X HAX1 mutations, respectively, showed no obvious neurological abnormalities. Moreover, two alternative HAX1 splice variants were identified in normal human tissues, including the brain. Both transcripts contained exon 5, harbouring the Q190X mutation, whereas the 5' end of exon 2 containing the W44X mutation was spliced out from the second transcript. CONCLUSIONS: We describe neurological and neuropsychological abnormalities for the first time in Kostmann disease patients. These central nervous system symptoms appear to be associated with specific HAX1 mutations.
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| 6. |
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| 7. |
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| 8. |
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| 9. |
- Kuchinskaya, E, et al.
(författare)
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Children and adults with acute lymphoblastic leukaemia have similar gene expression profiles
- 2005
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Ingår i: European Journal of Haematology. - Oxford : Blackwell Publishing. - 0902-4441 .- 1600-0609. ; 74:6, s. 466-480
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To compare the gene expression pattern in children and adults with acute lymphoblastic leukaemia (ALL) in order to improve our understanding of the difference in disease biology and prognosis.METHODS: The gene expression profiles in diagnostic samples from 29 children and 15 adults with ALL were analysed using the oligonucleotide chip Hu95ver2a, produced by Affymetrix.RESULTS: Unsupervised hierarchical cluster analysis revealed that, in spite of differences in outcome, patients clustered irrespective of age, first by T-cell or B-precursor immunophenotype, and second by cytogenetic changes within the B-precursor group. The expression pattern analysis allowed the reclassification of some samples into the proper cytogenetic group. We also showed that separate clustering of samples with the BCR/ABL translocation could be explained by different breakpoint regions in the BCR. No significant difference in gene expression was observed between samples with and without CDKN2A deletion within the B-precursor group. Analysis of different age groups revealed a similarity in expression profiles when infants with the MLL translocation and adults over 40 yr of age were compared irrespective of karyotype.CONCLUSIONS: In spite of the difference in clinical outcome, the gene expression pattern in children and adults with ALL is very similar and is primarily dependent on immunophenotype and cytogenetic aberrations. However, when age groups are compared, the expression patterns of infants and adults over 40 show a remarkable similarity.
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| 10. |
- Pestalozzi, B. C., et al.
(författare)
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Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup phase III BIG 02-98 trial
- 2008
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 19:11, s. 1837-1841
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Tidskriftsartikel (refereegranskat)abstract
- Background: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. Patients and methods: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG 02-98 trial comparing anthracycline-based adjuvant chemotherapy (control arms) to anthracycline-docetaxel-based sequential or concurrent chemotherapy (experimental arms). After a median follow-up of 5 years, 403 patients had died and detailed information on CNS relapse was collected for these patients. Results: CNS relapse occurred in 4.0% of control patients and3.7% of docetaxel-treated patients. CNS relapse occurred in 27% of deceased patients in both treatment groups. CNS relapse was usually accompanied by neurologic symptoms (90%), and 25% of patients with CNS relapse died without evidence of extra-CNS relapse. Only 20% of patients survived 1 year from the diagnosis of CNS relapse. Prognosis of CNS relapse was worse for patients with meningeal carcinomatosis when compared with brain metastases. Unexpected findings included a higher rate of positive cerebrospinal fluid cytology (8% versus 3%) and more frequent use of magnetic resonance imaging for diagnosis (47% versus 30%) in the docetaxel-treated patients. Conclusion: There is no evidence that adjuvant docetaxel treatment is associated with an increased frequency of CNS relapse. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
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| 11. |
- Reutter, Heiko, et al.
(författare)
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Genome-wide association study and mouse expression data identify a highly conserved 32kb intergenic region between WNT3 and WNT9b as possible susceptibility locus for isolated classic exstrophy of the bladder.
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:20, s. 5536-5544
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Tidskriftsartikel (refereegranskat)abstract
- Bladder Exstrophy-Epispadias Complex (BEEC), the severe end of the uro-rectal malformation spectrum, has a profound impact on continence as well as sexual and renal functions. It is widely accepted that for the majority of cases the genetic basis appears to be multifactorial. Here, we report the first study which utilizes genome-wide association methods to analyze a cohort comprising patients presenting the most common BEEC form, classic bladder exstrophy (CBE), to identify common variation associated with risk for isolated CBE. We employed discovery and follow-up samples comprising 218/865 cases/controls and 78 trios in total, all of European descent. Our discovery sample identified a marker near SALL1, showing genome-wide significant association with CBE. However, analyses performed on follow-up samples did not add further support to these findings. We were also able to identify an association with CBE across our study samples (discovery: P=8.88 x 10(-5); follow-up: P=0.0025; combined: 1.09 x 10(-6)) in a highly conserved 32kb intergenic region containing regulatory elements between WNT3 and WNT9B. Subsequent analyses in mice revealed expression for both genes in the genital region during stages relevant to the development of CBE in humans. Unfortunately, we were not able to replicate the suggestive signal for WNT3 and WNT9B in a sample that was enriched for non-CBE BEEC cases (P=0.51). Our suggestive findings support the hypothesis that larger samples are warranted to identify association of common variation with CBE.
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| 12. |
- Sahlén, Pelin, et al.
(författare)
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Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis– and psoriasis-associated genes
- 2020
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Ingår i: Journal of Allergy and Clinical Immunology. - : Mosby Inc.. - 0091-6749 .- 1097-6825.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear. Objective: We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate. Methods: We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies. Results: We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis. Conclusions: Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Eggers, Kai M., 1962-, et al.
(författare)
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Clinical and prognostic implications of C-reactive protein levels in myocardial infarction with nonobstructive coronary arteries
- 2021
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Ingår i: Clinical Cardiology. - : John Wiley & Sons. - 0160-9289 .- 1932-8737. ; 44:7, s. 1019-1027
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Tidskriftsartikel (refereegranskat)abstract
- Background Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a heterogeneous condition. Recent studies suggest that MINOCA patients may have a proinflammatory disposition. The role of inflammation in MINOCA may thus be distinct to myocardial infarction with significant coronary artery disease (MI-CAD). Hypothesis We hypothesized that inflammation reflected by C-reactive protein (CRP) levels might carry unique clinical information in MINOCA. Methods This retrospective registry-based cohort study (SWEDEHEART) included 9916 patients with MINOCA and 97 970 MI-CAD patients, used for comparisons. Multivariable-adjusted regressions were applied to investigate the associations of CRP levels with clinical variables, all-cause mortality and major cardiovascular events (MACE) during a median follow-up of up to 5.3 years. Results Median admission CRP levels in patients with MINOCA and MI-CAD were 5.0 (interquartile range 2.0-9.0) mg/dl and 5.0 (interquartile range 2.1-10.0 mg/dl), respectively. CRP levels in MINOCA exhibited independent associations with various cardiovascular risk factors, comorbidities and estimates of myocardial damage. The association of CRP with peripheral artery disease tended to be stronger compared to MI-CAD. The associations with female sex, renal dysfunction and myocardial damage were stronger in MI-CAD. CRP independently predicted all-cause mortality in MINOCA (hazard ratio 1.22 [95% confidence interval 1.17-1.26]), similar to MI-CAD (p interaction = 0.904). CRP also predicted MACE (hazard ratio 1.08 [95% confidence interval 1.04-1.12]) but this association was weaker compared to MI-CAD (p interaction<.001). Conclusions We found no evidence indicating the presence of a specific inflammatory pattern in acute MINOCA compared to MI-CAD. However, CRP levels were independently, albeit moderately associated with adverse outcome.
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| 17. |
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| 18. |
- Eggers, Kai M., 1962-, et al.
(författare)
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Morbidity and cause-specific mortality in first-time myocardial infarction with nonobstructive coronary arteries
- 2019
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Ingår i: Journal of Internal Medicine. - : Blackwell Publishing. - 0954-6820 .- 1365-2796. ; 285:4, s. 419-428
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is receiving increasing interest as a prognostically adverse entity distinct from myocardial infarction with significant coronary artery disease (MI-CAD). However, data are still limited regarding long-term cardiovascular morbidity and cause-specific mortality in MINOCA.METHODS: This is a registry-based cohort study using data from patients admitted to Swedish coronary care units. We investigated various nonfatal outcomes (recurrent MI, hospitalization for heart failure or stroke) and fatal outcomes (cardiovascular, respiratory or cancer-related mortality) in 4069 patients without apparent acute cardiovascular disease, used as non-MI controls, 7266 patients with first-time MINOCA and 69 267 patients with first-time MI-CAD.RESULTS: Almost all event rates (median follow-up 3.8 years) increased in a stepwise fashion across the three cohorts [rates of major adverse events (MAE; composite of all-cause mortality, recurrent MI, hospitalization for heart failure or stroke): n = 268 (6.6%), n = 1563 (21.5%), n = 17 777 (25.7%), respectively]. Compared to non-MI controls, MINOCA patients had an adjusted hazard ratio (HR) of 2.12 (95% confidence interval 1.84-2.43) regarding MAE. MINOCA patients had a substantial risk of cardiovascular mortality and the highest numerical risks of respiratory and cancer-related mortality. Male sex, previous heart failure and chronic obstructive pulmonary disease had a stronger prognostic impact in MINOCA than in MI-CAD. Female MINOCA patients with atrial fibrillation were at particular risk.CONCLUSIONS: Patients with first-time MINOCA have a considerable risk of adverse events. This stresses the need for a comprehensive search of the cause of MINOCA, thorough treatment of underlying disease triggers and close follow-up.
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| 19. |
- Eggers, Kai M., 1962-, et al.
(författare)
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Myocardial Infarction with Non-Obstructive Coronary Arteries : The Importance of Achieving Secondary Prevention Targets
- 2018
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Ingår i: American Journal of Medicine. - : Elsevier. - 0002-9343 .- 1555-7162. ; 131:5, s. 524-531
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Around 5-10% of all myocardial infarction patients have non-obstructive coronary arteries. Studies investigating the importance of follow-up and achievement of conventional secondary prevention targets in these patients are lacking.METHODS: In this analysis from the SWEDEHEART registry, we investigated 5830 myocardial infarction patients with non-obstructive coronary arteries (group 1) and 54,637 myocardial infarction patients with significant coronary artery disease (≥50% stenosis; group 2). Multivariable- and propensity score-adjusted statistics were used to assess the reduction in the one-year risk of major adverse events associated with prespecified secondary preventive measures: participation in follow-up at 6-10 weeks after the hospitalization; achievement of secondary prevention targets (blood pressure and low-density lipoprotein cholesterol levels in the target ranges, non-smoking, participation in exercise training).RESULTS: Patients in group 1 were less often followed up compared to patients in group 2 and less often achieved any of the secondary prevention targets. Participation in the 6-10 week follow-up was associated with a 3-20% risk reduction in group 1, similar as for group 2 according to interaction analysis. The improvement in outcome in group 1 was mainly mediated by achieving target range low-density lipoprotein cholesterol levels (24-32% risk reduction) and, to a smaller extent, by participation in exercise training (10-23% risk reduction).CONCLUSIONS: Selected secondary preventive measures are associated with prognostic benefit in myocardial infarction patients with non-obstructive coronary arteries, in particular achieving target range low-density lipoprotein cholesterol levels. Our results indicate that these patients should receive similar follow-up as myocardial infarction patients with significant coronary stenoses.
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| 20. |
- Ekholm, M., et al.
(författare)
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Effects of adjuvant tamoxifen over three decades on breast cancer–free and distant recurrence–free interval among premenopausal women with oestrogen receptor–positive breast cancer randomised in the Swedish SBII:2pre trial
- 2019
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 110, s. 53-61
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The primary aim was to compare 2 years of adjuvant tamoxifen versus no systemic treatment in premenopausal patients with oestrogen receptor (ER)–positive tumours, regarding breast cancer–free interval (BCFi) and distant recurrence–free interval (D-RFi), with 30 years of follow-up and for specified intervals. Moreover, we aimed to investigate the effects of adjuvant tamoxifen on the incidence of secondary malignancies and survival after distant recurrence. Methods: Premenopausal patients with primary breast cancer were randomised to 2 years of tamoxifen (n = 277) or no systemic treatment (n = 287), irrespective of ER status. Information regarding events was collected by a review of medical records and from national registers. Results: The median follow-up for all patients without events was 28 years, and only four of the patients alive had a follow-up of <20 years. With 30 years of follow-up, tamoxifen prolonged BCFi in the intention-to-treat population (hazard ratio [HR] = 0.76, 95% confidence interval (CI) 0.61–0.94, p = 0.011) compared with no treatment. In patients with ER-positive tumours (n = 362), tamoxifen prolonged BCFi (HR = 0.62, 95% CI 0.47–0.82, p = 0.001) and D-RFi (HR = 0.73, 95% CI 0.54–0.99, p = 0.043). The positive effect on BCFi was significant also for the interval >15–30 years (HR = 0.53, 95% CI 0.28–0.98, p = 0.042). For patients with ER-positive tumours who were diagnosed with distant recurrence (n = 165), survival after distant recurrence was shorter among tamoxifen-treated patients (median, 29 months versus 43 months). The incidence of contralateral breast cancer was 42% lower in the tamoxifen group (HR = 0.58, 95% CI 0.35–0.96, p = 0.035), whereas no differences were observed regarding other secondary malignancies. Conclusions: With three decades of follow-up, 2 years of adjuvant tamoxifen reduced the incidence of breast cancer–related events and distant recurrence, and the carryover effect seems to extend beyond 15 years. Moreover, adjuvant tamoxifen seems to be associated with shorter survival after diagnosis of distant recurrence.
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| 21. |
- Fadista, João, et al.
(författare)
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Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis.
- 2019
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 28:2, s. 332-340
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Tidskriftsartikel (refereegranskat)abstract
- Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of ∼2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P < 5 × 10-8), including novel associations with two single nucleotide polymorphisms (SNPs). One of these SNPs, rs6736913 [odds ratio (OR) = 2.32; P = 3.0 × 10-15], is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1 × 10-9) is 1 kb downstream of BARX1 at 9q22.32, an essential gene for stomach formation in embryogenesis. Using the genome-wide complex trait analysis method, we estimated the IHPS SNP heritability to be 30%, and using the linkage disequilibrium score regression method, we found support for a previously reported genetic correlation of IHPS with lipid metabolism. By combining the largest collection of IHPS cases to date (3822 cases), with results generalized across populations of different ancestry, we elucidate novel mechanistic avenues of IHPS disease architecture.
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| 22. |
- Ivanov Öfverholm, I., et al.
(författare)
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Overexpression of chromatin remodeling and tyrosine kinase genes in iAMP21-positive acute lymphoblastic leukemia
- 2020
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 61:3, s. 604-613
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Tidskriftsartikel (refereegranskat)abstract
- Intrachromosomal amplification of chromosome 21 (iAMP21) is a cytogenetic subtype associated with relapse and poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). The biology behind the high relapse risk is unknown and the aim of this study was to further characterize the genomic and transcriptional landscape of iAMP21. Using DNA arrays and sequencing, we could identify rearrangements and aberrations characteristic for iAMP21. RNA sequencing revealed that only half of the genes in the minimal region of amplification (20/45) were differentially expressed in iAMP21. Among them were the top overexpressed genes (p < 0.001) in iAMP21 vs. BCP ALL without iAMP21 and three candidate genes could be identified, the tyrosine kinase gene DYRK1A and chromatin remodeling genes CHAF1B and SON. While overexpression of DYRK1A and CHAF1B is associated with poor prognosis in malignant diseases including myeloid leukemia, this is the first study to show significant correlation with iAMP21-positive ALL.
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| 23. |
- Lindblad, L., et al.
(författare)
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Risk factors for mortality of medical causes within 30 days of electroconvulsive therapy
- 2023
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Ingår i: Journal of Affective Disorders. - : Elsevier. - 0165-0327 .- 1573-2517. ; 320, s. 527-533
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Electroconvulsive therapy (ECT) is used to treat severe psychiatric disorders and is associated with reduced risk of suicide and all-cause mortality in patients with severe depression. We investigated the causes of death occurring shortly after ECT and identified potential risk factors for medical causes of death.METHODS: Patients treated with ECT between 2012 and 2018 were included in this Swedish register-based study. Multivariate binary logistic regression was used to calculate odds ratios for covariates to determine potential predictors of 30-day mortality.RESULTS: Of the 20,225 included patients, 93 (0.46 %) died of suicide and 123 (0.61 %) died of medical causes after ECT. Cardiovascular disease was the most common medical cause of death (n = 49, 40 %). An older age, a Charlson Comorbidity Index of 1 or more, atrial fibrillation, kidney disease, reflux disease, dementia, and cancer were associated with increased risk of death by medical causes.LIMITATIONS: Real-life observational studies based on registry data may demonstrate associations, but cannot determine causality. If medical records had been available, we would be better able to determine if deaths were due to the ECT, anesthesia, pre-existing medical conditions, or the mental disorder.CONCLUSIONS: ECT appears to be a low-risk medical procedure. Older individuals with severe somatic diseases have the highest risk of death and extra measures should be considered to optimize their medical health during the pre-ECT workup, and during and after ECT.
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| 24. |
- Nordenskjöld, A., et al.
(författare)
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Copy number variants suggest different molecular pathways for the pathogenesis of bladder exstrophy
- 2023
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Ingår i: American Journal of Medical Genetics, Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 191:2, s. 378-390
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Tidskriftsartikel (refereegranskat)abstract
- Bladder exstrophy is a rare congenital malformation leaving the urinary bladder open in the midline of the abdomen at birth. There is a clear genetic background with chromosome aberrations, but so far, no consistent findings apart from 22q11-duplications detected in about 2%–3% of all patients. Some genes are implicated like the LZTR1, ISL1, CELSR3, and the WNT3 genes, but most are not explained molecularly. We have performed chromosomal microarray analysis on a cohort of 140 persons born with bladder exstrophy to look for submicroscopic chromosomal deletions and duplications. Pathogenic or possibly pathogenic microdeletions or duplications were found in 16 patients (11.4%) and further 9 with unknown significance. Two findings were in regions linked to known syndromes, two findings involved the same gene (MCC), and all other findings were unique. A closer analysis suggests a few gene networks that are involved in the pathogenesis of bladder exstrophy; the WNT-signaling pathway, the chromosome 22q11 region, the RIT2 and POU families, and involvement of the Golgi apparatus. Bladder exstrophy is a rare malformation and is reported to be associated with several chromosome aberrations. Our data suggest involvement of some specific molecular pathways.
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| 25. |
- Nordenskjöld, Anna M., 1977-, et al.
(författare)
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Circadian onset and prognosis of myocardial infarction with non-obstructive coronary arteries (MINOCA)
- 2019
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Many acute cardiovascular events such as myocardial infarction (MI) follow circadian rhythms. Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a newly noticed entity with limited data on onset pattern and its impact on prognosis.MATERIAL AND METHODS: In this observational study of Swedish MINOCA patients registered in the SWEDEHEART registry between 2003-2013 and followed until December 2013 we identified 9,092 unique patients with MINOCA out of 199,163 MI admissions in total. Incidence rate ratios (IRR) were calculated for whole hours, parts of the day, weekdays, months, seasons and major holidays.RESULTS: The mean age was 65.5 years, 62.0% were women and 16.6% presented with STEMI. The risk for MINOCA proved to be most common in the morning (IRR = 1.70, 95% CI [1.63-1.84]) with a peak at 08.00 AM (IRR = 2.25, 95% CI [1.96-2.59]) and on Mondays (IRR = 1.28, 95% CI [1.18-1.38]). No altered risk was detected during the different seasons, the Christmas and New Year holidays or the Swedish Midsummer festivities. There was no association between time of onset of MINOCA and short- or long-term prognosis.CONCLUSION: The onset of MINOCA shows a circadian and circaseptan variation with increased risk at early mornings and Mondays, similar to previous studies on all MI, suggesting stress related triggering. However, during holidays were traditional MI increase, we did not see any increase for MINOCA. No association was detected between time of onset and prognosis, indicating that the underlying pathological mechanisms of MINOCA and the quality of care are similar at different times of onset but triggering mechanism may be more active early mornings and Mondays.
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| 26. |
- Nordenskjöld, Anna M., 1977-, et al.
(författare)
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Predictors of adverse outcome in patients with myocardial infarction with non-obstructive coronary artery (MINOCA) disease
- 2018
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Ingår i: International Journal of Cardiology. - : Elsevier. - 0167-5273 .- 1874-1754. ; 261, s. 18-23
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Tidskriftsartikel (refereegranskat)abstract
- Background: Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCAs) is an increasingly recognized entity. No previous study has evaluated predictors for new major adverse cardiacvascular events (MACEs) and death in patients with MINOCA.Methods: We conducted an observational study of MINOCA patients recorded between July 2003 and June 2013 and followed until December 2013 for outcome events. Out of 199,163 MI admissions, 9092 consecutive unique patients with MINOCA were identified. The mean age was 65.5 years and 62% were women. MACE was defined as all-cause mortality, rehospitalization for acute MI, ischemic stroke and heart failure. Hazard ratio and 95% confidence interval (HR; 95% CI) was calculated using Cox-regression.Results: A total of 2147 patients (24%) experienced a new MACE and 1254 patients (14%) died during the mean follow-up of 4.5 years. Independent predictors for MACE after adjustment, were older age (1.05; 1.04-1.06), diabetes (1.44; 1.21-1.70), hypertension (1.25; 1.09-1.43), current smoking (1.38; 1.15-1.66), previous myocardial infarction (1.38; 1.04-2.82), previous stroke (1.69; 1.35-2.11), peripheral vascular disease (1.55; 1.97-2.23), chronic obstructive pulmonary disease (1.63; 1.32-2.00), reduced left ventricular ejection fraction (2.00; 1.54-2.60), lower level of total cholesterol (0.88; 0.83-0.94) and higher level of creatinine (1.01; 1.00-1.03). Independent predictors for all cause death were age, current smoking, diabetes, cancer, chronic obstructive pulmonary disease, previous stroke, reduced left ventricular fraction, lower level of total cholesterol and higher levels of creatinine and CRP.Conclusions: The clinical factors predicting new MACE and death of MINOCA patients seem to be strikingly similar to factors previously shown to predict new cardiovascular events in patients with MI and obstructive coronary artery disease.
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| 27. |
- Nordenskjöld, Anna M., 1977-, et al.
(författare)
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Short-and long-term individual variation in NT-proBNP levels in patients with stable coronary artery disease
- 2013
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Ingår i: Clinica Chimica Acta. - : Elsevier. - 0009-8981 .- 1873-3492. ; 422:25, s. 15-20
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to diagnosis of heart failure (HF) natriuretic peptides (BNP and NT-proBNP) may be used for risk prediction in stable and acute coronary artery disease. The aim of the study was to evaluate the short- and long-term individual variation of NT-proBNP in patients with stable coronary artery disease.Methods: Twenty-four patients with suspected stable coronary artery disease and scheduled for elective coronary angiography were included. Blood samples were drawn at enrolment and, on average 3 weeks later, serially the day prior to coronary angiography. NT-proBNP was determined using Elecsys proBNP sandwich immunoassay (Roche Diagnostics).Results: The individual variation in NT-proBNP over 4 h was 11.8%, over 20 h 12.4% and over 3 weeks 20.4%. The corresponding positive and negative lognormal reference change values (RCV) were +41/-29%, +42/-30% and + 76/-43%, respectively. No significant circadian variation was found.Conclusions: Our results suggest that an increase in NT-proBNP levels of >42% or a decrease of >30% is needed to indicate a reliable short-term change; and for a long-term change an increase of >76% or a decrease of >43% is required. This should be considered when interpreting changes in NT-proBNP levels.
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| 28. |
- Nordenskjöld, Anna M., 1977-, et al.
(författare)
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Unrecognized myocardial infarction assessed by cardiac magnetic resonance imaging : prognostic implications
- 2016
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clinically unrecognized myocardial infarctions (UMI) are not uncommon and may be associated with adverse outcome. The aims of this study were to determine the prognostic implication of UMI in patients with stable suspected coronary artery disease (CAD) and to investigate the associations of UMI with the presence of CAD.Methods and Findings: In total 235 patients late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) imaging and coronary angiography were performed. For each patient with UMI, the stenosis grade of the coronary branch supplying the infarcted area was determined. UMIs were present in 25% of the patients and 67% of the UMIs were located in an area supplied by a coronary artery with a stenosis grade >= 70%. In an age-and gender-adjusted model, UMI independently predicted the primary endpoint (composite of death, myocardial infarction, resuscitated cardiac arrest, hospitalization for unstable angina pectoris or heart failure within 2 years of follow-up) with an odds ratio of 2.9; 95% confidence interval 1.1-7.9. However, this association was abrogated after adjustment for age and presence of significant coronary disease. There was no difference in the primary endpoint rates between UMI patients with or without a significant stenosis in the corresponding coronary artery.Conclusions: The presence of UMI was associated with a threefold increased risk of adverse events during follow up. However, the difference was no longer statistically significant after adjustments for age and severity of CAD. Thus, the results do not support that patients with suspicion of CAD should be routinely investigated by LGE-CMR for UMI. However, coronary angiography should be considered in patients with UMI detected by LGE-CMR.
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| 29. |
- Nordenskjöld, Anna M., 1977-, et al.
(författare)
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Unrecognized myocardial infarctions detected by cardiac magnetic resonance imaging are associated with cardiac troponin I levels
- 2016
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Ingår i: Clinica Chimica Acta. - Amsterdam, Netherlands : Elsevier BV. - 0009-8981 .- 1873-3492. ; 455, s. 189-194
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Tidskriftsartikel (refereegranskat)abstract
- Background: Both unrecognized myocardial infarction (UMI) and elevated levels of biomarkers are common in patients with stable coronary artery disease (CAD). The objective of this study was to determine the association between levels of cardiac biomarkers, UMI and extent of CAD in patients with stable CAD.Methods: A total of 235 patients (median age: 65 years; 34% women) with stable CAD without previously known myocardial infarction were examined with late gadolinium enhancement cardiovascular magnetic resonance imaging and coronary angiography. Blood samples were drawn at enrolment and high sensitivity cardiac troponin I (cTnI), NT-proBNP and Galectin-3 were analyzed.Results: UMI was detected in 58 patients (25%). The median levels of cTnI, NT-proBNP and Galectin-3 were significantly higher in patients with UMI compared to those without, (p < 0.001, p = 0.006 and p = 0.033, respectively). After adjustment for cardiovascular risk factors, left ventricular ejection fraction and renal function, cTnI remained independently associated with the presence of UMI (p = 0.031) and the extent of CAD (p = 0.047). Neither NT-proBNP, nor Galectin-3, was independently associated with UMI or extent of CAD.Conclusions: The independent association between levels of cTnI and UMI indicates a common pathophysiological pathway for the cTnI elevation and development of UMI.
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| 30. |
- Nordenskjöld, Axel, 1977-, et al.
(författare)
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Major adverse cardiovascular events following electroconvulsive therapy in depression : A register-based nationwide Swedish cohort study with 1-year follow-up
- 2022
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Ingår i: Journal of Affective Disorders. - : Elsevier. - 0165-0327 .- 1573-2517. ; 296, s. 298-304
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The cardiovascular response during electroconvulsive therapy (ECT) could induce major adverse cardiovascular events (MACE) in the short-term, while reduced depression could decrease the risk of MACE in the long-term. The balance between these potential effects has not been thoroughly investigated.METHODS: This nationwide, registry-based cohort study included all patients admitted to Swedish hospitals due to moderate or severe unipolar depression between 2011 and 2018. Patients were divided into an ECT group and a non-ECT group, and followed for 1 year. Patients were matched by risk factors for cardiovascular disease by propensity score matching. Cox regression was used to examine the association between ECT and MACE.RESULTS: Out of a total of 28 584 inpatients, 5476 patients who had received ECT were matched to 5476 non-ECT patients. ECT was associated with reduced risk of MACE within 90 days and 1 year. Within 1 year after admission, a total of 127 patients (2.3%) in the non-ECT group and 82 patients (1.4%) in the ECT group had at least one MACE (hazard ratio [HR], 0.65; 95% confidence interval, 0.49-0.85).LIMITATIONS: Real-life observational studies carry risk for residual confounding.CONCLUSIONS: ECT in patients hospitalized for depression was not associated with any significant short-term risks of cardiovascular events. Instead, ECT was associated with a reduced risk of MACE within 1 year after admission compared with patients not treated with ECT. This association may be explained by reduced depressive symptoms after ECT, improved risk factor management in the ECT-group or by residual confounding by indication.
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| 31. |
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| 32. |
- Pasupathy, Sivabaskari, et al.
(författare)
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Survival in Patients With Suspected Myocardial Infarction With Nonobstructive Coronary Arteries : A Comprehensive Systematic Review and Meta-Analysis From the MINOCA Global Collaboration
- 2021
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Ingår i: Circulation. Cardiovascular Quality and Outcomes. - : Lippincott Williams & Wilkins. - 1941-7713 .- 1941-7705. ; 14:11
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: Suspected myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) occurs in ≈5% to 10% of patients with MI referred for coronary angiography. The prognosis of these patients may differ to those with MI and obstructive coronary artery disease (MI-CAD) and those without a MI (patients without known history of MI [No-MI]). The primary objective of this study is to evaluate the 12-month all-cause mortality of patients with MINOCA.METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the terms "MI," "nonobstructive," "angiography," and "prognosis" were searched in PubMed and Embase databases from inception to December 2018, including original, English language MINOCA studies with >100 consecutive patients. Publications with a heterogeneous cohort, unreported coronary stenosis, or exclusively focusing on MINOCA-mimicking conditions, were excluded. Unpublished data were obtained from the MINOCA Global Collaboration. Data were pooled and analyzed using Paule-Mandel, Hartung, Knapp, Sidik & Jonkman, or restricted maximum-likelihood random-effects meta-analysis methodology. Heterogeneity was assessed using Cochran's Q and I2 statistics. The primary outcome was 12-month all-cause mortality in patients with MINOCA, with secondary comparisons to MI-CAD and No-MI.RESULTS: The 23 eligible studies yielded 55 369 suspected MINOCA, 485 382 MI-CAD, and 33 074 No-MI. Pooled meta-analysis of 14 MINOCA studies accounting for 30 733 patients revealed an unadjusted 12-month all-cause mortality rate of 3.4% (95% CI, 2.6%-4.2%) and reinfarction (n=27 605; 10 studies) in 2.6% (95% CI, 1.7%-3.5%). MINOCA had a lower 12-month all-cause mortality than those with MI-CAD (3.3% [95% CI, 2.5%-4.1%] versus 5.6% [95% CI, 4.1%-7.0%]; odds ratio, 0.60 [95% CI, 0.52-0.70], P<0.001). In contrast, there was a statistically nonsignificant trend towards increased 12-month all-cause mortality in patients with MINOCA (2.6% [95% CI, 0%-5.9%]) compared with No-MI (0.7% [95% CI, 0.1%-1.3%]; odds ratio, 3.71 [95% CI, 0.58-23.61], P=0.09).CONCLUSIONS: In the largest contemporary MINOCA meta-analysis to date, patients with suspected MINOCA had a favorable prognosis compared with MI-CAD, but statistically nonsignificant trend toward worse outcomes compared to those with No-MI. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42020145356.
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| 33. |
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| 34. |
- Zachariadis, V., et al.
(författare)
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The frequency and prognostic impact of dic(9;20)(p13.2;q11.2) in childhood B-cell precursor acute lymphoblastic leukemia : results from the NOPHO ALL-2000 trial
- 2011
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Ingår i: Leukemia. - London : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 25:4, s. 622-628
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Tidskriftsartikel (refereegranskat)abstract
- The dic(9;20)(p13.2;q11.2) is reported to be present in similar to 2% of childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL). However, it easily escapes detection by G-banding analysis and its true prevalence is hence unknown. We performed interphase fluorescence in situ hybridization analyses-in a three-step manner-using probes for: (i) CDKN2A at 9p21, (ii) 20p and 20q subtelomeres and (iii) cen9 and cen20. Out of 1033 BCP ALLs diagnosed from 2001 to 2006, 533 were analyzed; 16% (84/533) displayed 9p21 deletions, of which 30% (25/84) had dic(9;20). Thus, dic(9;20)-positivity was found in 4.7% (25/533), making it the third most common genetic subgroup after high hyperdiploidy and t(12;21)(p13;q22). The dic(9;20) was associated with a female predominance and an age peak at 3 years; 18/25 (72%) were allocated to non-standard risk treatment at diagnosis. Including cases detected by G-banding alone, 29 dic(9;20)-positive cases were treated according to the NOPHO ALL 2000 protocol. Relapses occurred in 24% (7/29) resulting in a 5-year event-free survival of 0.69, which was significantly worse than for t(12;21) (0.87; P = 0.002) and high hyperdiploidy (0.82; P = 0.04). We conclude that dic(9;20) is twice as common as previously surmised, with many cases going undetected by G-banding analysis, and that dic(9;20) should be considered a non-standard risk abnormality.
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| 35. |
- Ahmad, I., et al.
(författare)
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Validity of diagnoses, treatment dates, and rating scales in the Swedish national quality register for electroconvulsive therapy
- 2022
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Ingår i: Nordic Journal of Psychiatry. - : Informa UK Limited. - 0803-9488 .- 1502-4725. ; 76:2, s. 96-103
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Tidskriftsartikel (refereegranskat)abstract
- Background The Swedish national quality register for electroconvulsive therapy (Q-ECT) contains data on patients receiving treatment with electroconvulsive therapy (ECT) in Sweden. Aim This study determined the validity of diagnoses, treatment dates, and rating scales in the Q-ECT by investigating the degree of accordance between data from the Q-ECT and patient records. Materials and methods From January 2016 to December 2017, 200 treatment series were randomly selected from the Q-ECT. The corresponding patient records were requested from the treating hospitals. Data on the indicative diagnosis, dates for the first and the last ECT session, and rating scales were compared between the Q-ECT and patient records using (i) a strict and (ii) a liberal method of assessment. Using the liberal method, each variable was assessed as accordant if it belonged to the same diagnosis group, or if the dates differed by less than 1 week, or ratings differed by only 1 point on the Clinical Global Impression Scale (CGI- S), or no more than 3 points on the Montgomery angstrom sberg Depression Rating Scale between the Q-ECT and the patient record. Results A total of 179 patient records were received. The strict method of assessment showed an accordance of 89% or higher for all studied variables. The liberal method showed an accordance of 95% or higher. Conclusions We conclude that data on the studied variables in the Q-ECT have high validity. However, limited use of some rating scales makes the results uncertain. Measures can be taken to further improve the data quality.
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| 36. |
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| 37. |
- Brooks, Samantha J, et al.
(författare)
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Late-life obesity is associated with smaller global and regional gray matter volumes : a voxel-based morphometric study
- 2013
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 37:2, s. 230-236
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Obesity adversely affects frontal lobe brain structure and function. Here we sought to show that people who are obese versus those who are of normal weight over a 5-year period have differential global and regional brain volumes.DESIGN: Using voxel-based morphometry, contrasts were done between those who were recorded as being either obese or of normal weight over two time points in the 5 years prior to the brain scan. In a post-hoc preliminary analysis, we compared scores for obese and normal weight people who completed the trail-making task.SUBJECTS: A total of 292 subjects were examined following exclusions (for example, owing to dementia, stroke and cortical infarcts) from the Prospective Investigation of the Vasculature in Uppsala Seniors cohort with a body mass index of normal weight (<25 kg m−2) or obese (30 kg m−2).RESULTS: People who were obese had significantly smaller total brain volumes and specifically, significantly reduced total gray matter (GM) volume (GMV) (with no difference in white matter or cerebrospinal fluid). Initial exploratory whole brain uncorrected analysis revealed that people who were obese had significantly smaller GMV in the bilateral supplementary motor area, bilateral dorsolateral prefrontal cortex (DLPFC), left inferior frontal gyrus and left postcentral gyrus. Secondary more stringent corrected analyses revealed a surviving cluster of GMV difference in the left DLPFC. Finally, post-hoc contrasts of scores on the trail-making task, which is linked to DLPFC function, revealed that obese people were significantly slower than those of normal weight.CONCLUSION: These findings suggest that in comparison with normal weight, people who are obese have smaller GMV, particularly in the left DLPFC. Our results may provide evidence for a potential working memory mechanism for the cognitive suppression of appetite that may lower the risk of developing obesity in later life.
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| 38. |
- Brus, Ole, 1982-, et al.
(författare)
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Self-assessed remission rates after electroconvulsive therapy of depressive disorders
- 2017
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Ingår i: European Psychiatry. - : Cambridge University Press (CUP). - 0924-9338 .- 1778-3585. ; 45, s. 154-160
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Tidskriftsartikel (refereegranskat)abstract
- Background Electroconvulsive therapy (ECT) effectively treats severe depression, but not all patients remit. The aim of the study was to identify clinical factors that associate with ECT-induced remission in a community setting. Methods Depressed patients who underwent ECT in 2011–2014 were identified from the Swedish National Quality Register for ECT. Remission was defined as self-rated Montgomery-Åsberg Depression Rating Scale scores of 0–10 after ECT. Other registers provided data on previous antidepressant use, comorbidities, and demographics. Results Of 1671 patients fulfilling the inclusion criteria, 42.8% achieved remission. Older age, education length over 9 years, psychotic symptoms, shorter duration of preceding antidepressant use, pulse width stimulus ≥ 0.50 ms, absence of substance use disorders, anxiety diagnosis, lamotrigine, and benzodiazepines, were associated with remission. Conclusions This study shows that psychotic subtype of depression and older age are clinically relevant predictors of a beneficial ECT effect. Additionally, ECT outcomes can be further improved by optimizing the treatment technique and concomitant medication. © 2017 The Author(s)
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| 39. |
- Buckley, Patrick G., et al.
(författare)
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Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2
- 2005
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 26:6, s. 540-9
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Tidskriftsartikel (refereegranskat)abstract
- Schwannomatosis is characterized by multiple peripheral and cranial nerve schwannomas that occur in the absence of bilateral 8th cranial nerve schwannomas. The latter is the main diagnostic criterion of neurofibromatosis type 2 (NF2), which is a related but distinct disorder. The genetic factors underlying the differences between schwannomatosis and NF2 are poorly understood, although available evidence implicates chromosome 22 as the primary location of the gene(s) of interest. To investigate this, we comprehensively profiled the DNA copy number in samples from sporadic and familial schwannomatosis, NF2, and a large cohort of normal controls. Using a tiling-path chromosome 22 genomic array, we identified two candidate regions of copy number variation, which were further characterized by a PCR-based array with higher resolution. The latter approach allows the detection of minute alterations in total genomic DNA, with as little as 1.5 kb per measurement point of nonredundant sequence on the array. In DNA derived from peripheral blood from a schwannomatosis patient and a sporadic schwannoma sample, we detected rearrangements of the immunoglobulin lambda (IGL) locus, which is unlikely to be due to a B-cell specific somatic recombination of IGL. Analysis of normal controls indicated that these IGL rearrangements were restricted to schwannomatosis/schwannoma samples. In the second candidate region spanning GSTT1 and CABIN1 genes, we observed a frequent copy number polymorphism at the GSTT1 locus. We further describe missense mutations in the CABIN1 gene that are specific to samples from schwannomatosis and NF2 and make this gene a plausible candidate for contributing to the pathogenesis of these disorders.
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| 40. |
- Carlsson, G, et al.
(författare)
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Hematopoietic stem cell transplantation in severe congenital neutropenia
- 2011
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 56:3, s. 444-451
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Severe congenital neutropenia (SCN) is an immunodeficiency characterized by disturbed myelopoiesis and an absolute neutrophil count (ANC) <0.5 × 10(9)/L. SCN is also a premalignant condition; a significant proportion of patients develop myelodysplastic syndrome or leukemia (MDS/L). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCN.PROCEDURE:Since 2004, eight HSCT have been performed in seven patients at our center. The indications were transformation to MDS/L (n = 2), granulocyte colony-stimulating factor receptor (CSF3R) mutation(s) (n = 2), granulocyte colony-stimulating factor (G-CSF) resistance (n = 2), and at the patient's own request (n = 1).RESULTS:The mean age at transplantation was 13 years (2.8-28 years) (mean follow-up 32 months, range 21-60). Three patients harbored ELANE mutations, three HAX1 mutations, and in one patient no causative mutation was identified. Two of the ELANE mutations were novel mutations. Three patients initially received myeloablative conditioning and four had reduced intensity conditioning (RIC). Three grafts were from HLA-identical siblings, three from matched unrelated donors and two were cord blood units. Engraftment occurred in all patients. Two of seven (29%) patients died; both had MDS/L and both were among the three that underwent myeloablative conditioning. One patient has chronic GVHD 2 years post-transplant.CONCLUSIONS:The role of HSCT should be explored further in patients with SCN. In particular, the influence of the conditioning regime needs to be evaluated in a larger cohort of patients.
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| 41. |
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| 42. |
- Clements, C. C., et al.
(författare)
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Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26:10
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Tidskriftsartikel (refereegranskat)abstract
- Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.
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| 43. |
- de Ståhl, Teresita Díaz, et al.
(författare)
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Profiling of copy number variations (CNVs) in healthy individuals from three ethnic groups using a human genome 32 K BAC-clone-based array
- 2008
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 29:3, s. 398-408
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Tidskriftsartikel (refereegranskat)abstract
- To further explore the extent of structural large-scale variation in the human genome, we assessed copy number variations (CNVs) in a series of 71 healthy subjects from three ethnic groups. CNVs were analyzed using comparative genomic hybridization (CGH) to a BAC array covering the human genome, using DNA extracted from peripheral blood, thus avoiding any culture-induced rearrangements. By applying a newly developed computational algorithm based on Hidden Markov modeling, we identified 1,078 autosomal CNVs, including at least two neighboring/overlapping BACs, which represent 315 distinct regions. The average size of the sequence polymorphisms was approximately 350 kb and involved in total approximately 117 Mb or approximately 3.5% of the genome. Gains were about four times more common than deletions, and segmental duplications (SDs) were overrepresented, especially in larger deletion variants. This strengthens the notion that SDs often define hotspots of chromosomal rearrangements. Over 60% of the identified autosomal rearrangements match previously reported CNVs, recognized with various platforms. However, results from chromosome X do not agree well with the previously annotated CNVs. Furthermore, data from single BACs deviating in copy number suggest that our above estimate of total variation is conservative. This report contributes to the establishment of the common baseline for CNV, which is an important resource in human genetics.
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| 44. |
- Djekic, Demir, 1989-
(författare)
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Novel and Traditional Risk Factors for Coronary Artery Disease : Role of Coronary Artery Calcium, Lipidomics, Psychosocial Factors and Diet
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The aim of the research reported in this thesis was to determine the association of novel and traditional risk factors with coronary artery calcium (CAC), a marker of subclinical coronary artery disease (CAD) in healthy individuals. In addition, we investigated the effects of a vegetarian, compared to a meat diet, on novel and traditional risk factors in patients with diagnosed CAD.Methods: Studies I-II evaluated the inter-laboratory reproducibility of liquid chromatography-mass spectrometry (LC-MS) lipid analysis and the association of serum lipidome with CAC in a cohort of 70 patients. Studies III and IV analysed data of 1067 participants in the pilot study of the Swedish CArdioPulmonary bioImage Study to determine associations of psychosocial (residential area, education, housing, and social support) and traditional risk factors with CAC. Cardiac computed tomography was used to obtain a coronary artery calcium score (CACS) (Studies I–IV). Study V employed a crossover design in which 31 patients with CAD were randomly allocated to a four-week vegetarian diet alternating with four weeks of an isocaloric meat diet. Enzyme-linked immunosorbent assay was used to measure oxidised LDL-cholesterol. Plasma metabolome, including choline, trimethylamine N-oxide, L-carnitine, and acetyl-carnitine, as well as plasma lipidome were determined with LC-MS. Gut microbiota and faecal short- and branched-chain fatty acids were analysed with 16S rRNA gene sequencing and gas chromatography-MS, respectively.Results: In Study I, two laboratories independently identified six lipids in common that differentiated serum of patients with CACS >250 from that of those with CACS=0. Study II, revealed higher levels of phosphatidylcholine(PC)(16:0/20:4) and lower levels of PC(18:2/18:2), PC(36:3) and phosphatidylethanolamine (PE)(20:0/18:2) in patients with CACS >250 than found in those with CACS=0. Study III showed a CACS >0 prevalence of 46.3% and 36.6% in low and high socioeconomic residential areas, respectively, but the traditional risk factor–adjusted odds ratio for CACS >0 was not significantly higher in subjects living in low socioeconomic areas. In Study III, the traditional risk factor–adjusted odds ratio for CACS >100 relative to CACS=0 was significantly higher in women with low education level and living in a rented apartment. Studies III and IV showed traditional risk factor–adjusted odds ratios for CACS >0 to be significantly higher in women with a family history of premature cardiovascular disease and low social support. No relationship of psychosocial factors with CAC was observed in men. The vegetarian diet implemented in Study V significantly lowered mean oxidized LDL-cholesterol (-2.73 U/L), total cholesterol (-0.13 mmol/L), LDL-cholesterol (-0.10 mmol/L), and body mass index (-0.21 kg/m2), as well as the relative abundance of PCs, PEs, and several microbial genera compared with the meat diet. The effect of the vegetarian diet on oxidized LDL-C was associated with higher relative abundance of Ruminococcaceae genera and of Barnesiella and reduced abundance of Flavonifractor. The vegetarian diet lowered the relative abundance of ceramide(d18:1/16:0) and triacylglycerols with saturated fatty acyl chains and raised the relative abundance of triacylglycerols with high carbon and polyunsaturated fatty acyl chains compared with the meat diet.Conclusions: Novel and traditional cardiovascular risk factors are associated with subclinical CAD. Psychosocial factors are associated with subclinical CAD in women, but not in men. Short-term intervention with a vegetarian diet in individuals with CAD can positively impact novel and traditional factors that have been associated with risk of future cardiovascular events.
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| 45. |
- Eggers, Kai M., 1962-, et al.
(författare)
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Combining different biochemical markers of myocardial ischemia does not improve risk stratification in chest pain patients compared to troponin I alone
- 2005
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Ingår i: Coronary Artery Disease. - : Ovid Technologies (Wolters Kluwer Health). - 0954-6928 .- 1473-5830. ; 16:5, s. 315-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Early evaluation of patients with chest pain is important not only for the detection of acute myocardial infarction (AMI) but also for identification of patients at high risk for future cardiac events. A multimarker strategy applying results of early measurements of different biochemical markers of cardiac necrosis in combination may improve risk prediction in chest pain patients. METHODS: Rapid measurements of troponin I (TnI), creatine kinase MB and myoglobin were performed in 191 consecutive patients with chest pain and a non-diagnostic electrocardiogram for AMI. The prognostic value of these markers and different multimarker strategies was evaluated and compared. RESULTS: Ten (5.2%) patients died during follow-up, which for eight (4.2%) patients was due to cardiac causes. Myocardial reinfarctions occurred in 17 (6.8%) patients. TnI was most predictive for cardiac mortality (TnI>or=0.1 microg/l, 10.7% event rate compared with TnI<0.1 microg/l, 0%, P<0.001) and myocardial reinfarction (14.9% compared with 1.7%, P<0.001). The other markers and multimarker strategies had a lower capacity for predicting adverse events apart from myoglobin and the combination of TnI or myoglobin regarding the endpoint of total mortality. CONCLUSION: The combinations of different markers were prognostically non-superior compared to TnI, which thus, should be preferred as a biochemical marker for risk stratification in patients with chest pain.
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| 46. |
- Eggers, Kai M., 1962-, et al.
(författare)
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Risk prediction in patients with chest pain : early assessment by the combination of troponin I results and electrocardiographic findings
- 2005
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Ingår i: Coronary Artery Disease. - : Ovid Technologies (Wolters Kluwer Health). - 0954-6928 .- 1473-5830. ; 16:3, s. 181-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate the prognostic value of point of care troponin I (TnI) results in combination with findings from the admission electrocardiogram (ECG) in patients with chest pain. METHODS: Rapid measurements of TnI were performed in 191 consecutive patients with chest pain and a non-diagnostic ECG for myocardial infarction. RESULTS: Within 6 h from admission, maximum TnI elevations of > or = 0.07 microg/l and > or = 0.1 microg/l were noted in 59 and 39% of all patients, respectively. TnI elevations in the range of 0.07-0.09 microg/l were found in many patients with diagnoses other than acute coronary syndrome. By 6-month follow-up, cardiac death had occurred in 7.1 and 11% of patients with maximum TnI > or = 0.07 microg/l and > or = 0.1 microg/l, respectively and myocardial reinfarction was documented in 12 and 15%, respectively. ST-segment depression on the admission ECG was present in 16% of all patients and was the electrocardiographic abnormality with the highest risk (cardiac death 7.7%, myocardial reinfarction 15%). The combination of TnI > or = 0.1 microg/l and ST-segment depression or an abnormal admission ECG in general allowed the identification of patients at low, intermediate and high cardiac risk, 3 h after admission. CONCLUSION: A threshold of TnI > or = 0.1 microg/l corresponding to the 10% coefficient of variation is prognostically most suitable for prediction of cardiac events in patients with chest pain. The combination of TnI results and findings from the admission ECG improves prognostic assessment and allows early and reliable risk stratification in this patient population.
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| 47. |
- Ek, Sara, et al.
(författare)
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Gene expression profiling of mantle cell lymphonas
- 2003
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Ingår i: Immunology Letters (Abstracts of the 15th European Immunology Congress (EFIS 2003)). - 0165-2478 .- 1879-0542. ; 87:1-3, s. 01-24
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 48. |
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| 49. |
- Green, Anna, 1973-, et al.
(författare)
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Copy number variants in familial hypercholesterolemia genes using targeted NGS, validated through optical genome mapping
- 2024
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Ingår i: European Journal of Human Genetics. - : Nature Portfolio. - 1018-4813 .- 1476-5438. ; 32:Suppl. 1, s. 159-159
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background/Objectives: Familial hypercholesterolemia (FH) is a common genetic disorder which is primarily caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. Approximately 10% of pathogenic variants in LDLR may be CNVs. Here, we combine NGS, MLPA, and Optical Genome Mapping (OGM) to investigate CNVs in LDLR.Methods: A NGS panel was designed for whole gene sequencing (8 genes) of 100 FH patients using Twist technology and Illumina platform. CNVs were detected using CNVexpo, and an in-house pipeline for base-resolved normalized coverage. Identified CNVs were validated using MLPA and OGM. Bionano Services Lab performed the OGM procedure. Purified gDNA was labeled using Direct Label and Stain DNA Labeling Kit. Saphyr chip was run aiming for 100X coverage. De novo assembly and Variant Annotation pipelines were executed on Bionano Solve v3.7. Bionano Access v1.7 was used for CNV reporting and visualization.Results: In five out of 100 samples NGS and MLPA data showed heterozygous deletions in LDLR. Three deletions, affecting different exons, was analyzed and confirmed using OGM. In two samples, OGM better defined the breakpoints as well as the size of the event, which expanded far beyond the gene of interest. In one sample, an additional CNV of SLCO1B1, a pharmaco-gene, important for transport of statins used for FH treatment was identified.Conclusion: CNVs in FH genes in FH patients could be detected using targeted NGS, which was further confirmed by MLPA and characterized using OGM.
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| 50. |
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