| 1. |
- Anney, Richard, et al.
(författare)
-
A genome-wide scan for common alleles affecting risk for autism.
- 2010
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
-
Tidskriftsartikel (refereegranskat)abstract
- Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
|
|
| 2. |
- Anney, Richard, et al.
(författare)
-
Individual common variants exert weak effects on the risk for autism spectrum disorders.
- 2012
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:21, s. 4781-92
-
Tidskriftsartikel (refereegranskat)abstract
- While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASD), the contribution of common variation to ASD risk is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating association of individual SNPs, we also sought evidence that common variants, en masse, might affect risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest p-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. By contrast, allele-scores derived from the transmission of common alleles to Stage 1 cases significantly predict case-status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele-score results, it is reasonable to conclude that common variants affect ASD risk but their individual effects are modest.
|
|
| 3. |
- Casey, Jillian P, et al.
(författare)
-
A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
- 2012
-
Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:4, s. 565-579
-
Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
|
|
| 4. |
- Damén, Tor, et al.
(författare)
-
Effects of different mean arterial pressure targets on plasma volume, ANP and glycocalyx-A randomized trial.
- 2021
-
Ingår i: Acta anaesthesiologica Scandinavica. - : Wiley. - 1399-6576 .- 0001-5172. ; 65:2, s. 220-227
-
Tidskriftsartikel (refereegranskat)abstract
- Arterial haematocrit (Hct) has been shown to decrease after anaesthesia induction, most probably because of an increased plasma volume (PV). The primary objective was to quantify change in PV if mean arterial pressure (MAP) was kept at baseline level or allowed to decrease to 60mm Hg. Our secondary objective was to evaluate underlying mechanisms of this response.Twenty-four coronary artery bypass patients were randomized to a higher (90mm Hg, intervention group) or lower (60mm Hg, control group) MAP by titration of norepinephrine. During the experimental procedure, no fluids were administered. Baseline PV was measured by 125 I-albumin and the change in PV was calculated from the change in Hct. Changes in MAP, plasma 125 I-albumin, colloid osmotic pressure, albumin, Mid Regional-pro Atrial Natriuretic Peptide (MR-proANP) and endothelial glycocalyx components were measured from baseline to 50minutes after anaesthesia induction.The MAP during the trial was 93±9mm Hg in the intervention group and 62±5mm Hg in the control group. PV increased with up to 420±180mL in the control group and 45±130mL in the intervention group (P<.001). Albumin and colloid osmotic pressure decreased significantly more in the control group. MR-proANP increased in the control group but no shedding of the glycocalyx layer was detected in either of the groups.Allowing mean arterial pressure to fall to 60mm Hg during anaesthesia induction, increases the plasma volume due to reabsorption of interstitial water, with no ANP-induced degradation of the endothelial glycocalyx.
|
|
| 5. |
- Gullbo, Joachim, et al.
(författare)
-
Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo.
- 2004
-
Ingår i: Investigational new drugs. - 0167-6997. ; 22:4, s. 411-20
-
Tidskriftsartikel (refereegranskat)abstract
- The novel alkylating dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) was evaluated for acute toxicity and antitumor activity in mice, with melphalan as a reference. To determine a safe and tolerable dose for efficacy studies the acute toxicity following intravenous injection in the tail vein was monitored using a 14-day schedule with up to four doses. The highest tested dose, 25 micromoles/kg, was considered close to this level, with minor effects on body weight gain but significant effects on hematological parameters. Melphalan and J1 appeared equitoxic with no statistically significant differences. Subsequently a mouse hollow fiber model was employed with subcutaneous implantation of fibers containing human tumor cells. Three different human tumor cell lines as well as two samples of primary human tumor cells (ovarian carcinoma and chronic lymphatic leukemia) were used as tumor models. At the dose level tested there was a marked and statistically significant decrease in both T-cell leukemia CCRF-CEM and small cell lung cancer NCI-H69 tumor cell growth and viability in response to J1 as compared with both placebo and melphalan treated groups. In primary ovarian carcinoma cells only J1 treatment resulted in significant tumor regression (net cell kill). In summary the results indicate that, despite an expected short half time in the blood circulation, the promising in vitro data from the previous studies of J1 seems translatable into the in vivo situation. At equal doses of alkylating units J1, compared to melphalan, was more active in the mouse hollow-fiber model, but showed similar general toxicity.
|
|
| 6. |
- Malmberg, Per, 1974, et al.
(författare)
-
Imaging of lipids in human adipose tissue by cluster ion TOF-SIMS
- 2007
-
Ingår i: Microsc Res Tech. - : Wiley. - 1059-910X .- 1097-0029. ; 70:9, s. 828-35
-
Tidskriftsartikel (refereegranskat)abstract
- Biopsies of human subcutaneous adipose tissue were taken from healthy donors. Samples were high-pressure frozen, freeze-fractured, and freeze dried. Imaging mass spectrometry of samples was performed in a TOF-SIMS mass spectrometer equipped with a bismuth cluster ion source. Blood vessels, the connective tissue, and adipocytes can be seen in TOF-SIMS images. Blood vessels were found labeled by a high content of sodium ions and potassium ions in their lumen and phosphocholine signal in smooth muscle cells of the vessel wall. The connective tissue showed high signal levels of CN(-) fragments, derived from proteins and nucleic acids. Adipocytes showed high signal levels of phosphocholine and cholesterol ubiquitously in their membranes and diacylglycerols in some membrane sites. The central part of adipocytes showed high levels of triacylglycerols and fatty acids. These results are in accordance to those of biochemical studies; however, a precise spatial localization of lipids in adipocytes is demonstrated with MS imaging.
|
|
| 7. |
- Malmberg, Per, 1974, et al.
(författare)
-
Localization of lipids in the aortic wall with imaging TOF-SIMS
- 2007
-
Ingår i: Biochim Biophys Acta. - 0006-3002. ; 1771:2, s. 185-95
-
Tidskriftsartikel (refereegranskat)abstract
- Time-of-flight secondary-ion-mass-spectrometry (TOF-SIMS) was utilized to address the issue of localization of lipids and inorganic ions in healthy rat aorta and human atherosclerotic plaque. Pieces of rat aorta were high pressure frozen, freeze-fractured and freeze dried. The samples were analyzed by imaging TOF-SIMS equipped with a Bi(1-7)(+)-source. Reference lipid samples were analyzed and compared to data obtained by analysis of the rat aorta samples. Fatty acids, cholesterol, oxysterol and diacylglycerols were detected and localized. A heterogeneous lipid distribution could be shown in the aorta, where the lamellae of the aorta, distinguished by imaging of CN(-), appeared enriched in cholesterol, oxysterol and diacylglycerols, while the smooth muscle tissue, identified by imaging of PO(3), appeared enriched in phosphocholine. Palmitic/palmitoleic acid and stearic/oleic acid appeared to be heterogeneously distributed over the aorta with high concentration areas located especially in the tunica media region of the aorta. Human atherosclerotic plaque showed an irregular cholesterol distribution mainly located in spots in the intima region with elongated diacylglycerol regions located mainly in the media region.
|
|
| 8. |
- Malmberg, Per, 1974, et al.
(författare)
-
Subcellular localisation of cholesterol and phosphocholine with pattern-recognition-imaging-TOF-SIMS
- 2004
-
Ingår i: Spectroscopy. ; 18:4, s. 503-512
-
Tidskriftsartikel (refereegranskat)abstract
- Molecular ions of cholesterol, and its fragments, and phosphocholine fragments of phospholipids, were localized in single cells with a resolution of <1 μm. This is the first example of subcellular localisation of membrane lipids with pattern-recognition, imaging time-of-flight secondary ion mass spectrometry (PRITS) here utilized for identification and subcellular localisation of cholesterol and phosphocholine in PMN leukocytes. Cell imprints were produced by transferring the cell constituents of freeze-dried cells to a silver foil, and the silver surface was analyzed by TOF-SIMS. TOF-SIMS spectra were recorded by scanning the primary ion beam over the analysis area and acquiring a positive mass spectrum of the ions leaving the surface. Data were collected at either high mass resolution m/Δm>7000 or high lateral resolution. High mass resolution spectra were recorded on reference samples of pure cholesterol and phosphatidylcholine. Characteristic fragment peaks and the silver cationised quasimolecular ion [M+Ag]+ were selected as a pattern for the identification of the lipids in TOF-SIMS images of surface-adhering leukocytes. The localisation of membrane lipids showed lateral heterogeneity over the cell surface.
|
|
| 9. |
- Malmstroem, Nina, et al.
(författare)
-
Living with a parent with ALS-adolescents' need for professional support from the adolescents' and the parents' perspectives
- 2023
-
Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 24:7-8, s. 727-735
-
Tidskriftsartikel (refereegranskat)abstract
- AimThe aim of the study was to qualitatively investigate the adolescents' need for professional support when a parent has amyotrophic lateral sclerosis (ALS) - from the adolescents' and the parents' perspectives.MethodsA total of 37 individual semi-structured single interviews with 18 families were conducted, including 11 adolescents aged 8-25 and 26 parents, 13 with ALS and 13 co-parents. Data was analysed using qualitative content analysis.ResultsBoth adolescents and parents described the adolescents as needing professional support but found it difficult to articulate this need. However, the results indicate that the adolescents needed help in bringing manageability into their lives due to the uncertainty of living with the illness in the family. It was therefore essential to ensure that the adolescents were not forgotten in the disease context and that their needs for being involved as well as for obtaining information and understanding, was addressed. The importance of offering the adolescents support early was emphasized, but also of actively helping the families to master challenges in their everyday life. Support adapted to each family's unique situation and preferences was desired, as the adolescents' need for support seemed to be individual, disease-dependent and varied during different phases.ConclusionGiven the adolescents' need for information and understanding, healthcare professionals must actively work to reach the adolescents as early as possible. It is crucial to ensure that the adolescents are given the opportunity to be involved based on their own conditions, as well as to support the families to strengthen their communication.
|
|
| 10. |
- Malmström, Nina, et al.
(författare)
-
Adolescents' challenging and grief-filled transitions when living with a parent with ALS: A qualitative interpretive study
- 2024
-
Ingår i: SOCIAL SCIENCE & MEDICINE. - : Elsevier. - 0277-9536 .- 1873-5347. ; 354
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The study aimed to explore the meaning for adolescents of living with a parent with amyotrophic lateral sclerosis (ALS). Methods: The design is qualitative. Interviews were conducted between December 2020 and April 2022 with 11 adolescents (8-25 y), living in households with a parent with ALS in Sweden. The analysis was phenomenologically hermeneutical. Results: The adolescents were in a difficult and exposed situation, especially if the parent had a severe disability and assistant care providers were in the home. Witnessing the gradual loss of the parent in an indefinite battle against time, while still needing them, elicited grief-filled and hard-to-manage emotions. Everyday life was turned upside down, resulting in greater responsibility for the adolescents, not only in helping with household chores and assisting the ill parent, but also in emotionally protecting both parents. It forced the adolescents to mature faster and put their own life on hold, triggering experiences of being limited. This, together with changing family roles yet being more attached to home, reinforced the imbalance in the adolescents' lives. The interpreted whole of the adolescents' narratives revealed that living with a parent with ALS meant a challenging and grieving transition during an already transition-filled adolescence, which left the adolescents struggling to keep a foothold on a life torn apart. Conclusion: The unbalanced life situation may hinder the adolescents' identity formation and emancipation, which are developmentally important for managing a healthy and independent adulthood. The results emphasize the importance of early targeted support to reach this vulnerable group in order to secure their health.
|
|
