| 1. |
- Michelet, Mona, et al.
(författare)
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Associations between unmet needs for daytime activities and company and scores on the Neuropsychiatric Inventory-Questionnaire in people with dementia : a longitudinal study
- 2021
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Ingår i: Aging & Mental Health. - : Informa UK Limited. - 1360-7863 .- 1364-6915. ; 26:4, s. 725-734
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES To examine prospectively the association between unmet needs for daytime activities and company and behavioural and psychological symptoms of dementia.METHODS We included 451 people with mild or moderate dementia, from eight European countries, who were assessed three times over 12 months. Unmet needs were measured with the Camberwell Assessment of Need for the Elderly. Three sub-syndromes of the Neuropsychiatric Inventory-Questionnaire were regressed, one-by-one, against unmet needs for daytime activities and company, adjusting for demographic and clinical-functional covariates.RESULTS Unmet needs for daytime activities were associated with more affective symptoms at baseline, six and twelve months, mean 0.74 (p < 0.001), 0.76 (p < 0.001) and 0.78 (p = 0.001) points higher score respectively, and with more psychotic symptoms at baseline (mean 0.39 points, p = 0.007) and at six months follow-up (mean 0.31 points, p = 0.006). Unmet needs for company were associated with more affective symptoms at baseline, six and twelve months, mean 0.44 (p = 0.033), 0.67 (p < 0.001) and 0.91 (p < 0.001) points higher score respectively, and with more psychotic symptoms at baseline (mean 0.40 points, p = 0.005) and at six months (mean 0.35 points, p = 0.002) follow-up.CONCLUSION Interventions to reduce unmet needs for daytime activities and company could reduce affective and psychotic symptoms in people with dementia.
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| 2. |
- Argiropoulos, Bob, et al.
(författare)
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Linkage of the potent leukemogenic activity of Meis1 to cell-cycle entry and transcriptional regulation of cyclin D3.
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 115:20, s. 4071-82
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Tidskriftsartikel (refereegranskat)abstract
- MEIS1 is a three-amino acid loop extension class homeodomain-containing homeobox (HOX) cofactor that plays key roles in normal hematopoiesis and leukemogenesis. Expression of Meis1 is rate-limiting in MLL-associated leukemias and potently interacts with Hox and NUP98-HOX genes in leukemic transformation to promote self-renewal and proliferation of hematopoietic progenitors. The oncogenicity of MEIS1 has been linked to its transcriptional activation properties. To further reveal the pathways triggered by Meis1, we assessed the function of a novel engineered fusion form of Meis1, M33-MEIS1, designed to confer transcriptional repression to Meis1 target genes that are otherwise up-regulated in normal and malignant hematopoiesis. Retroviral overexpression of M33-Meis1 resulted in the rapid and complete eradication of M33-Meis1-transduced normal and leukemic cells in vivo. Cell-cycle analysis showed that M33-Meis1 impeded the progression of cells from G(1)-to-S phase, which correlated with significant reduction of cyclin D3 levels and the inhibition of retinoblastoma (pRb) hyperphosphorylation. We identified cyclin D3 as a direct downstream target of MEIS1 and M33-MEIS1 and showed that the G(1)-phase accumulation and growth suppression induced by M33-Meis1 was partially relieved by overexpression of cyclin D3. This study provides strong evidence linking the growth-promoting activities of Meis1 to the cyclin D-pRb cell-cycle control pathway.
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| 3. |
- Olsson, Bob, 1969, et al.
(författare)
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Cerebrospinal Fluid Levels of Heart Fatty Acid Binding Protein are Elevated Prodromally in Alzheimer's Disease and Vascular Dementia
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 34:3, s. 673-679
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Tidskriftsartikel (refereegranskat)abstract
- Heart fatty acid binding protein (HFABP) is expressed in the brain and is elevated in cerebrospinal fluid (CSF) from patients with several forms of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease with dementia, Lewy body dementia, vascular dementia (VaD), and Creutzfeldt-Jakob disease. However, whether HFABP in CSF is a stable biomarker or if it can help predict conversion from mild cognitive impairment (MCI) to AD or VaD has not been well studied. To address the role of HFABP in neurodegeneration, we analyzed CSF levels of HFABP in 96 AD patients and 65 controls and also in 170 patients with MCI with an average follow up time of 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six month interval in between. HFABP levels in CSF were very stable over the six month period (r = 0.93, p < 0.001). Furthermore, the CSF levels of HFABP were significantly elevated in AD compared with controls after adjustments for age and gender (p < 0.001). They were also elevated in the patients with MCI that subsequently converted to AD or VaD compared with those that remained stable (p < 0.001 and p < 0.05, respectively). However, ROC curve analysis showed that HFABP had lesser predictive value in determining conversion from MCI to AD and VaD than A beta(42), t-tau, and p-tau. In conclusion, HFABP seems to be a stable CSF biomarker that reflects neuronal cell death in several neurodegenerative disorders, including early stages of AD and VaD.
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| 4. |
- Argiropoulos, Bob, et al.
(författare)
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Linkage of Meis1 leukemogenic activity to multiple downstream effectors including Trib2 and Ccl3.
- 2008
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Ingår i: Experimental hematology. - : Elsevier BV. - 0301-472X. ; 36:7, s. 845-59
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: MEIS1, a HOX cofactor, collaborates with multiple HOX and NUP98-HOX fusion proteins to accelerate the onset of acute myeloid leukemia (AML) through largely unknown molecular mechanisms. MATERIALS AND METHODS: To further resolve these mechanisms, we conducted a structure-function analysis of MEIS1 and gene-expression profiling, in the context of NUP98-HOXD13 (ND13) leukemogenesis. RESULTS: We show, in a murine bone marrow transplantation model, that the PBX-interaction domain, the homeodomain, and the C-terminal domain of MEIS1, are all required for leukemogenic collaboration with ND13. In contrast, the N-terminal domain of MEIS1 is dispensable for collaboration with ND13, but is required for Flt3 upregulation, indicating additional roles for MEIS1 in induction of leukemia independent of alterations in Flt3 expression. Gene-expression profiling of a cloned ND13 preleukemic cell line transduced with wild-type or Meis1 mutant forms revealed deregulation of multiple genes, including a set not previously implicated as MEIS1 targets. Chromatin immunoprecipitation revealed the in vivo occupancy of MEIS1 on regulatory sequences of Trib2, Flt3, Dlk1, Ccl3, Ccl4, Pf4, and Rgs1. Furthermore, engineered overexpression of Trib2 complements ND13 to induce AML while Ccl3 potentiates the repopulating ability of ND13. CONCLUSION: This study shows that Meis1-induced leukemogenesis with ND13 can occur in the absence of Flt3 upregulation and reveals the existence of other pathways activated by MEIS1 to promote leukemia.
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| 5. |
- Löwenberg, Bob, et al.
(författare)
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Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML : the HOVON-SAKK-132 trial
- 2021
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 5:4, s. 1110-1121
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Tidskriftsartikel (refereegranskat)abstract
- Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)-adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% +/- 2% standard error and overall survival, 54% = 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.
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| 6. |
- Olsson, Bob, 1969, et al.
(författare)
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The glial marker YKL-40 is decreased in synucleinopathies.
- 2013
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Ingår i: Movement disorders : official journal of the Movement Disorder Society. - : Wiley. - 1531-8257. ; 28:14, s. 1882-1885
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Tidskriftsartikel (refereegranskat)abstract
- Microglia are resident immunosurveillant cells in the central nervous system, and astrocytes are important for blood flow, plasticity, and neurotransmitter regulation. The aim of this study was to investigate whether astrocyte and microglial activation, estimated through markers in cerebrospinal fluid and serum, differed between synucleinopathies, tauopathies, and controls.
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| 7. |
- Saxena, Richa, et al.
(författare)
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Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
- 2007
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5829, s. 1331-1336
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Tidskriftsartikel (refereegranskat)abstract
- New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 - and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
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| 8. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Cerebrospinal Fluid Microglial Markers in Alzheimer's Disease: Elevated Chitotriosidase Activity but Lack of Diagnostic Utility
- 2011
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Ingår i: NeuroMolecular Medicine. - : Springer Science and Business Media LLC. - 1535-1084 .- 1559-1174. ; 13:2, s. 151-159
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Tidskriftsartikel (refereegranskat)abstract
- Activated microglial cells, which are the resident macrophages of the central nervous system, surround amyloid beta-plaques in Alzheimer's disease (AD) brains. Inflammation including microglial activation may contribute in AD pathogenesis, and biomarkers for this process may thus be of value to study AD pathogenesis and might facilitate development of therapies targeting these cells. We therefore examined cerebrospinal fluid (CSF) biomarkers in patients with AD, other dementias, mild cognitive impairment and in healthy controls. Samples were analyzed for markers with known association to macrophage activity, including chitotriosidase, YKL-40 (CHI3L1, HC gp-39) and chemokine CC motif ligand 2 (CCL2, MCP1). Patients with AD had higher chitotriosidase activity than controls and patients with stable mild cognitive impairment, consistent with the presence of activated microglial cells in AD brains, but with large overlaps between groups. CCL2 and YKL-40 concentrations did not differ among groups. Microglial markers are unlikely to be useful for AD diagnosis, but might be useful for identification of distinct subgroups of patients, and for the development and implementation of drugs targeting microglial pathology.
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| 9. |
- Olsson, Bob, 1969, et al.
(författare)
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Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura.
- 2005
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Ingår i: Thrombosis and haemostasis. - 0340-6245. ; 93:1, s. 139-44
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic thrombocytopenic purpura (ITP) is an organ specific autoimmune disorder in which T-lymphocyte abnormalities have pathogenetic importance. In a DNA microarray screen of CD3+ T-lymphocytes from ITP patients and healthy controls we found an altered expression of genes associated with apoptosis, e.g. A20, caspase-8 and Bax. This together with our previous findings of increased gene expression of Fas, interferon-g and IL-2 receptor beta (IL2RB) indicated an altered activation induced cell death (AICD) of T-cells in ITP. Using a proliferation assay we found that CD3+ lymphocytes from ITP patients were significantly more resistant to dexamethasone induced suppression compared to normal lymphocytes. We also found that cultured CD3+ lymphocytes from ITP patients in remission were more susceptible to apoptosis both in the presence and absence of dexamethasone compared to cells from patient with active ITP and healthy controls, as indicated by increased staining of AnnexinV binding. Our findings suggest that apoptotic resistance of activated T-lymphocytes in patients with active ITP may lead to defective clearance of autoreactive T-lymphocytes through AICD, which might cause a continued immune destruction of platelets. Conversely, a loss of resistance to AICD in ITP patients in remission might be an important mechanism for the achievement of remission.
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| 10. |
- Olsson, Bob, 1969, et al.
(författare)
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Microglial markers are elevated in the prodromal phase of Alzheimer's disease and vascular dementia.
- 2013
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908 .- 1387-2877. ; 33:1, s. 45-53
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Tidskriftsartikel (refereegranskat)abstract
- Microglia manage immunosurveillance and mediate inflammation, both suggested to be important in Alzheimer's disease (AD). The aim of this study was to investigate if microglial markers could differentiate, firstly between AD and controls, and secondly between stable mild cognitive impairment (MCI) and those progressing to AD and vascular dementia (VaD). Furthermore, we investigated if these markers were sufficiently stable to be used in clinical trials. We quantified YKL-40 and sCD14 in cerebrospinal fluid (CSF) from 96 AD patients, 65 healthy controls, and 170 patients with MCI from baseline and over 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six-month interval in between. YKL-40, but not sCD14, was significantly elevated in AD compared with healthy controls (p = 0.003). Furthermore, YKL-40 and sCD14 were increased in MCI patients who converted to VaD (p = 0.029 and p = 0.008), but not to AD according to NINCDS-ADRDA. However, when stratified according to CSF levels of tau and Aβ42, YKL-40 was elevated in those with an AD-indicative profile compared with stable MCI with a normal profile (p = 0.037). In addition, YKL-40 and sCD14 were very stable in AD patients with good correlation between time-points (r = 0.94, p = 3.4 × 10-25; r = 0.77, p = 2.0 × 10-11) and the cortical damage marker T-tau. Thus, microglial markers are stable and may be used as safety markers for monitoring CNS inflammation and microglia activation in clinical trials. Moreover, YKL-40 differentiates between AD and controls and between stable MCI to AD and those that convert to AD and VaD.
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