| 51. |
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| 52. |
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| 53. |
- Eriksson, Olof, et al.
(author)
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Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates
- 2019
-
In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 14960-
-
Journal article (peer-reviewed)abstract
- The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [68Ga]Ga-DO3A-S01-GCG as a biomarker for GCGR occupancy in liver, the tissue with highest GCGR expression, in non-human primates (NHP) by PET. [68Ga]Ga-DO3A-S01-GCG was evaluated by dynamic PET in NHPs by a dose escalation study design, where up to 67 µg/kg DO3A-S01-GCG peptide mass was co-injected. The test-retest reproducibility of [68Ga]Ga-DO3A-S01-GCG binding in liver was evaluated. Furthermore, we investigated the effect of pre-treatment with acylated glucagon agonist 1-GCG on [68Ga]Ga-DO3A-S01-GCG binding in liver. [68Ga]Ga-DO3A-S01-GCG bound to liver in vivo in a dose-dependent manner. Negligible peptide mass effect was observed for DO3A-S01-GCG doses <0.2 µg/kg. In vivo Kd for [68Ga]Ga-DO3A-S01-GCG corresponded to 0.7 µg/kg, which indicates high potency. The test-retest reproducibility for [68Ga]Ga-DO3A-S01-GCG binding in liver was 5.7 ± 7.9%. Pre-treatment with 1-GCG, an acylated glucagon agonist, resulted in a GCGR occupancy of 61.5 ± 9.1% in liver. Predicted human radiation dosimetry would allow for repeated annual [68Ga]Ga-DO3A-S01-GCG PET examinations. In summary, PET radioligand [68Ga]Ga-DO3A-S01-GCG is a quantitative biomarker of in vivo GCGR occupancy.
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| 54. |
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| 55. |
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| 56. |
- Laitinen, MH, et al.
(author)
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Fat intake at midlife and risk of dementia and Alzheimer's disease: a population-based study
- 2006
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In: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 22:1, s. 99-107
-
Journal article (peer-reviewed)abstract
- <i>Background:</i> Lifestyle and vascular factors have been linked to dementia and Alzheimer’s disease (AD), but the role of dietary fats in the development of dementia is less clear. <i>Methods:</i> Participants were derived from random, population-based samples initially studied in midlife (1972, 1977, 1982, or 1987). Fat intake from spreads and milk products was assessed using a structured questionnaire and an interview. After an average follow-up of 21 years, a total of 1,449 (73%) individuals aged 65–80 years participated in the re-examination in 1998. Altogether 117 persons had dementia. <i>Results: </i>Moderate intake of polyunsaturated fats at midlife decreased the risk of dementia even after adjustment for demographic variables, other subtypes of fats, vascular risk factors and disorders, and apolipoprotein E (ApoE) genotype (OR 0.40, CI 0.17–0.94 for the 2nd quartile vs. 1st quartile), whereas saturated fat intake was associated with an increased risk (OR 2.45, CI 1.10–5.47 for the 2nd quartile). The associations were seen only among the ApoE Ε4 carriers. <i>Conclusions:</i> Moderate intake of unsaturated fats at midlife is protective, whereas a moderate intake of saturated fats may increase the risk of dementia and AD, especially among ApoE Ε4 carriers. Thus, dietary interventions may potentially modify the risk of dementia, particularly among genetically susceptible individuals.
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| 57. |
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| 58. |
- Linden, M, et al.
(author)
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Airway inflammation in smokers with nonobstructive and obstructive chronic bronchitis
- 1993
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In: The American Review of Respiratory Disease. - 0003-0805. ; 148:5, s. 1226-1232
-
Journal article (peer-reviewed)abstract
- To assess the manifestation and location of airway inflammation in smokers with chronic bronchitis (CB) or chronic obstructive pulmonary disease (COPD), we lavaged the airways of 12 smokers with CB and 11 smokers with COPD and coexisting CB (OCB). For comparison, the airways of 5 asymptomatic smokers (AS) and 10 healthy nonsmokers (HNS) were lavaged. In all cases, the first lavage aliquot, labeled "bronchial lavage" (BL), was processed separately from the four subsequent aliquots, which were combined and labeled "bronchoalveolar lavage" (BAL). The composition of BL and BAL fluids indicate an ongoing inflammatory process in the airways of all three groups of smokers. CB patients with obstruction had significantly lower concentrations of inflammatory cells in the BL and BAL fluids compared with subjects with nonobstructed CB. Furthermore, airway obstruction, indicated by a reduced FEV1, was significantly correlated with the concentrations of glutathione (p < 0.001), myeloperoxidase (MPO; p < 0.01), and eosinophil cationic protein (ECP; p < 0.01) in BAL fluids. Taken together, these findings suggest that the manifestations of inflammation present in the airways of smokers with CB are different in those who have developed obstruction compared with those who have not.
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| 59. |
- Patel, Jayendra Z., et al.
(author)
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Chiral 1,3,4-Oxadiazol-2-ones as Highly Selective FAAH Inhibitors
- 2013
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:21, s. 8484-8496
-
Journal article (peer-reviewed)abstract
- In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in the potency and selectivity toward both FAAH and MAGL. Additionally, the importance of the chirality on the inhibitory activity and selectivity was proven by the simplification approach by removing a methyl group at the 3-position of the 1,3,4-oxadiazol-2-one ring. The most potent compound of the series, the S-enantiomer of 3-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A, Si), inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 mu M), whereas its corresponding R-enantiomer 52 showed only moderate inhibition toward hrFAAH (IC50 = 0.24 mu M). In contrast to hrFAAH, R-enantiomer 52 was more potent in inhibiting the activity of hrMAGL compared to S-enantiomer 51 (IC50 = 4.0 mu M and 16% inhibition at 10 mu M, respectively). The FAAH selectivity of the compound Si over the supposed main off-targets, MAGL and COX, was found to be >900-fold. In addition, activity-based protein profiling (ABPP) indicated high selectivity over other serine hydrolases. Finally, the selected Senantiomers 51, 53, and 55 were shown to be tight binding, slowly reversible inhibitors of the hrFAAH.
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| 60. |
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| 61. |
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| 62. |
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| 63. |
- Qi, QB, et al.
(author)
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Dietary Intake, FTO Genetic Variants, and Adiposity: A Combined Analysis of Over 16,000 Children and Adolescents
- 2015
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 64:7, s. 2467-2476
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Journal article (peer-reviewed)abstract
- The FTO gene harbors variation with the strongest effect on adiposity and obesity risk. Previous data support a role for FTO variation in influencing food intake. We conducted a combined analysis of 16,094 boys and girls aged 1–18 years from 14 studies to examine the following: 1) the association between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake, and the effect on BMI. We found that the BMI-increasing allele (minor allele) of the FTO variant was associated with increased total energy intake (effect per allele = 14.3 kcal/day [95% CI 5.9, 22.7 kcal/day], P = 6.5 × 10−4), but not with protein, carbohydrate, or fat intake. We also found that protein intake modified the association between the FTO variant and BMI (interactive effect per allele = 0.08 SD [0.03, 0.12 SD], P for interaction = 7.2 × 10−4): the association between FTO genotype and BMI was much stronger in individuals with high protein intake (effect per allele = 0.10 SD [0.07, 0.13 SD], P = 8.2 × 10−10) than in those with low intake (effect per allele = 0.04 SD [0.01, 0.07 SD], P = 0.02). Our results suggest that the FTO variant that confers a predisposition to higher BMI is associated with higher total energy intake, and that lower dietary protein intake attenuates the association between FTO genotype and adiposity in children and adolescents.
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| 64. |
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| 65. |
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| 66. |
- Saarinen, NVV, et al.
(author)
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A novel rat CVB1-VP1 monoclonal antibody 3A6 detects a broad range of enteroviruses
- 2018
-
In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 33-
-
Journal article (peer-reviewed)abstract
- Enteroviruses (EVs) are common RNA viruses that cause diseases ranging from rash to paralytic poliomyelitis. For example, EV-A and EV-C viruses cause hand-foot and mouth disease and EV-B viruses cause encephalitis and myocarditis, which can result in severe morbidity and mortality. While new vaccines and treatments for EVs are under development, methods for studying and diagnosing EV infections are still limited and therefore new diagnostic tools are required. Our aim was to produce and characterize new antibodies that work in multiple applications and detect EVs in tissues and in vitro. Rats were immunized with Coxsackievirus B1 capsid protein VP1 and hybridomas were produced. Hybridoma clones were selected based on their reactivity in different immunoassays. The most promising clone, 3A6, was characterized and it performed well in multiple techniques including ELISA, immunoelectron microscopy, immunocyto- and histochemistry and in Western blotting, detecting EVs in infected cells and tissues. It recognized several EV-Bs and also the EV-C representative Poliovirus 3, making it a broad-spectrum EV specific antibody. The 3A6 rat monoclonal antibody can help to overcome some of the challenges faced with commonly used EV antibodies: it enables simultaneous use of mouse-derived antibodies in double staining and it is useful in murine models.
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| 67. |
- Schumann, Gunter, et al.
(author)
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Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption
- 2011
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:17, s. 7119-7124
-
Journal article (peer-reviewed)abstract
- Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of similar to 2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10(-8) to P = 4 x 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Downregulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.
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| 68. |
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| 69. |
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| 70. |
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| 71. |
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| 72. |
- Cirulli, Elizabeth T., et al.
(author)
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A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury
- 2019
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In: Gastroenterology. - : W B SAUNDERS CO-ELSEVIER INC. - 0016-5085 .- 1528-0012. ; 156:6, s. 1707-1716
-
Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings.RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 x 10(-9) and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 x 10(-6); allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 x 10(-6); allele frequency = 11.5%). Among amoxicillin-and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A* 02: 01 and DRB1* 15: 01.CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
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| 73. |
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| 74. |
- Greco, D, et al.
(author)
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Gene expression in human NAFLD
- 2008
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In: American journal of physiology. Gastrointestinal and liver physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 294:5, s. G1281-G1287
-
Journal article (peer-reviewed)abstract
- Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), little is known of its pathogenesis based on study of human liver samples. By the use of Affymetrix GeneChips (17,601 genes), we investigated gene expression in the human liver of subjects with extreme steatosis due to NAFLD without histological signs of inflammation (liver fat 66.0 ± 6.8%) and in subjects with low liver fat content (6.4 ± 2.7%). The data were analyzed by using sequence-based reannotation of Affymetrix probes and a robust model-based normalization method. We identified genes involved in hepatic glucose and lipid metabolism, insulin signaling, inflammation, coagulation, and cell adhesion to be significantly associated with liver fat content. In addition, genes involved in ceramide signaling (MAP2K4) and metabolism (UGCG) were found to be positively associated with liver fat content. Genes involved in lipid metabolism (PLIN, ACADM), fatty acid transport (FABP4, CD36), amino acid catabolism (BCAT1), and inflammation (CCL2) were validated by real-time PCR and were found to be upregulated in subjects with high liver fat content. The data show that multiple changes in gene expression characterize simple steatosis.
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| 75. |
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| 76. |
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| 77. |
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| 78. |
- Hankaniemi, MM, et al.
(author)
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Structural Insight into CVB3-VLP Non-Adjuvanted Vaccine
- 2020
-
In: Microorganisms. - : MDPI AG. - 2076-2607. ; 8:9
-
Journal article (peer-reviewed)abstract
- Coxsackievirus B (CVB) enteroviruses are common pathogens that can cause acute and chronic myocarditis, dilated cardiomyopathy, aseptic meningitis, and they are hypothesized to be a causal factor in type 1 diabetes. The licensed enterovirus vaccines and those currently in clinical development are traditional inactivated or live attenuated vaccines. Even though these vaccines work well in the prevention of enterovirus diseases, new vaccine technologies, like virus-like particles (VLPs), can offer important advantages in the manufacturing and epitope engineering. We have previously produced VLPs for CVB3 and CVB1 in insect cells. Here, we describe the production of CVB3-VLPs with enhanced production yield and purity using an improved purification method consisting of tangential flow filtration and ion exchange chromatography, which is compatible with industrial scale production. We also resolved the CVB3-VLP structure by Cryo-Electron Microscopy imaging and single particle reconstruction. The VLP diameter is 30.9 nm on average, and it is similar to Coxsackievirus A VLPs and the expanded enterovirus cell-entry intermediate (the 135s particle), which is ~2 nm larger than the mature virion. High neutralizing and total IgG antibody levels, the latter being a predominantly Th2 type (IgG1) phenotype, were detected in C57BL/6J mice immunized with non-adjuvanted CVB3-VLP vaccine. The structural and immunogenic data presented here indicate the potential of this improved methodology to produce highly immunogenic enterovirus VLP-vaccines in the future.
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| 79. |
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| 80. |
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| 81. |
- Hietala, H., et al.
(author)
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Supermagnetosonic Jets behind a Collisionless Quasiparallel Shock
- 2009
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In: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 103:24, s. 245001-
-
Journal article (peer-reviewed)abstract
- The downstream region of a collisionless quasiparallel shock is structured containing bulk flows with high kinetic energy density from a previously unidentified source. We present Cluster multispacecraft measurements of this type of supermagnetosonic jet as well as of a weak secondary shock front within the sheath, that allow us to propose the following generation mechanism for the jets: The local curvature variations inherent to quasiparallel shocks can create fast, deflected jets accompanied by density variations in the downstream region. If the speed of the jet is super(magneto)sonic in the reference frame of the obstacle, a second shock front forms in the sheath closer to the obstacle. Our results can be applied to collisionless quasiparallel shocks in many plasma environments.
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| 82. |
- Hoellein, Alexander, et al.
(author)
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Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma.
- 2014
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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 124:13, s. 2081-90
-
Journal article (peer-reviewed)abstract
- Myc oncogenic transcription factors (c-Myc, N-Myc, and L-Myc) coordinate the control of cell growth, division, and metabolism. In cancer, Myc overexpression is often associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system (eg, SCF(Skp2)-directed destruction of the Cdk inhibitor p27(Kip1)). We reasoned that Myc would also regulate SUMOylation, a related means of posttranslational modification of proteins, and that this circuit would play essential roles in Myc-dependent tumorigenesis. Here, we report marked increases in the expression of genes that encode regulators and components of the SUMOylation machinery in mouse and human Myc-driven lymphomas, resulting in hyper-SUMOylation in these tumors. Further, inhibition of SUMOylation by genetic means disables Myc-induced proliferation, triggering G2/M cell-cycle arrest, polyploidy, and apoptosis. Using genetically defined cell models and conditional expression systems, this response was shown to be Myc specific. Finally, in vivo loss-of-function and pharmacologic studies demonstrated that inhibition of SUMOylation provokes rapid regression of Myc-driven lymphoma. Thus, targeting SUMOylation represents an attractive therapeutic option for lymphomas with MYC involvement.
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| 83. |
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| 84. |
- Jarvela-Reijonen, Elina, et al.
(author)
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The Effects of Acceptance and Commitment Therapy (ACT) Intervention on Inflammation and Stress Biomarkers : a Randomized Controlled Trial
- 2020
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In: International Journal of Behavioral Medicine. - : Springer Science and Business Media LLC. - 1070-5503 .- 1532-7558. ; 27:5, s. 539-555
-
Journal article (peer-reviewed)abstract
- Background Psychological processes can be manifested in physiological health. We investigated whether acceptance and commitment therapy (ACT), targeted on psychological flexibility (PF), influences inflammation and stress biomarkers among working-age adults with psychological distress and overweight/obesity. Method Participants were randomized into three parallel groups: (1) ACT-based face-to-face (n = 65; six group sessions led by a psychologist), (2) ACT-based mobile (n = 73; one group session and mobile app), and (3) control (n = 66; only the measurements). Systemic inflammation and stress markers were analyzed at baseline, at 10 weeks after the baseline (post-intervention), and at 36 weeks after the baseline (follow-up). General PF and weight-related PF were measured with questionnaires (Acceptance and Action Questionnaire, Acceptance and Action Questionnaire for Weight-Related Difficulties). Results A group x time interaction (p = .012) was detected in the high-sensitivity C-reactive protein (hsCRP) level but not in other inflammation and stress biomarkers. hsCRP decreased significantly in the face-to-face group from week 0 to week 36, and at week 36, hsCRP was lower among the participants in the face-to-face group than in the mobile group (p = .035, post hoc test). Age and sex were stronger predictors of biomarker levels at follow-up than the post-intervention PF. Conclusion The results suggest that ACT delivered in group sessions may exert beneficial effects on low-grade systemic inflammation. More research is needed on how to best apply psychological interventions for the health of both mind and body among people with overweight/obesity and psychological distress.
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| 85. |
- Järvelä-Reijonen, Elina, et al.
(author)
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Sleep-time physiological recovery is associated with eating habits in distressed working-age Finns with overweight : Secondary analysis of a randomised controlled trial
- 2021
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In: Journal of Occupational Medicine and Toxicology. - : BioMed Central (BMC). - 1745-6673. ; 16:1
-
Journal article (peer-reviewed)abstract
- Background: Association of physiological recovery with nutrition has scarcely been studied. We investigated whether physiological recovery during sleep relates to eating habits, i.e., eating behaviour and diet quality. Methods: Cross-sectional baseline analysis of psychologically distressed adults with overweight (N = 252) participating in a lifestyle intervention study in three Finnish cities. Recovery measures were based on sleep-time heart rate variability (HRV) measured for 3 consecutive nights. Measures derived from HRV were 1) RMSSD (Root Mean Square of the Successive Differences) indicating the parasympathetic activation of the autonomic nervous system and 2) Stress Balance (SB) indicating the temporal ratio of recovery to stress. Eating behaviour was measured with questionnaires (Intuitive Eating Scale, Three-Factor Eating Questionnaire, Health and Taste Attitude Scales, ecSatter Inventory (TM)). Diet quality was quantified using questionnaires (Index of Diet Quality, Alcohol Use Disorders Identification Test Consumption) and 48-h dietary recall. Results: Participants with best RMSSD reported less intuitive eating (p = 0.019) and less eating for physical rather than emotional reasons (p = 0.010) compared to those with poorest RMSSD; participants with good SB reported less unconditional permission to eat (p = 0.008), higher fibre intake (p = 0.028), higher diet quality (p = 0.001), and lower alcohol consumption (p < 0.001) compared to those with poor SB, although effect sizes were small. In subgroup analyses among participants who reported working regular daytime hours (n = 216), only the associations of SB with diet quality and alcohol consumption remained significant. Conclusions: Better nocturnal recovery showed associations with better diet quality, lower alcohol consumption and possibly lower intuitive eating. In future lifestyle interventions and clinical practice, it is important to acknowledge sleep-time recovery as one possible factor linked with eating habits.
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| 86. |
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| 87. |
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| 88. |
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| 89. |
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| 90. |
- Kukli, Kaupo, et al.
(author)
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Atomic layer deposition of Ru films from bis(2,5-dimethylpyrrolyl)ruthenium and oxygen
- 2012
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In: Thin Solid Films. - : Elsevier BV. - 0040-6090 .- 1879-2731. ; 520:7, s. 2756-2763
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Journal article (peer-reviewed)abstract
- Ru thin films were grown on hydrogen terminated Si, SiO2, Al2O3, HfO2, and TiO2 surfaces by atomic layer deposition from bis(2,5-dimethylpyrrolyl)ruthenium precursor and oxygen. The 4-20 nm thick films on these surfaces consisted of nanocrystalline hexagonal metallic ruthenium, regardless of the deposition temperature. At the lowest temperatures examined, 250-255 degrees C, the growth of the Ru films was favored on silicon, compared to the growth on Al2O3, TiO2 and HfO2. At higher temperatures the nucleation and growth of Ru became enhanced in particular on HfO2, compared to the process on silicon. At 320-325 degrees C, no growth occurred on Si-H and SiO2-covered silicon. Resistivity values down to 18 mu Omega.cm were obtained for ca. 10 nm thick Ru films.
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| 91. |
- Laiterä, Tiina, et al.
(author)
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Effects of Alzheimer's Disease-Associated Risk Loci on Amyloid-β Accumulation in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients
- 2017
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 55:3, s. 995-1003
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer's disease (AD) patients, diffuse aggregates of amyloid-β (Aβ) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aβ is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aβ-related cellular processes. Apart from the apolipoprotein E ɛ4 allele (APOE4), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing the combined effects.OBJECTIVE: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aβ in the brain samples of iNPH patients.METHODS: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aβ pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aβ deposition.RESULTS: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aβ in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aβ deposition.CONCLUSION: Novel AD-associated risk genes have no significant effect on Aβ accumulation in the brain of iNPH patients. However, APOE4 affects the Aβ deposition in the brain of iNPH and AD patients in a similar manner.
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| 92. |
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| 93. |
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| 94. |
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| 95. |
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| 96. |
- Lappalainen, Raimo, et al.
(author)
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The effectiveness and applicability of different lifestyle interventions for enhancing wellbeing : the study design for a randomized controlled trial for persons with metabolic syndrome risk factors and psychological distress.
- 2014
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In: BMC Public Health. - : BioMed Central. - 1471-2458. ; 14
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Obesity and stress are among the most common lifestyle-related health problems. Most of the current disease prevention and management models are not satisfactorily cost-effective and hardly reach those who need them the most. Therefore, novel evidence-based controlled interventions are necessary to evaluate models for prevention and treatment based on self-management. This randomized controlled trial examines the effectiveness, applicability, and acceptability of different lifestyle interventions with individuals having symptoms of metabolic syndrome and psychological distress. The offered interventions are based on cognitive behavioral approaches, and are designed for enhancing general well-being and supporting personalized lifestyle changes.METHODS/DESIGN: 339 obese individuals reporting stress symptoms were recruited and randomized to either (1) a minimal contact web-guided Cognitive Behavioral Therapy-based (CBT) intervention including an approach of health assessment and coaching methods, (2) a mobile-guided intervention comprising of mindfulness, acceptance and value-based exercises, (3) a face-to-face group intervention using mindfulness, acceptance and value-based approach, or (4) a control group. The participants were measured three times during the study (pre = week 0, post = week 10, and follow-up = week 36). Psychological well-being, lifestyles and habits, eating behaviors, and user experiences were measured using online surveys. Laboratory measurements for physical well-being and general health were performed including e.g. liver function, thyroid glands, kidney function, blood lipids and glucose levels and body composition analysis. In addition, a 3-day ambulatory heart rate and 7-day movement data were collected for analyzing stress, recovery, physical activity, and sleep patterns. Food intake data were collected with a 48 -hour diet recall interview via telephone. Differences in the effects of the interventions would be examined using multiple-group modeling techniques, and effect-size calculations.DISCUSSION: This study will provide additional knowledge about the effects of three low intensity interventions for improving general well-being among individuals with obesity and stress symptoms. The study will show effects of two technology guided self-help interventions as well as effect of an acceptance and value-based brief group intervention. Those who might benefit from the aforesaid interventions will increase knowledge base to better understand what mechanisms facilitate effects of the interventions.TRIAL REGISTRATION: Current Clinical Trials NCT01738256, Registered 17 August, 2012.
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| 97. |
- Lappalainen, T, et al.
(author)
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Migration waves to the Baltic Sea region
- 2008
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In: Annals of Human Genetics. - Oxford : Blackwell Publishing. - 0003-4800 .- 1469-1809. ; 72, s. 337-348
-
Journal article (peer-reviewed)abstract
- In this study, the population history of the Baltic Sea region, known to be affected by a variety of migrations and genetic barriers, was analyzed using both mitochondrial DNA and Y-chromosomal data. Over 1200 samples from Finland, Sweden, Karelia, Estonia, Setoland, Latvia and Lithuania were genotyped for 18 Y-chromosomal biallelic polymorphisms and 9 STRs, in addition to analyzing 17 coding region polymorphisms and the HVS1 region from the mtDNA. It was shown that the populations surrounding the Baltic Sea are genetically similar, which suggests that it has been an important route not only for cultural transmission but also for population migration. However, many of the migrations affecting the area from Central Europe, the Volga-Ural region and from Slavic populations have had a quantitatively different impact on the populations, and, furthermore, the effects of genetic drift have increased the differences between populations especially in the north. The possible explanations for the high frequencies of several haplogroups with an origin in the Iberian refugia (H1, U5b, I1a) are also discussed.
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| 98. |
- Launonen, AP, et al.
(author)
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Epidemiology of proximal humerus fractures
- 2015
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In: Archives of osteoporosis. - : Springer Science and Business Media LLC. - 1862-3514 .- 1862-3522. ; 10:1, s. 209-
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Journal article (peer-reviewed)
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| 99. |
- Launonen, Antti P., et al.
(author)
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Operative versus non-operative treatment for 2-part proximal humerus fracture : A multicenter randomized controlled trial
- 2019
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In: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 16:7
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Journal article (peer-reviewed)abstract
- BackgroundAlthough increasingly used, the benefit of surgical treatment of displaced 2-part proximal humerus fractures has not been proven. This trial evaluates the clinical effectiveness of surgery with locking plate compared with non-operative treatment for these fractures.Methods and findingsThe NITEP group conducted a superiority, assessor-blinded, multicenter randomized trial in 6 hospitals in Finland, Estonia, Sweden, and Denmark. Eighty-eight patients aged 60 years or older with displaced (more than 1 cm or 45 degrees) 2-part surgical or anatomical neck proximal humerus fracture were randomly assigned in a 1:1 ratio to undergo either operative treatment with a locking plate or non-operative treatment. The mean age of patients was 72 years in the non-operative group and 73 years in the operative group, with a female sex distribution of 95% and 87%, respectively. Patients were recruited between February 2011 and April 2016. The primary outcome measure was Disabilities of Arm, Shoulder, and Hand (DASH) score at 2-year follow-up. Secondary outcomes included Constant–Murley score, the visual analogue scale for pain, the quality of life questionnaire 15D, EuroQol Group’s 5-dimension self-reported questionnaire EQ-5D, the Oxford Shoulder Score, and complications. The mean DASH score (0 best, 100 worst) at 2 years was 18.5 points for the operative treatment group and 17.4 points for the non-operative group (mean difference 1.1 [95% CI −7.8 to 9.4], p = 0.81). At 2 years, there were no statistically or clinically significant between-group differences in any of the outcome measures. All 3 complications resulting in secondary surgery occurred in the operative group. The lack of blinding in patient-reported outcome assessment is a limitation of the study. Our assessor physiotherapists were, however, blinded.ConclusionsThis trial found no significant difference in clinical outcomes at 2 years between surgery and non-operative treatment in patients 60 years of age or older with displaced 2-part fractures of the proximal humerus. These results suggest that the current practice of performing surgery on the majority of displaced proximal 2-part fractures of the humerus in older adults may not be beneficial.
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| 100. |
- Launonen, Antti P, et al.
(author)
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Surgery with locking plate or hemiarthroplasty versus nonoperative treatment of 3-4-part proximal humerus fractures in older patients (NITEP) : An open-label randomized trial
- 2023
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In: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 20:11
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Journal article (peer-reviewed)abstract
- BACKGROUND: Proximal humerus fractures (PHFs) are common fractures, especially in older female patients. These fractures are commonly treated surgically, but the consensus on the best treatment is still lacking.METHODS AND FINDINGS: The primary aim of this multicenter, randomized 3-arm superiority, open-label trial was to assess the results of nonoperative treatment and operative treatment either with locking plate (LP) or hemiarthroplasty (HA) of 3- and 4-part PHF with the primary outcome of Disabilities of the Arm, Shoulder, and Hand (DASH) at 2-year follow-up. Between February 2011 and December 2019, 160 patients 60 years and older with 3- and 4-part PHFs were randomly assigned in 1:1:1 fashion in block size of 10 to undergo nonoperative treatment (control) or operative intervention with LP or HA. In total, 54 patients were assigned to the nonoperative group, 52 to the LP group, and 54 to the HA group. Five patients assigned to the LP group were reassigned to the HA group perioperatively due to high comminution, and all of these patients had 4-part fractures. In the intention-to-treat analysis, there were 42 patients in the nonoperative group, 44 in the LP group, and 37 in the HA group. The outcome assessors were blinded to the study group. The mean DASH score at 2-year follow-up was 30.4 (standard error (SE) 3.25), 31.4 (SE 3.11), and 26.6 (SE 3.23) points for the nonoperative, LP, and HA groups, respectively. At 2 years, the between-group differences were 1.07 points (95% CI [-9.5,11.7]; p = 0.97) between nonoperative and LP, 3.78 points (95% CI [-7.0,14.6]; p = 0.69) between nonoperative and HA, and 4.84 points (95% CI [-5.7,15.4]; p = 0.53) between LP and HA. No significant differences in primary or secondary outcomes were seen in stratified age groups (60 to 70 years and 71 years and over). At 2 years, we found 30 complications (3/52, 5.8% in nonoperative; 22/49, 45% in LP; and 5/49, 10% in HA group, p = 0.0004) and 16 severe pain-related adverse events. There was a revision rate of 22% in the LP group. The limitation of the trial was that the recruitment period was longer than expected due to a high number of exclusions after the assessment of eligibility and a larger exclusion rate than anticipated toward the end of the trial. Therefore, the trial was ended prematurely.CONCLUSIONS: In this study, no benefit was observed between operative treatment with LP or HA and nonoperative treatment in displaced 3- and 4-part PHFs in patients aged 60 years and older. Further, we observed a high rate of complications related to operative treatments.TRIAL REGISTRATION: ClinicalTrials.gov NCT01246167.
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