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- Eyjolfsdottir, H., et al.
(författare)
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Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer's disease patients: application of a second-generation encapsulated cell biodelivery device
- 2016
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Targeted delivery of nerve growth factor (NGF) has emerged as a potential therapy for Alzheimer's disease (AD) due to its regenerative effects on basal forebrain cholinergic neurons. This hypothesis has been tested in patients with AD using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-human study. We report our results from a third-dose cohort of patients receiving second-generation NGF-ECB implants with improved NGF secretion. Methods: Four patients with mild to moderate AD were recruited to participate in an open-label, phase Ib dose escalation study with a 6-month duration. Each patient underwent stereotactic implant surgery with four NGF-ECB implants targeted at the cholinergic basal forebrain. The NGF secretion of the second-generation implants was improved by using the Sleeping Beauty transposon gene expression technology and an improved three-dimensional internal scaffolding, resulting in production of about 10 ng NGF/device/day. Results: All patients underwent successful implant procedures without complications, and all patients completed the study, including implant removal after 6 months. Upon removal, 13 of 16 implants released NGF, 8 implants released NGF at the same rate or higher than before the implant procedure, and 3 implants failed to release detectable amounts of NGF. Of 16 adverse events, none was NGF-, or implant-related. Changes from baseline values of cholinergic markers in cerebrospinal fluid (CSF) correlated with cortical nicotinic receptor expression and Mini Mental State Examination score. Levels of neurofilament light chain (NFL) protein increased in CSF after NGF-ECB implant, while glial fibrillary acidic protein (GFAP) remained stable. Conclusions: The data derived from this patient cohort demonstrate the safety and tolerability of sustained NGF release by a second-generation NGF-ECB implant to the basal forebrain, with uneventful surgical implant and removal of NGF-ECB implants in a new dosing cohort of four patients with AD.
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- Beck, J. J., et al.
(författare)
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Genetic meta-analysis of twin birth weight shows high genetic correlation with singleton birth weight
- 2021
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 30:19, s. 1894-1905
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Tidskriftsartikel (refereegranskat)abstract
- Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardiometabolic disorders, autoimmune diseases and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson's r = 0.66, 95% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [r(g)]= 0.92, 95% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in the UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers.
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- Bender, Hagen, et al.
(författare)
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Metamorphic Zonation by Out‐of‐Sequence Thrusting at Back‐Stepping Subduction Zones : Sequential Accretion of the Caledonian Internides, Central Sweden
- 2018
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Ingår i: Tectonics. - : John Wiley & Sons. - 0278-7407 .- 1944-9194. ; 37:10, s. 3545-3576
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Tidskriftsartikel (refereegranskat)abstract
- Exhumation of the high‐grade metamorphic Seve Nappe Complex and its emplacement between lower‐grade nappes has been related to wedge extrusion in the central Scandinavian Caledonides. To test this hypothesis, the kinematic evolution of the Caledonian nappe pile is studied by systematic structural mapping in central and northern Jämtland, Sweden. Structural data, combined with petrological and quartz microstructure observations, document pervasive top‐to‐the‐ESE, foreland‐directed shearing under progressively decreasing metamorphic grade across the entire nappe pile. Mylonitic foliation, foliation‐parallel boudinage, and abundant top‐to‐the‐ESE and rare, scattered top‐to‐the‐WNW shear‐sense indicators imply foreland‐directed general shear. This deformation regime caused exhumation by concurrent thrusting and vertical ductile thinning. We propose a specific succession of in‐ and out‐of‐sequence thrusts that generated the metamorphic zonation. Our model envisions in‐sequence propagation of thrusts during exhumation of the Seve Nappe Complex, related to subduction of Baltica beneath a volcanic arc within Iapetus. Concurrently, Iapetus subducted beneath Laurentia farther to the west. When Iapetus was closed, Baltica subduction stepped westward and continued beneath Laurentia. The back stepping of subduction at the onset of continental collision caused out‐of‐sequence propagation of the orogenic wedge. Thrusting cut downsection across the existing tectonostratigraphy, emplacing units of lower metamorphic grade above the high‐grade Seve Nappe Complex. This imbrication generated the present metamorphic zonation of the Caledonian nappe pile during sustained convergence between Laurentia and Baltica.
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- Chong, S S, et al.
(författare)
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Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease : evidence from single sperm analyses.
- 1997
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 6:2, s. 301-9
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Tidskriftsartikel (refereegranskat)abstract
- New mutations for Huntington disease (HD) arise from intermediate alleles (IAs) with between 29 and 35 CAG repeats that expand on transmission through the paternal germline to 36 CAGs or greater. Using single sperm analysis, we have assessed CAG mutation frequencies for four IAs in families with sporadic HD (IANM) and IAs ascertained from the general population (IAGP) by analyzing 1161 single sperm from three persons. We show that IANM are more unstable than IAGP with identical size and sequence. Furthermore, comparison of different sized IAs and IAs with different sequences between the CAG and the adjacent CCG tracts indicates that DNA sequence is a major influence on CAG stability. These studies provide estimates of the likelihood of expansion of IANM and IAGP to > or = 36 CAG repeats for these individuals. For an IA with a CAG of 35 in this family with sporadic HD, the likelihood for siblings to inherit a recurrent mutation > or = 36 CAG is approximately 10%. For IAGP of a similar size, the risk of inheriting an expanded allele of > or = 36 CAG through the paternal germline is approximately 6%. These risk estimates are higher than previously reported and provide additional information for counselling in these families. Further studies on persons with IAs will be needed to determine whether these results can be generalized to other families.
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