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| 2. |
- Silventoinen, K., et al.
(författare)
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The CODATwins Project : The current status and recent findings of COllaborative Project of Development of Anthropometrical Measures in Twins
- 2019
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Ingår i: Twin Research and Human Genetics. - : Cambridge University Press. - 1832-4274 .- 1839-2628. ; 22:6, s. 800-808
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Tidskriftsartikel (refereegranskat)abstract
- The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural-geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
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- Papadopoulos, N G, et al.
(författare)
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Viruses and bacteria in acute asthma exacerbations - A GA(2) LEN-DARE* systematic review.
- 2010
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538.
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Forskningsöversikt (refereegranskat)abstract
- To cite this article: Papadopoulos NG, Christodoulou I, Rohde G, Agache I, Almqvist C, Bruno A, Bonini S, Bont L, Bossios A, Bousquet J, Braido F, Brusselle G, Canonica GW, Carlsen KH, Chanez P, Fokkens WJ, Garcia-Garcia M, Gjomarkaj M, Haahtela T, Holgate ST, Johnston SL, Konstantinou G, Kowalski M, Lewandowska-Polak A, Lødrup-Carlsen K, Mäkelä M, Malkusova I, Mullol J, Nieto A, Eller E, Ozdemir C, Panzner P, Popov T, Psarras S, Roumpedaki E, Rukhadze M, Stipic-Markovic A, Todo Bom A, Toskala E, van Cauwenberge P, van Drunen C, Watelet JB, Xatzipsalti M, Xepapadaki P, Zuberbier T. Viruses and bacteria in acute asthma exacerbations - A GA(2) LEN-DARE systematic review. Allergy 2010; DOI: 10.1111/j.1398-9995.2010.02505.x. ABSTRACT: A major part of the burden of asthma is caused by acute exacerbations. Exacerbations have been strongly and consistently associated with respiratory infections. Respiratory viruses and bacteria are therefore possible treatment targets. To have a reasonable estimate of the burden of disease induced by such infectious agents on asthmatic patients, it is necessary to understand their nature and be able to identify them in clinical samples by employing accurate and sensitive methodologies. This systematic review summarizes current knowledge and developments in infection epidemiology of acute asthma in children and adults, describing the known impact for each individual agent and highlighting knowledge gaps. Among infectious agents, human rhinoviruses are the most prevalent in regard to asthma exacerbations. The newly identified type-C rhinoviruses may prove to be particularly relevant. Respiratory syncytial virus and metapneumovirus are important in infants, while influenza viruses seem to induce severe exacerbations mostly in adults. Other agents are relatively less or not clearly associated. Mycoplasma and Chlamydophila pneumoniae seem to be involved more with asthma persistence rather than with disease exacerbations. Recent data suggest that common bacteria may also be involved, but this should be confirmed. Although current information is considerable, improvements in detection methodologies, as well as the wide variation in respect to location, time and populations, underline the need for additional studies that should also take into account interacting factors.
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| 7. |
- 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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| 8. |
- Ivanova, M. Y., et al.
(författare)
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Effects of individual differences, society, and culture on youth-rated problems and strengths in 38 societies
- 2022
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Ingår i: Journal of Child Psychology and Psychiatry. - : Wiley. - 0021-9630 .- 1469-7610. ; 63:11, s. 1297-1307
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clinicians increasingly serve youths from societal/cultural backgrounds different from their own. This raises questions about how to interpret what such youths report. Rescorla et al. (2019, European Child & Adolescent Psychiatry, 28, 1107) found that much more variance in 72,493 parents' ratings of their offspring's mental health problems was accounted for by individual differences than by societal or cultural differences. Although parents' reports are essential for clinical assessment of their offspring, they reflect parents' perceptions of the offspring. Consequently, clinical assessment also requires self-reports from the offspring themselves. To test effects of individual differences, society, and culture on youths' self-ratings of their problems and strengths, we analyzed Youth Self-Report (YSR) scores for 39,849 11-17 year olds in 38 societies. Methods: Indigenous researchers obtained YSR self-ratings from population samples of youths in 38 societies representing 10 culture cluster identified in the Global Leadership and Organizational Behavioral Effectiveness study. Hierarchical linear modeling of scores on 17 problem scales and one strengths scale estimated the percent of variance accounted for by individual differences (including measurement error), society, and culture cluster. ANOVAs tested age and gender effects. Results: Averaged across the 17 problem scales, individual differences accounted for 92.5% of variance, societal differences 6.0%, and cultural differences 1.5%. For strengths, individual differences accounted for 83.4% of variance, societal differences 10.1%, and cultural differences 6.5%. Age and gender had very small effects. Conclusions: Like parents' ratings, youths' self-ratings of problems were affected much more by individual differences than societal/cultural differences. Most variance in self-rated strengths also reflected individual differences, but societal/cultural effects were larger than for problems, suggesting greater influence of social desirability. The clinical significance of individual differences in youths' self-reports should thus not be minimized by societal/cultural differences, which-while important-can be taken into account with appropriate norms, as can gender and age differences.
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| 11. |
- Ask, Maria, et al.
(författare)
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The Innovative Exploration Drilling and Data Acquisition Research School
- 2021
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Ingår i: NSG2021 27th European Meeting of Environmental and Engineering Geophysics. - : European Association of Geoscientists and Engineers.
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Konferensbidrag (refereegranskat)abstract
- The Innovative Exploration Drilling and Data Acquisition Research School (I-EDDA-RS) is aimed at educating emerging scientists and engineers in on-site drilling and geoscientific investigation technology for mining. I-EDDA-RS consists if a consortium of scientists and specialists from six universities and research institutes in Germany and Sweden. A central component of the research school is that the courses have hands-on components at drill sites, boreholes and repositories. In addition, a course on entrepreneurial skills required in the exploration industry is also included in I-EDDA-RS. The arrival of the Covid-19 pandemic resulted in altered plans. Instead of offering ten courses with strong field work, practical, and entrepreneurial components during 2020, four courses via distant learning were offered. While this was disappointing in many aspects, two of the courses attracted a larger group of students from a wider part of the world than original envisioned. Outreach via on-line and open webinars is also a route to explore, as a complement to meetings and conferences in real life. The I-EDDA-RS courses in 2021 welcomes students at MSc & PhD level, as well as experienced professionals for lifelong learning (c.f. https://www.iedda.eu/rs). The form and type of teaching is to be determined.
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| 12. |
- Eyjolfsdottir, H, et al.
(författare)
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Fast Alpha Activity in EEG of Patients With Alzheimer's Disease Is Paralleled by Changes in Cognition and Cholinergic Markers During Encapsulated Cell Biodelivery of Nerve Growth Factor
- 2022
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Ingår i: Frontiers in aging neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14, s. 756687-
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Tidskriftsartikel (refereegranskat)abstract
- Basal forebrain cholinergic neurons are dependent on nerve growth factor (NGF) for growth and survival and these cells are among the first to degenerate in Alzheimer’s disease (AD). Targeted delivery of NGF has been suggested as a potential therapy for AD. This hypothesis was tested in a clinical trial with encapsulated cell biodelivery of NGF (NGF-ECB) in AD patients. Three of six patients showed improved biomarkers for cognition by the end of the study. Here, we report on the effects of targeted delivery of NGF on human resting EEG.Materials and methodsNGF-ECB implants were implanted bilaterally in the basal forebrain of six AD patients for 12 months. EEG recordings and quantitative analysis were performed at baseline, 3 and 12 months of NGF delivery, and analyzed for correlation with changes in Mini-mental state examination (MMSE) and levels of the cholinergic marker choline acetyltransferase (ChAT) in cerebrospinal fluid (CSF).ResultsWe found significant correlations between the topographic variance of EEG spectral power at the three study points (baseline, 3 and 12 months) and changes in MMSE and CSF ChAT. This possible effect of NGF was identified in a narrow window of alpha frequency 10–11.5 Hz, where a stabilization in MMSE score during treatment was related to an increase in EEG alpha power. A similar relation was observed between the alpha power and ChAT. More theta power at 6.5 Hz was on the contrary associated with a decrease in CSF ChAT during the trial period.ConclusionIn this exploratory study, there was a positive correlative pattern between physiological high-frequency alpha activity and stabilization in MMSE and increase in CSF ChAT in AD patients receiving targeted delivery of NGF to the cholinergic basal forebrain.
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| 13. |
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| 14. |
- Ivanova, M.Y, et al.
(författare)
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Testing Syndromes of Psychopathology in Parent and Youth Ratings Across Societies
- 2019
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Ingår i: Journal of clinical child and adolescent psychology. - : Informa UK Limited. - 1537-4416 .- 1537-4424. ; 48:4, s. 596-609
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Tidskriftsartikel (refereegranskat)abstract
- As societies become increasingly diverse, mental health professionals need instruments for assessing emotional, behavioral, and social problems in terms of constructs that are supported within and across societies. Building on decades of research findings, multisample alignment confirmatory factor analyses tested an empirically based 8-syndrome model on parent ratings across 30 societies and youth self-ratings across 19 societies. The Child Behavior Checklist for Ages 6–18 and Youth Self-Report for Ages 11–18 were used to measure syndromes descriptively designated as Anxious/ Depressed, Withdrawn/Depressed, Somatic Complaints, Social Problems, Thought Problems, Attention Problems, Rule-Breaking Behavior, and Aggressive Behavior. For both parent ratings (N = 61,703) and self-ratings (N = 29,486), results supported aggregation of problem items into 8 first-order syndromes for all societies (configural invariance), plus the invariance of item loadings (metric invariance) across the majority of societies. Supported across many societies in both parent and self-ratings, the 8 syndromes offer a parsimonious phenotypic taxonomy with clearly operatio- nalized assessment criteria. Mental health professionals in many societies can use the 8 syndromes to assess children and youths for clinical, training, and scientific purposes.
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| 19. |
- Merid, Simon Kebede, et al.
(författare)
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Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age
- 2020
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Ingår i: Genome Medicine. - Stockholm : Karolinska Institutet, Dept of Clinical Science and Education, Södersjukhuset. - 1756-994X.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
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| 21. |
- Slob, E. M. A., et al.
(författare)
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Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study
- 2021
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Ingår i: International journal of epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 50:2, s. 475-484
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Tidskriftsartikel (refereegranskat)abstract
- Background: Development of the gut-brain axis in early life may be disturbed by antibiotic use. It has been hypothesized that this disturbance may contribute to development of neurodevelopmental disorders, including autism spectrum disorder and attention-deficit hyperactivity disorder. We aimed to assess the association between antibiotic use in early life and the risk of developing attention-deficit hyperactivity disorder or autism spectrum disorder, while controlling for shared genetic and environmental factors in a discordant twin design. Methods: We conducted a cohort study in twins (7-12 years; 25 781 twins) from the Netherlands Twin Register (NTR) and a replication study in the Childhood and Adolescent Twin Study in Sweden (CATSS; 7946 9-year-old twins). Antibiotic use was recorded before age 2 years. Attention-deficit hyperactivity disorder and autism spectrum disorder were parent-reported in the Netherlands Twin Register and register-based in the Childhood and Adolescent Twin Study in Sweden. Results: Early-life antibiotic use was associated with increased risk of attention-deficit hyperactivity disorder development [pooled odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.17] and autism spectrum disorder (pooled OR 1.15, 95% CI 1.06-1.25) in a case-control design. When restricting to monozygotic twin pairs discordant for the outcome, associations disappeared for both disorders in both cohorts (attention-deficit hyperactivity disorder OR 0.90, 95% CI 0.48-1.69 and OR 0.80, 95% CI 0.37-1.76, and autism spectrum disorder OR 0.66, 95% CI 0.38-1.16 and OR 0.29, 95% CI 0.02-4.50, respectively). Conclusions: Our findings suggest that the association between early-life antibiotic use and risk of attention-deficit hyperactivity and autism spectrum disorder may be confounded by shared familial environment and genetics.
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| 24. |
- Almqvist, Fredrik, et al.
(författare)
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Spirobicyclo[2.2.2]octane derivatives: mimetics of baccatin III and paclitaxel (Taxol)
- 2004
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Ingår i: Organic & Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 2:21, s. 3085-3090
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Tidskriftsartikel (refereegranskat)abstract
- The formylated spirobyclic alcohol 8a was computer modeled to be a mimetic of paclitaxel. In this model, the formyl group was used as a truncated paclitaxel side chain in order to reduce the computational work. Compound 8c, carrying the paclitaxel side chain, was synthesized in six steps from optically active 1,3-diketone 12. Microtubule stabilization was not observed for 8c, indicating that the model needs to be adjusted.
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| 27. |
- Almqvist, Monica, et al.
(författare)
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Characterization of micromachined ultrasonic transducers using light diffraction tomography
- 2005
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Ingår i: IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. - 0885-3010. ; 52:12, s. 2298-2302
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Tidskriftsartikel (refereegranskat)abstract
- This paper demonstrates that light diffraction tomography can be used to measure the acoustic field of micromachined ultrasonic transducers (MUT) in cases in which standard methods like hydrophone and microphone measurements fail. Two types of MUTs have been characterized with the method, one air-coupled capacitive MUT (cMUT) and one waterloaded continuous wave (CW) miniature multilayer lead zirconate titanate (PZT) transducer. Light diffraction tomography is an ultrasound measurement method with some special characteristics. Based on the interaction of light and ultrasound, it combines light intensity measurements with tomography algorithms to produce a measurement system. The method offers nonperturbing pressure measurements with high spatial resolution. It has been shown that, under certain circumstances, light diffraction tomography can be used as an absolute pressure measurement method with accuracy in the order of 10% in water and 13% in air. The results show that air-coupled cMUTs in the frequency range of about 1 MHz as well as the extreme near field of a miniaturized CW 10 MHz waterloaded transducer were successfully characterized with light diffraction tomography.
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| 30. |
- Antzutkin, Oleg, et al.
(författare)
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Binding of Aluminium(III)-Citrate Complexes, [Al3(H-1Cit)3(OH)]-4 and [Al3(H-1Cit)3(OH)4]-7, to Alzheimer's A-beta(1-40) Peptides : In situ Atomic Force, Electron Microscopy and Solid State 13C and 27Al NMR Studies
- 2005
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Ingår i: Sixth Keele Meeting on Aluminium. - : Centro de Estudos do Ambiente e Mar, Universidade de Aveiro. ; , s. 16-
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- It is believed that Alzheimer's disease (AD) amyloid-β-peptide (Aβ) deposits contribute directly to the disease's progressive neurodegeneration. Aggregation cascade for Aβ peptides, its relevance to neurotoxicity in the course of AD, various factors modulating Aβ aggregation kinetics and experimental methods useful for these studies were recently discussed [1]. Al(III), Zn(II), Cu(II) and Fe(III) ions are often colocalized at the center of the core of Alzheimer's amyloid plaques [2] and are suggested to promote aggregation of physiological concentrations of Aβ [3]. It has also been suggested that Al can block calcium permeable putative Aβ-peptide channels in bilayer membranes [4]. Therefore studies of complexation of metal ions with Aβ-oligomers and fibrils are important in the search for the causes of and potential treatments for AD.We studied effects of highly soluble and biologically relevant aluminium(III)-citrate compounds, [Al3(H-1Cit)3(OH)]-4 and [Al3(H-1Cit)3(OH)4]-7, on the fibrillogenesis of Aβ(1-40). All resonances in 156.37 MHz 27Al and 90.52 MHz 13C MAS NMR spectra of powder Al(III)-citrate complexes were assigned. 27Al MAS NMR of dialysed samples of Aβ(1-40) co-incubated with the Al(III)-citrate complexes at different concentrations in TRIS buffer solutions, pH 7.4, shows that Al(III)-citrates bind to Aβ(1-40) as [Al3(H-1Cit)3(OH)]-4 and either accelerate ([Al3(H-1Cit)3(OH)]-4 complex) or retard ([Al3(H-1Cit)3(OH)4]-7 compound) aggregation of Aβ(1-40) as revealed by AFM. [1] ON Antzutkin, Magn. Reson. Chem. 42 (2004) 231; [2] MA Lovell et al., J. Neurol. Sci. 158 (1998) 47; Ch Exley et al., Al and Alzheimer's disease, Ch Exley (Ed)1998) 47; Ch Exley , Ch Exley (Ed) Elsevier Science, 2001, 421; [3] PW Mantyh et al., J. Neurochem. 61 (1993) 1171; [4] N Arispe et al, PNAS 90 (1993) 567.
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| 35. |
- Barange, Deepak Kumar, et al.
(författare)
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Regio- and Stereoselective Alkylation of Pyridine-N-oxides : Synthesis of Substituted Piperidines and Pyridines
- 2016
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Ingår i: Organic Letters. - : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 18:24, s. 6228-6231
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Tidskriftsartikel (refereegranskat)abstract
- Regio- and stereoselective addition of alkyl Grignard reagents to pyridine-N-oxides gave C2-alkylated N-hydroxy-1,2,5,6-tetrahydropyridines and trans-2,3-disubstituted N-hydroxy-1,2,5,6-tetrahydropyridines in good to excellent yields. These intermediates were aromatized or alternatively reduced in one-pot methodologies for efficient syntheses of alkylpyridines or piperidines, respectively. These reactions have a broad substrate scope and short reaction times.
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| 41. |
- Creighton, S, et al.
(författare)
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Predictive, pre-natal and diagnostic genetic testing for Huntington's disease : the experience in Canada from 1987 to 2000.
- 2003
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Ingår i: Clinical Genetics. - 0009-9163 .- 1399-0004. ; 63:6, s. 462-75
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Tidskriftsartikel (refereegranskat)abstract
- Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.
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| 42. |
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| 43. |
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| 44. |
- 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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| 49. |
- Goellner, G M, et al.
(författare)
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Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer.
- 1997
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Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 60:4, s. 879-90
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Tidskriftsartikel (refereegranskat)abstract
- Two recent lines of evidence raise the possibility that instability in germ-line or somatic cells arises by a common mechanism that involves defective mismatch repair. Mutations in mismatch-repair proteins are known to cause instability in hereditary nonpolyposis colorectal cancer, instability that is physically similar to germ-line instability observed in Huntington disease (HD). Furthermore, both germ-line and somatic-cell instability are likely to be mitotic defects, the former occurring early in embryogenesis. To test the hypothesis that defective repair is a common prerequisite for instability, we have utilized two disease groups that represent different instability "conditions." Germ-line instability within simple tandem repeats (STR) at 10 loci in 29 HD families were compared with somatic instability at the same loci in 26 colon cancer (CC) patients with identified or suspected defects in mismatch-repair enzymes. HD is known to be caused by expansion within the CAG repeat of the locus, but the extent or pattern of STR instability outside this region has not been examined systematically. We find a distinctly different pattern of STR mutation in the two disease groups, suggesting different mechanisms. Instability in HD is generally confined to a single locus, whereas instability is widespread for the same loci in CC. Our data do not support a causative role for defective mismatch-repair enzymes in instability associated with HD; rather, our data are consistent with a model in which DNA structure may inhibit normal mismatch repair at the expansion site.
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| 50. |
- Goldberg, Y P, et al.
(författare)
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Increased instability of intermediate alleles in families with sporadic Huntington disease compared to similar sized intermediate alleles in the general population.
- 1995
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 4:10, s. 1911-8
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Tidskriftsartikel (refereegranskat)abstract
- We have directly compared intergenerational stability of intermediate alleles (IAs) derived from new mutation families (IANM) for Huntington disease (HD) with IAs in the general population (IAGP) which occur in approximately 1 in 50 persons. Analysis of meiotic events in blood and sperm reveals that IANM are significantly more unstable than IAGP despite similar size. However, for both IANM and IAGP CAG changes were small and risks for inheriting an expansion into the HD affected range were low. Sequence analysis reveals that the CAG tract is generally interrupted by a penultimate CAA in IAGP, IANM and alleles in the affected range. In one new mutation family, however, two A-->G mutations result in a pure CAG tract which is associated with very marked instability. These mutations alter the predicted DNA hairpin structure with a predicted increase in the likelihood of large expansion, supporting the model that hairpin loop formation plays an important role in trinucleotide instability.
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