| 1. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 2. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Tidskriftsartikel (refereegranskat)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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| 3. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.
- 2015
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Ingår i: JAMA. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 313:19, s. 1924-38
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.
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| 4. |
- O'Connell, Adam, et al.
(författare)
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The structure and dynamics of locust bean gum in aqueous solution
- 2023
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Ingår i: Food Hydrocolloids. - : Elsevier BV. - 0268-005X. ; 138
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Tidskriftsartikel (refereegranskat)abstract
- Locust bean gum (LBG) is an industrially important polysaccharide used widely in food, cosmetics, textiles, and biopharmaceutical applications, where understanding its solution behaviour is important for formulation design. To address this, we investigate the structure and dynamics of LBG in aqueous solution using steady state shear rheology, static light scattering (SLS), ultra-small-angle light scattering (USALS), and dynamic light scattering (DLS). We find that steady state shear rheology mainly probes the well-dispersed LBG fraction, whereas the scattering response is dominated by supramolecular LBG aggregates. We identify three viscosity-concentration regimes (dilute, semidilute unentangled, and semidilute entangled), with scaling behaviour largely consistent with predictions for neutral flexible polymers. SLS and USALS provide evidence for the existence of two separate populations of aggregated structures, where SLS mainly probes the internal structure of the smaller aggregate population. The solution dynamics are dominated by a ‘slow’ decay mode, which is consistent with Zimm dynamics and attributed to relaxations within the aggregates. In dilute solutions, the apparent viscosity associated with this mode is greater than the solution viscosity, but the two converge as concentration is increased. An additional ‘fast’ mode is observed within the semidilute range, associated with the dispersed polymer fraction, and attributed to cooperative diffusion. Our study provides comprehensive insight into the structure and dynamics of aqueous LBG solutions—paving the way for a greater fundamental understanding of galactomannans in solution, and for increased control over LBG-based formulations of industrial interest.
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| 5. |
- Wide, Peter, 1972-, et al.
(författare)
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Four-hour voiding observation with provocation test reveals significant abnormalities of bladder function in newborns with spinal dysraphism
- 2020
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Ingår i: Journal of Pediatric Urology. - : Elsevier. - 1477-5131 .- 1873-4898. ; 16:4, s. 491.e1-491.e7
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Four-hour voiding observation with provocation test (VOP) using a scale, a damp detector and ultrasound for determination of residuals, is an easily performed non-invasive method for the evaluation of bladder function in newborns. Neonatal bladder function evaluated with VOP has been described for healthy newborns (HN) but not for children with spinal dysraphism (SD), for whom early bladder evaluation is essential for decisions regarding Clean Intermittent Catheterization and follow-up. The aim of the present study was to describe voiding observation with provocation test in newborns with spinal dysraphism and compare with corresponding data for healthy newborns.METHODS AND MATERIALS: At a tertiary hospital, a 4 h voiding observation with provocation (VOP) was performed in 50 neonates (22 girls, 28 boys) with spinal dysraphism (37 open SD, 13 closed SD) consecutively evaluated for possible neurogenic bladder-sphincter dysfunction (1998-2019). All newborns with open SD and 4/13 with closed SD had been through postnatal neurosurgery before the test. Mean age was 10 days. Voiding observation was performed during 4 h with visual observation the fourth hour recording behavior and urinary flow (e.g. stream, dribbling). Finally, bladder provocations (e.g. suprapubic compression) were performed, and any leakage was noted. Findings were compared to those of 50 healthy newborns (HN) earlier published (Gladh et al., 2002). There were no significant differences in background data such as gender, age or diuresis between newborns with SD and HN.RESULTS AND DISCUSSION: Voiding observation with provocation test of children with SD revealed significant differences compared to HN see summary table. Some children with SD had frequent small voids/leakages and low bladder volumes while three had no voiding and high volumes. Leakage during bladder provocation test and not voiding with a stream was not seen in HN but were common in newborns with SD (69% resp. 74%) (p < 0.01). A child with these findings should thus be investigated further. Identifying children needing Clean Intermittent Catheterization is important as well as being able to postpone or refrain from invasive urodynamic studies if not strongly indicated. VOP may give valuable information for these judgements.CONCLUSION: Newborns with spinal dysraphism differ from healthy newborns in many aspects of bladder function. Bladder function varies between newborns with closed and open spinal dysraphism. Many newborns with spinal dysraphism leak at bladder provocation and void without a stream but healthy newborns do not. Early determination of post-void residuals is mandatory in children with spinal dysraphism and non-invasive VOP gives this information in a standardized way, also adding information on frequency, voiding with a stream and leakage at provocation.
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| 6. |
- Wide, Peter, et al.
(författare)
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Independence does not come with the method - treatment of neurogenic bowel dysfunction in children with myelomeningocele
- 2014
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Ingår i: Acta Paediatrica. - : Wiley: 12 months. - 0803-5253 .- 1651-2227. ; 103:11, s. 1159-1164
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Tidskriftsartikel (refereegranskat)abstract
- AimThe aim was to evaluate and compare different bowel regimes with regard to satisfaction, faecal incontinence and independence, and the relationship to quality of life among children with myelomeningocele (MMC). MethodsA questionnaire, including the health-related quality of life instrument PedsQL 4.0, was sent to all children aged seven to 16years (n=172) with MMC, treated at two centres in Sweden and one in Norway. The three centres cover a third of the population in the two countries. The response rate was 62%. ResultsParents of children (30%) using antegrade colonic enemas (ACE) reported higher satisfaction (p=0.01) than the parents of those (47%) using transanal irrigation (TAI). The children reported no significant difference. Children and parents in the ACE group reported more complete evacuation of the bowels than the TAI group. No significant difference was found in faecal incontinence or independent toileting. The children (40%) who emptied their bowels independently reported a higher quality of life. Children using TAI or ACE spent around one hour on the toilet at every bowel emptying. ConclusionTAI and ACE are effective treatments, but time-consuming and difficult to perform independently. Higher parental satisfaction is obtained with ACE. Irrespective of method the children who can use the toilet independently report a higher quality of life, which makes efforts to support independence valuable.
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| 7. |
- Wide, Peter, 1972-
(författare)
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Neurogenic bladder and bowel dysfunction : Clinical aspects in children with spinal dysraphism
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Spinal dysraphism (SD) is a congenital malformation that to a varying extent, often severely, affects the life of the child and the family. Most individuals with SD suffer from neurogenic bladder and bowel dysfunction—with the risk of urinary tract infections, renal deterioration, urinary and fecal incontinence—that affects social participation and quality of life negatively. In newborns with SD, early detection of neurogenic bladder dysfunction and determination of post-void residual urine are required to determine the need of clean intermittent catheterization (CIC) and follow-up.The non-invasive method of four-hour voiding observation with provocation test (VOP) was used to evaluate bladder function in 50 newborn children with SD. Voiding patterns for the children were described and compared with those of 50 healthy newborns evaluated with VOP in an earlier study. Comparison revealed significant differences among several variables. In particular, leakage at provocation test and not voiding with a stream were common in newborns with SD but did not occur in healthy newborns. VOP is a non-invasive standardized method to determine residual urine in newborns with SD. It also adds information on voiding pattern, frequency, voiding with a stream and leakage at provocation.Findings in neonatal VOP of the same cohort of newborns with SD were then related to radiology, presence of urinary tract infections during the first year, and urodynamic findings and use of CIC at the age of one year. It was found that, in children with SD, not voiding with a stream may have a predictive value for the need of CIC at the age of one year, followed probably by lifelong CIC. Despite this, the presence of an open SD per se has stronger predictive value, and each child needs to be evaluated individually while considering a number of factors. The main value of VOP may be as a structured non-invasive screening method to uncover neurogenic bladder-sphincter dysfunction in the newborn. Studies with a larger number of subjects than the present are needed to evaluate the potential of VOP in newborns with closed spinal dysraphism in whom the neurological consequences vary.A retrospective analysis detected renal damage on DMSA scintigraphy in 5 of 41 children with SD who were followed according to a proactive national program with minimal use of surgery. Median follow-up time was 10 years. High baseline pressure was confirmed as a risk factor for renal damage. Compliance with treatment and follow-up is likely to be an important factor for renal health. Therefore, efforts to support children and their families are crucial. A questionnaire-based study of 107 children with SD (age 6–16y) in Sweden and Norway examined aspects of treatment for neurogenic bowel dysfunction focusing on incontinence, independence, general satisfaction and quality of life. It was found that transanal irrigation (TAI) and antegrade colonic enemas (ACE) are effective treatments, but are time-consuming and difficult to perform independently. The majority of children using TAI (72%) and ACE (63%) never went to the toilet alone to empty their bowels. As children achieving independence on the toilet reported higher quality of life, efforts to support independence are beneficial.Continent, self-managing children with healthy kidneys enjoy high quality of life and contribute more fully to society. Therefore, further research is required to investigate and develop existing and new technologies and methods that mitigate the problems related to SD, and to make them accessible to all children with spinal dysraphism.
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| 8. |
- Wide, Peter, et al.
(författare)
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Renal preservation in children with neurogenic bladder-sphincter dysfunction followed in a national program
- 2012
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Ingår i: Journal of Pediatric Urology. - : Elsevier. - 1477-5131 .- 1873-4898. ; 8:2, s. 187-193
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Neurogenic bladder-sphincter dysfunction (NBSD) constitutes the major reason for morbidity in children with spina bifida. The aim of this study was to identify risk factors for renal damage in children with NBSD followed according to the Swedish national guidelines. MATERIALS AND METHODS: Records and cystometries from 6 to 16 years (median 11) follow up of 41 consecutive children born 1993-2003 with NBSD were evaluated. The children were divided into a high pressure group (baseline pressure above 30 cmH(2)O at maximal clean intermittent catheterization volume in at least two cystometries) and a low pressure group. Most children (34/41) were followed from birth. RESULTS: Although renal scarring on DMSA-scintigraphy was found in 5/41 children, all but one had normal renal function. Two already had renal scars on entering the follow-up program at age 2.5 and 3 years. Renal scarring was more frequent in the high pressure group (P < 0.01). Most children with renal scars (4/5) had a combination of low compliant bladder and insufficient compliance with treatment and follow up. CONCLUSION: High baseline pressure is confirmed as a risk factor that, in combination with complex social issues, creates a demanding situation for families and professionals. A structured early follow up with treatment compliance effectively prevents renal damage.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Abreu-Vieira, Gustavo, et al.
(författare)
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Cidea improves the metabolic profile through expansion of adipose tissue
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative.
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| 13. |
- Adolfsson, Peter, et al.
(författare)
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Education and individualized support regarding exercise and diabetes improves glucose control and level of physical activity in type 1 diabetes individuals
- 2015
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Ingår i: Journal of Endocrinology Diabetes & Obesity. - : JSciMed Central. - 2333-6692. ; 3:2, s. 1071-1077
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Tidskriftsartikel (refereegranskat)abstract
- Background: Physical activity is advocated in all individuals with diabetes. However, good glycemic control can be difficult to achieve due to exercise induced glucose excursions.Objective: To evaluate the impact on glucose control of a structured diabetes education concerning physical activity, delivered via the web/internet together with telemedical care (individualized feedback by phone).Methods: Eighty-two individuals with type 1 (T1D) were included in the pre-race intervention and randomized into two groups: intervention (I) (n=48) and control (C) (n=48). Both groups received web-based training of sports and nutrition in relation to diabetes. The intervention group also received structured and individualized feedback on two different occasions. HbA1c was measured at baseline, after 3 and 6 months when a 45 km cross-country skiing race (the HalvVasa) was performed. Only the individuals attending the skiing race were eligible to be included in the study. Level of Physical Activity (LPA), Multidimensional Health Locus of Control (MHLC) and Confidence In Diabetes Self-care (CIDS) were assessed at baseline and after 7 months.Results: HbA1c at start was 58.5 ± 10.0 (I) respectively 60.7 ± 9.5 (C) mmol/mol. At 3 months 56.7 ± 8.7 (I) respectively 61.0 ± 9.6 (C) mmol/mol and at 6 months 55.7 ± 8.1 (I) respectively 60.3 ± 9.7 (C) mmol/mol. A significant in (I) at 3 months: 2.2 ± 3.8 mmol/mol (0.7-3.7, 95% CI), (p<0.05) and after 6 months: 2.8 ± 5.5 mmol/mol (0.5-5.0, 95% CI), (p<0.05). No reduction was seen in (C). However between the two groups no difference was noted. The LPA was increased in 52% of the participants in (I) respectively 7% in (C), a significant difference, p<0.05. No differences were seen regarding HbA1c or LPA in the control group.Conclusion: Education and individualized feedback, delivered via telemedicine, to physical active individuals with T1D resulted in improvements in glycemic control within the intervention group and improved level of physical activity and locus of control when compared to the control group(12) (PDF) Education and individualized support regarding exercise and diabetes improves glucose control and level of physical activity in type 1 diabetes individuals.
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| 14. |
- Adolfsson, Peter, 1963, et al.
(författare)
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Evaluation of glucose control when a new strategy of increased carbohydrate supply is implemented during prolonged physical exercise in type 1 diabetes
- 2015
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Ingår i: European Journal of Applied Physiology. - New York, USA : Springer. - 1439-6319 .- 1439-6327. ; 115:12, s. 2599-2607
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: In healthy individuals, high carbohydrate intake is recommended during prolonged exercise for maximum performance. In type 1 diabetes (T1D), this would alter the insulin requirements. The aim of the study was to evaluate the safety of high glucose supplementation during prolonged exercise and the glucose control when a novel strategy of increased carbohydrate supply was implemented during prolonged exercise in T1D.Methods: Eight subjects with T1D participated in a sports camp including sessions of prolonged exercise and individualized feedback during three consecutive days. This was later followed by a 90 km cross-country skiing race. Large amounts of carbohydrates, 75 g/h, were supplied during exercise and the insulin requirements were registered. Glucose was measured before, during and after exercise aiming at euglycaemia, 4-8 mmol/L (72-144 mg/dL). During the race, continuous glucose monitoring (CGM) was used as an aspect of safety and to allow direct and individual adjustments.Results: Compared to ordinary carbohydrate supply during exercise, the high carbohydrate supplementation resulted in significantly increased insulin doses to maintain euglycaemia. During the cross-country skiing race, the participants succeeded to reach mean target glucose levels; 6.5 ± 1.9 mmol/L (117 ± 34 mg/dL) and 5.7 ± 1.5 mmol/L (103 ± 27 mg/dL) at the start and finish of the race, respectively. Episodes of documented hypoglycemia (<4 mmol/L/72 mg/dL) were rare. CGM was used for adjustments.Conclusion: In this study, large carbohydrate supplementation in T1D individuals during prolonged aerobic exercise is safe and allows the subjects to maintain glycaemic control and indicates the feasibility of CGM under these conditions.
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| 15. |
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| 16. |
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| 17. |
- Alinezhad, Saeid, et al.
(författare)
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Validation of novel biomarkers for prostate cancer progression by the combination of bioinformatics, clinical and functional studies
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- The identification and validation of biomarkers for clinical applications remains an important issue for improving diagnostics and therapy in many diseases, including prostate cancer. Gene expression profiles are routinely applied to identify diagnostic and predictive biomarkers or novel targets for cancer. However, only few predictive markers identified in silico have also been validated for clinical, functional or mechanistic relevance in disease progression. In this study, we have used a broad, bioinformatics-based approach to identify such biomarkers across a spectrum of progression stages, including normal and tumor-adjacent, premalignant, primary and late stage lesions. Bioinformatics data mining combined with clinical validation of biomarkers by sensitive, quantitative reverse-transcription PCR (qRT-PCR), followed by functional evaluation of candidate genes in disease-relevant processes, such as cancer cell proliferation, motility and invasion. From 300 initial candidates, eight genes were selected for validation by several layers of data mining and filtering. For clinical validation, differential mRNA expression of selected genes was measured by qRT-PCR in 197 clinical prostate tissue samples including normal prostate, compared against histologically benign and cancerous tissues. Based on the qRT-PCR results, significantly different mRNA expression was confirmed in normal prostate versus malignant PCa samples (for all eight genes), but also in cancer-adjacent tissues, even in the absence of detectable cancer cells, thus pointing to the possibility of pronounced field effects in prostate lesions. For the validation of the functional properties of these genes, and to demonstrate their putative relevance for disease-relevant processes, siRNA knock-down studies were performed in both 2D and 3D organotypic cell culture models. Silencing of three genes (DLX1, PLA2G7 and RHOU) in the prostate cancer cell lines PC3 and VCaP by siRNA resulted in marked growth arrest and cytotoxicity, particularly in 3D organotypic cell culture conditions. In addition, silencing of PLA2G7, RHOU, ACSM1, LAMB1 and CACNA1D also resulted in reduced tumor cell invasion in PC3 organoid cultures. For PLA2G7 and RHOU, the effects of siRNA silencing on proliferation and cell-motility could also be confirmed in 2D monolayer cultures. In conclusion, DLX1 and RHOU showed the strongest potential as useful clinical biomarkers for PCa diagnosis, further validated by their functional roles in PCa progression. These candidates may be useful for more reliable identification of relapses or therapy failures prior to the recurrence local or distant metastases.
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| 18. |
- Andreasson, Erik, et al.
(författare)
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The MAP kinase substrate MKS1 is a regulator of plant defence responces
- 2005
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Ingår i: EMBO Journal. - : Wiley. - 1460-2075 .- 0261-4189. ; 24:14, s. 2579-2589
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Tidskriftsartikel (refereegranskat)abstract
- Arabidopsis MAP kinase 4 (MPK4) functions as a regulator of pathogen defense responses, because it is required for both repression of salicylic acid (SA)-dependent resistance and for activation of jasmonate (JA)-dependent defense gene expression. To understand MPK4 signaling mechanisms, we used yeast two-hybrid screening to identify the MPK4 substrate MKS1. Analyses of transgenic plants and genome-wide transcript profiling indicated that MKS1 is required for full SA-dependent resistance in mpk4 mutants, and that overexpression of MKS1 in wild-type plants is sufficient to activate SA-dependent resistance, but does not interfere with induction of a defense gene by JA. Further yeast two-hybrid screening revealed that MKS1 interacts with the WRKY transcription factors WRKY25 and WRKY33. WRKY25 and WRKY33 were shown to be in vitro substrates of MPK4, and a wrky33 knockout mutant was found to exhibit increased expression of the SA-related defense gene PR1. MKS1 may therefore contribute to MPK4-regulated defense activation by coupling the kinase to specific WRKY transcription factors.
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| 19. |
- Angot, Elodie, et al.
(författare)
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Alpha-Synuclein Cell-to-Cell Transfer and Seeding in Grafted Dopaminergic Neurons In Vivo.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Several people with Parkinson's disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10-22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, α-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of α-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred α-synuclein. We now demonstrate frequent transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in vivo, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the transferred α-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology.
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| 20. |
- Bajic, Dragan, 1957-, et al.
(författare)
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Incomplete hippocampal inversion-is there a relation to epilepsy?
- 2009
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Ingår i: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 19:10, s. 2544-2550
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Tidskriftsartikel (refereegranskat)abstract
- Incomplete hippocampal inversion (IHI) has been described in patients with epilepsy or severe midline malformations but also in nonepileptic subjects without obvious developmental anomalies. We studied the frequency of IHI in different epilepsy syndromes to evaluate their relationship. Three hundred patients were drawn from the regional epilepsy register. Of these, 99 were excluded because of a disease or condition affecting the temporal lobes or incomplete data. Controls were 150 subjects without epilepsy or obvious intracranial developmental anomalies. The coronal MR images were analysed without knowledge of the clinical data. Among epilepsy patients, 30% had IHI (40 left-sided, 4 right-sided, 16 bilateral). Of controls, 18% had IHI (20 left-sided, 8 bilateral). The difference was statistically significant (P < 0.05). Of temporal lobe epilepsy (TLE) patients, 25% had IHI, which was not a significantly higher frequency than in controls (P = 0.34). There was no correlation between EEG and IHI laterality. A total of 44% of Rolandic epilepsy patients and 57% of cryptogenic generalised epilepsy patients had IHI. The IHI frequency was very high in some epileptic syndromes, but not significantly higher in TLE compared to controls. No causality between TLE and IHI could be found. IHI can be a sign of disturbed cerebral development affecting other parts of the brain, maybe leading to epilepsy.
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| 21. |
- Bajic, Dragan, et al.
(författare)
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Incomplete inversion of the hippocampus : a common developmental anomaly
- 2008
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Ingår i: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 18:1, s. 138-142
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Tidskriftsartikel (refereegranskat)abstract
- Incomplete inversion of the hippocampus, an imperfect fetal development, has been described in patients with epilepsy or severe midline malformations. We studied this condition in a nonepileptic population without obvious developmental anomalies. We analyzed the coronal MR images of 50 women and 50 men who did not have epilepsy. Twenty of them were healthy volunteers and 80 were patients without obvious intracranial developmental anomalies, intracranial masses, hydrocephalus or any condition affecting the temporal lobes. If the entire hippocampus (the head could not be evaluated) were affected, the incomplete inversion was classified as total, otherwise as partial. Incomplete inversion of the hippocampus was found in 19/100 subjects (9 women, 10 men). It was unilateral, always on the left side, in 13 subjects (4 women, 9 men): 9 were of the total type, 4 were partial. It was bilateral in six subjects (five women, one man): four subjects had total types bilaterally, two had a combination of total and partial types. The collateral sulcus was vertically oriented in all subjects with a deviating hippocampal shape. We conclude that incomplete inversion of the hippocampus is not an unusual morphologic variety in a nonepileptic population without other obvious intracranial developmental anomalies.
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| 22. |
- Baumeister, Hannah, et al.
(författare)
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A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings
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Ingår i: Brain : a journal of neurology. - 1460-2156. ; 147:7, s. 2400-2413
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Tidskriftsartikel (refereegranskat)abstract
- Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.
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| 23. |
- Bemark, Mats, 1967, et al.
(författare)
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A Unique Role of the Cholera Toxin A1-DD Adjuvant for Long-Term Plasma and Memory B Cell Development
- 2011
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 186:3, s. 1399-1410
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Tidskriftsartikel (refereegranskat)abstract
- Adjuvants have traditionally been appreciated for their immunoenhancing effects, whereas their impact on immunological memory has largely been neglected. In this paper, we have compared three mechanistically distinct adjuvants: aluminum salts (Alum), Ribi (monophosphoryl lipid A), and the cholera toxin A1 fusion protein CTA1-DD. Their influence on long-term memory development was dramatically different. Whereas a single immunization i.p. with 4-hydroxy-3-nitrophenyl acetyl (NP)-chicken γ-globulin and adjuvant stimulated serum anti-NP IgG titers that were comparable at 5 wk, CTA1-DD–adjuvanted responses were maintained for >16 mo with a half-life of anti-NP IgG ∼36 wk, but <15 wk after Ribi or Alum. A CTA1-DD dose-dependent increase in germinal center (GC) size and numbers was found, with >60% of splenic B cell follicles hosting GC at an optimal CTA1-DD dose. Roughly 7% of these GC were NP specific. This GC-promoting effect correlated well with the persistence of long-term plasma cells in the bone marrow and memory B cells in the spleen. CTA1-DD also facilitated increased somatic hypermutation and affinity maturation of NP-specific IgG Abs in a dose-dependent fashion, hence arguing that large GC not only promotes higher Ab titers but also high-quality Ab production. Adoptive transfer of splenic CD80+, but not CD80−, B cells, at 1 y after immunization demonstrated functional long-term anti-NP IgG and IgM memory cells. To our knowledge, this is the first report to specifically compare and document that adjuvants can differ considerably in their support of long-term immune responses. Differential effects on the GC reaction appear to be the basis for these differences.
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| 24. |
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| 25. |
- Berg, Ulrika, et al.
(författare)
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Lack of sex differences in the IGF-IGFBP response to ultra endurance exercise.
- 2008
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : Wiley. - 0905-7188 .- 1600-0838. ; 18:6, s. 706-714
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Tidskriftsartikel (refereegranskat)abstract
- The insulin-like growth factor (IGF)-IGF binding proteins (BP) and the pituitary-gonadal axes were investigated during ultra endurance exercise in 16 endurance-trained athletes (seven women). Median duration of the race was 6.3 days. Although food and drink were ad libitum, energy balance was negative. Blood samples were drawn before (PRE), at the end of (END) and 24 h after (POST24h) the race. Serum concentrations of total IGF-I (t-IGF-I) and free IGF-I (f-IGF-I) decreased by 33 (SD 38)% and 54 (19)%, respectively. The decrease in t-IGF-I appeared to be associated to the total energy deficit during the race. At END, the IGFBP-3 fragmentation and IGFBP-1 were increased but these changes did not predict changes in f-IGF-I. An increase in POST24h IGFBP-2 levels in women was the only sex difference. Testosterone was decreased by 67 (12)% in the men and estradiol became undetectable in the women without any detectable increase in LH and/or FSH. In conclusion ultra endurance exercise results in similar IGF-IGFBP responses in men and women reflecting a catabolic state. IGFBP-2 was the only exception, with increased levels in women after exercise. A concomitant decrease in gonadal hormones was not related to endocrine changes in the IGF-IGFBP axis but may be related to local changes in IGF-I expression.
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