| 1. |
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| 2. |
- Ihalainen, Saara, et al.
(författare)
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Proteome analysis of cultivated vascular smooth muscle cells from a CADASIL patient
- 2007
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Ingår i: Molecular Medicine. - 1076-1551 .- 1528-3658. ; 13:5-6, s. 305-314
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a vascular dementing disease caused by mutations in NOTCH3 gene, a majority of which are missense mutations leading to an uneven number of cysteine residues in epidermal growth factor like repeats in the extracellular domain of Notch3 receptor (N3ECD). Disease is characterized by degeneration of vascular smooth muscle cells (VSMC) and accumulation of N3ECD on the VSMCs of small and middle-sized arteries. Recent studies have demonstrated that impairment of Notch3 signaling is not the primary cause of the disease. In the present study we have characterized the protein expression pattern of a unique material of genetically genuine cultured human CADASIL VSMCs by proteomic analysis. We identified 11 differentially expressed proteins, which are involved in protein degradation and folding, contraction of VSMCs and cellular stress. Based on the results the misfolding of Notch3 seems to cause endoplasmic reticulum stress and activation of unfolded protein response leading to increased reactive oxygen species and inhibition of cell proliferation. In addition, upregulation of contractile proteins suggests an alteration in the signalling system of VSMC contraction. The accumulation of the N3ECD on the cell surface possibly upregulates the angiotensin II regulatory feedback loop and thereby enhances the readiness of the cells to respond to angiotensin II stimulation.
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| 3. |
- Järvelä, Sally, et al.
(författare)
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Antioxidant enzymes in oligodendroglial brain tumors : association with proliferation, apoptotic activity and survival
- 2006
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Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 77:2, s. 131-40
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Tidskriftsartikel (refereegranskat)abstract
- Purpose of the study was to investigate the relationship between antioxidant enzyme expression and clinicopathological features in oligodendroglial tumors. The expression of antioxidant enzymes and related proteins (AOEs), manganese superoxide dismutase (MnSOD), thioredoxin (Trx), thioredoxin reductase (TrxR) and gammaglutamylcysteine synthetase catalytic and regulatory subunits (GLCL-C and GLCL-R), was studied in 85 oligodendroglial tumors. The material included 71 primary (43 grade II and 28 grade III) and 14 recurrent (6 grade II and 8 grade III) tumors. Fifty-seven cases were pure oligodendrogliomas and 28 were mixed oligoastrocytomas. Immunoreactivity for MnSOD was found in 89%, Trx in 29%, TrxR in 76%, GLCL-C in 70% and GLCL-R in 68% of cases. Increased Trx expression was associated with higher tumor grade, cell proliferation and apoptosis (P=0.006, P=0.001 and P=0.003, Mann-Whitney test). Pure oligodendrogliomas showed more intense staining than oligoastrocytomas, especially for MnSOD (P=0.002, Mann-Whitney test). In the total series Trx was associated with poor prognosis in univariate survival analysis (P=0.0343, log-rank test) and furthermore in Cox multivariate analysis (P=0.009) along with age (P=0.002). The results suggest that the expression of Trx has a correlation to patient outcome and that there may be some association between AOEs, like MnSOD and Trx, and clinicopathological features of oligodendrogliomas.
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| 4. |
- Järvelä, Sally, et al.
(författare)
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Decreased expression of antioxidant enzymes is associated with aggressive features in ependymomas
- 2008
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Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 90:3, s. 283-291
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to investigate the relationship between antioxidant enzyme expression and clinicopathological features in 67 ependymal tumors. We included into the analysis antioxidant enzymes (AOEs) and related proteins, such as, manganese superoxide dismutase (MnSOD), gammaglutamylcysteine synthetase catalytic and regulatory subunits (GLCL-C and GLCL-R), thioredoxin (Trx) and thioredoxin reductase (TrxR). Their expression was studied in 46 primary (10 grade I, 30 grade II and 6 grade III) and 21 recurrent (3 grade I, 12 grade II and 6 grade III) tumors. Immunoreactivity for MnSOD was found in 87%, GLCL-C in 74%, GLCL-R in 89%, Trx in 72%, TrxR in 54%, of primary tumors. Lower GLCL-C and GLCL-R expression was associated with higher tumor grade (P = 0.047 and 0.049, respectively). MnSOD, GLCL-C and TrxR expressions were significantly higher in tumors located in the spinal cord compared to those in the brain (P = 0.044, 0.046 and 0.004, respectively). In the primary tumors Trx-positivity was found to correlate significantly with patient survival. In univariate survival analysis patients whose tumors did not express Trx had shorter survival (P = 0.045) and there was even more significant association (P = 0.011) when only adults were included in the analysis (in the total material median follow-up time of Trx-positive tumors was 9.7 years and of Trx-negative 5.4 years). The results indicate that AOEs have several biological functions in ependymal tumors. Trx had important prognostic value: all adults with Trx-positive tumors were alive at follow-up (median 7.8 years).
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| 5. |
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| 6. |
- Raheem, Olayinka, et al.
(författare)
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Hartia-lantiodystrofioiden molekyyligenetiikka Suomessa
- 2006
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Ingår i: Duodecim; lääketieteellinen aikakauskirja. - 0012-7183. ; 122:17, s. 2130-2136
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Tidskriftsartikel (refereegranskat)abstract
- Hartia-lantiolihasdystrofia (limb girdle muscular dystrophy, LGMD) oli ennen kyseisen taudin geenien löytämistä käytetty diagnoosi potilasryhmälle, jolla ei ole todettu muuta tunnistettua dystrofiaa, kuten X-kromosomaalista Duchennen tai Beckerin lihasdystrofiaa, vallitsevasti periytyvää fasioskapulohumeraalista lihasdystrofiaa, distaalista myopatiaa tai synnynnäistä lihasdystrofiaa. Suomessa tämän ryhmän potilailla on usein ollut diagnoosina dystrophia musculorum progressiva NUD. Vuonna 1991 löydettiin ensimmäinen LGMD:tä aiheuttava geenivirhe, ja nykyään voidaan molekyyligeneettisesti eritellä 17 eri alalajia, eivätkä nämäkään kata kaikkia tapauksia. Joidenkin alalajien diagnoosi on ollut mahdollista tehdä proteiinipuutoksen osoittavalla immunohistokemiallisella biopsialeikkeen värjäyksellä, ja menetelmä on tarjolla maamme neuropatologian laboratorioissa. TAYS:aan perustetussa lihastautien erityisdiagnostiikan keskuksessa on mahdollista etsiä tämän ryhmän geeni- ja proteiinivirheitä DNA- ja Western blotting -menetelmin. Mutaatiot kalpaiini 3-, FKRP- (fukutin-related protein) ja alfasarkoglykaanigeeneissä näyttävät olevan tärkeimmät suomalaisessa väestössä.
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| 7. |
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| 8. |
- Aaltonen, Minna, et al.
(författare)
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Inhaled nitric oxide treatment inhibits neuronal injury after meconium aspiration in piglets
- 2007
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Ingår i: Early Human Development. - : Elsevier BV. - 0378-3782 .- 1872-6232. ; 83:2, s. 77-85
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Tidskriftsartikel (refereegranskat)abstract
- Background: Meconium aspiration-induced hypertensive lung injury is frequently associated with neuronal damage. Inhaled nitric oxide (iNO) is widely used in the treatment of pulmonary hypertension, but its effects on the brain are poorly known. Aims: The aim of this study was to determine the effects of iNO treatment on the neuronal tissue after meconium aspiration. Study design: 71 anesthetized, catheterized and ventilated newborn piglets were studied for 6 h. Thirty-five piglets were instilled with a bolus of human meconium intratracheally and 36 piglets with saline instillation served as controls. Nineteen meconium piglets and 17 control piglets were continuously treated with 20 ppm of iNO, started at 30 min after the insult. The extent of neuronal injury was analysed histologically, and the levels of brain tissue lipid peroxidation products, reduced glutathione (GSH), myeloperoxidase activity and oxidized DNA were analysed as indicators of oxidative stress. Results: iNO treatment diminished the pulmonary hypertensive response caused by meconium aspiration, but did not change systemic or carotid hemodynamics. NO administration was associated with reduced neuronal injury and diminished amount of oxidized DNA in the hippocampus of the meconium piglets. Further, iNO treatment was associated with decreased level of GSH in the cortex, but no change in lipid peroxidation production or myeloperoxidase activity was detected in any of the studied brain areas. Conclusions: Our results suggest that iNO treatment may inhibit DNA oxidation and neuronal injury in the hippocampus, associated with newborn meconium aspiration.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
- Craggs, L. J. L., et al.
(författare)
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Clusterin/Apolipoprotein J immunoreactivity is associated with white matter damage in cerebral small vessel diseases
- 2016
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 42:2, s. 194-209
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Tidskriftsartikel (refereegranskat)abstract
- AimBrain clusterin is known to be associated with the amyloid- deposits in Alzheimer's disease (AD). We assessed the distribution of clusterin immunoreactivity in cerebrovascular disorders, particularly focusing on white matter changes in small vessel diseases. MethodsPost-mortem brain tissues from the frontal or temporal lobes of a total of 70 subjects with various disorders including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral amyloid angiopathy (CAA) and AD were examined using immunohistochemistry and immunofluorescence. We further used immunogold electron microscopy to study clusterin immunoreactivity in extracellular deposits in CADASIL. ResultsImmunostaining with clusterin antibodies revealed strong localization in arterioles and capillaries, besides cortical neurones. We found that clusterin immunostaining was significantly increased in the frontal white matter of CADASIL and pontine autosomal dominant microangiopathy and leukoencephalopathy subjects. In addition, clusterin immunostaining correlated with white matter pathology severity scores. Immunostaining in axons ranged from fine punctate deposits in single axons to larger confluent areas with numerous swollen axon bulbs, similar to that observed with known axon damage markers such as non-phosphorylated neurofilament H and the amyloid precursor protein. Immunofluorescence and immunogold electron microscopy experiments showed that whereas clusterin immunoreactivity was closely associated with vascular amyloid- in CAA, it was lacking within the granular osmiophilic material immunolabelled by NOTCH3 extracelluar domain aggregates found in CADASIL. ConclusionsOur results suggest a wider role for clusterin associated with white matter damage in addition to its ability to chaperone proteins for clearance via the perivascular drainage pathways in several disease states.
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| 14. |
- Craggs, Lucinda, et al.
(författare)
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Quantitative vascular pathology and phenotyping familial and sporadic cerebral small vessel diseases
- 2013
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Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 23:5, s. 547-557
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Tidskriftsartikel (refereegranskat)abstract
- We quantified vascular changes in the frontal lobe and basal ganglia of four inherited small vessel diseases (SVDs) including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), hereditary multi-infarct dementia of Swedish type (Swedish hMID), and hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Vascular pathology was most severe in CADASIL, and varied with marginally greater severity in the basal ganglia compared to the frontal lobe. The overall sclerotic index values in frontal lobe were in the order CADASIL≥HERNS>PADMAL>Swedish hMID>sporadic SVD, and in basal ganglia CADASIL>HERNS>Swedish hMID>PADMAL> sporadic SVD. The subcortical white matter was almost always more affected than any gray matter. We observed glucose transporter-1 (GLUT-1) protein immunoreactivities were most affected in the white matter indicating capillary degeneration whereas collagen IV (COL4) immunostaining was increased in PADMAL cases in all regions and tissue types. Overall, GLUT-1:COL4 ratios were higher in the basal ganglia indicating modifications in capillary density compared to the frontal lobe. Our study shows that the extent of microvascular degeneration varies in these genetic disorders exhibiting common end-stage pathologies but is the most aggressive in CADASIL.
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| 15. |
- Deshpande, J, et al.
(författare)
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Ultrastructural changes in the hippocampal CA1 region following transient cerebral ischemia: evidence against programmed cell death.
- 1992
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Ingår i: Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. - 0014-4819. ; 88:1, s. 91-105
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Tidskriftsartikel (refereegranskat)abstract
- The ultrastructural changes in the pyramidal neurons of the CA1 region of the hippocampus were studied 6 h, 24 h, 48 h, and 72 h following a transient 10 min period of cerebral ischemia induced by common carotid occlusion combined with hypotension. The pyramidal neurons showed delayed neuronal death (DND), i.e. at 24 h and 48 h postischemia few structural alterations were noted in the light microscope, while at 72 h extensive neuronal degeneration was apparent. The most prominent early ultrastructural changes were polysome disaggregation, and the appearance of electron-dense fluffy dark material associated with tubular saccules. Mitochondria and nuclear elements appeared intact until frank neuronal degeneration. The dark material accumulated with extended periods of recirculation in soma and in the main trunks of proximal dendrites, often beneath the plasma membrane, less frequently in the distal dendrites and seldom in spines. Protein synthesis inhibitors (anisomycin, cycloheximide) and an RNA synthesis inhibitor (actinomycin D), administered by intrahippocampal injections or subcutaneously, did not mitigate neuronal damage. Therefore, DND is probably not apoptosis or a form of programmed cell death. We propose that the dark material accumulating in the postischemic period represents protein complexes, possibly aggregates of proteins or internalized plasma membrane fragments, which may disrupt vital cellular structure and functions, leading to cell death.
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| 16. |
- Eeg-Olofsson, Orvar, et al.
(författare)
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Duchenne muscular dystrophy and idiopathic hyperCKemia in the same family
- 2008
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Ingår i: European journal of paediatric neurology. - : Elsevier BV. - 1090-3798 .- 1532-2130. ; 12:5, s. 404-7
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Tidskriftsartikel (refereegranskat)abstract
- Familial hyperCKemia is a rare condition, and a combination with Duchenne muscular dystrophy (DMD) is extremely rare. A boy showed muscle weakness from the age of 10 months and presented typical signs of DMD at the age of 18 months. The diagnosis was supported by markedly elevated serum creatine kinase (CK) value as well as by neurophysiological and muscle biopsy findings at the age of 23 months. The diagnosis was confirmed by identification of a stop codon in exon 43 (p.2095Arg>X) of the dystrophin gene. Interestingly, the father and his near relatives had increased serum CK values without any clinical symptoms or signs, nor a defect in caveolin-3 gene. We suggest that the occurrence of familial hyperCKemia may have triggered the early onset of symptoms in our patient.
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| 17. |
- Fagerqvist, Therese, et al.
(författare)
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Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation
- 2013
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Ingår i: Journal of Neurochemistry. - : Wiley-Blackwell. - 0022-3042 .- 1471-4159. ; 126:1, s. 131-144
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Tidskriftsartikel (refereegranskat)abstract
- Inclusions of intraneuronal alpha-synuclein (-synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of -synuclein is a central feature of the disease pathogenesis. Among the different -synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large -synuclein oligomers were generated. These antibodies, which do not bind amyloid-beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in -synuclein transgenic mice than linear epitope antibodies. An oligomer-selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of -synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of -synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer-selective -synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker.
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| 18. |
- Falck, Björn, et al.
(författare)
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Neuromuskulaaritaudit
- 2004
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Ingår i: Lasten neurologia. - : Kustannus Oy Duodecim, Helsinki. - 951656058X ; , s. 391-419
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 19. |
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| 20. |
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| 21. |
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| 22. |
- Hägerstrand, Daniel, et al.
(författare)
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Gene expression analyses of grade II gliomas and identification of rPTPbeta/ as a candidate oligodendroglioma marker
- 2008
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Ingår i: Neuro-Oncology. - : Oxford University Press (OUP). - 1522-8517 .- 1523-5866. ; 10:1, s. 2-9
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Tidskriftsartikel (refereegranskat)abstract
- Grade 11 gliomas are morphologically and clinically heterogeneous tumors for which histopathological typing remains the major tool for clinical classification. To what extent the major histological subtypes-astrocytomas, oligodendrogliomas, and oligoastrocytomas-constitute true biological entities is largely unresolved. Furthermore, morphological classification is often ambiguous and would be facilitated by specific subtype markers. In this study, 23 grade II gliomas were expression-profiled and subjected to hierarchical clustering. All six oligodendrogliomas were grouped together in one of two major clusters; a significant correlation was thus observed between gene expression and histopathological subtype. Supervised analyses were performed to identify genes differentiating oligodendrogliomas from other grade II tumors. In a leave-one-out test using 10 features for classification, 20 out of 23 tumors were correctly classified. Among the most differentially expressed genes was rPT beta/zeta. The expression of the rPTP beta/zeta protein in oligodendrogliomas and astrocytomas was further validated by immunohistochemistry in an independent set of tumors. All 11 oligodendrogliomas of this set displayed strong staining. In contrast, neoplastic astrocytes were mostly negative for rPTP beta/zeta staining. In summary, this study demonstrates a correlation between gene expression pattern and histological subtype in grade 11 gliomas. Furthermore, the results from the immunohistochemical analyses of rPTP beta/zeta expression should prompt further evaluation of this protein as a novel oligodendroglioma marker.
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| 23. |
- Jin, Shaobo, et al.
(författare)
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Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells
- 2008
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Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 102:12, s. 1483-1491
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Tidskriftsartikel (refereegranskat)abstract
- Notch signaling is critically important for proper architecture of the vascular system, and mutations in NOTCH3 are associated with CADASIL, a stroke and dementia syndrome with vascular smooth muscle cell (VSMC) dysfunction. In this report, we link Notch signaling to platelet-derived growth factor (PDGF) signaling, a key determinant of VSMC biology, and show that PDGF receptor (PDGFR)-beta is a novel immediate Notch target gene. PDGFR-beta expression was upregulated by Notch ligand induction or by activated forms of the Notch receptor. Moreover, upregulation of PDGFR-beta expression in response to Notch activation critically required the Notch signal integrator CSL. In primary VSMCs, PDGFR-beta expression was robustly upregulated by Notch signaling, leading to an augmented intracellular response to PDGF stimulation. In newborn Notch3-deficient mice, PDGFR-beta expression was strongly reduced in the VSMCs that later develop an aberrant morphology. In keeping with this, PDGFR-beta upregulation in response to Notch activation was reduced also in Notch3-deficient embryonic stem cells. Finally, in VSMCs from a CADASIL patient carrying a NOTCH3 missense mutation, upregulation of PDGFR-beta mRNA and protein in response to ligand-induced Notch activation was significantly reduced. In sum, these data reveal a hierarchy for 2 important signaling systems, Notch and PDGF, in the vasculature and provide insights into how dysregulated Notch signaling perturbs VSMC differentiation and function.
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| 24. |
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| 25. |
- Järvinen, Tero A. H., et al.
(författare)
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Muscle injuries : optimising recovery
- 2007
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Ingår i: Baillière's Best Practice & Research. - : Elsevier BV. - 1521-6942 .- 1532-1770. ; 21:2, s. 317-331
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Tidskriftsartikel (refereegranskat)abstract
- Muscle injuries are one of the most common traumas occurring in sports. Despite their clinical importance, there are only a few clinical studies on the treatment of muscle injuries. Lack of clinical studies is most probably attributable to the fact that there is not only a high heterogeneity in the severity of injuries, but also the injuries take place in different muscles, making it very demanding to carry out clinical trials. Accordingly, the current treatment principles of muscle injuries have either been derived from experimental studies or been tested empirically only. Clinically, first aid for muscle injuries follows the RICE (Rest, Ice, Compression and Elevation) principle. The objective of RICE is to stop the injury-induced bleeding into the muscle tissue and thereby minimise the extent of the injury. Clinical examination should be carried out immediately after the injury and 5-7 days after the initial trauma, at which point the severity of the injury can be assessed more reliably. At that time, a more detailed characterisation of the injury can be made using imaging diagnostic modalities (ultrasound or MRI) if desired. The treatment of injured skeletal muscle should be carried out by immediate immobilisation of the injured muscle (clinically, relative immobility/avoidance of muscle contractions). However, the duration of immobilisation should be limited to a period sufficient to produce a scar of sufficient strength to bear the forces induced by remobilisation without re-rupture and the return to activity (mobilisation) should then be started gradually within the limits of pain. Early return to activity is needed to optimise the regeneration of healing muscle and recovery of the flexibility and strength of the injured skeletal muscle to pre-injury levels. The rehabilitation programme should be built around progressive agility and trunk stabilisation exercises, as these exercises seem to yield better outcome for injured skeletal muscle than programmes based exclusively on stretching and strengthening of the injured muscle.
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| 26. |
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| 27. |
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| 28. |
- Kalimo, Hannu, et al.
(författare)
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Hereditary Forms of Vascular Dementia
- 2005
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Ingår i: Cerebrovascular Diseases. - : ISN Neuropath Press, Basel. ; , s. 350-
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 29. |
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| 30. |
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| 31. |
- Kalimo, Hannu, et al.
(författare)
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The Arctic AβPP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated Aβ
- 2013
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 1:1, s. 60-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer's disease. Here we report the special character of Arctic AD neuropathology in four deceased patients.RESULTS: Aβ deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aβ aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aβ deposits contained variably truncated and modified wild type and mutated Aβ species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42. In the fourth patient plaque centres contained almost no Aβ making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aβ plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aβ plaques appeared relatively intact.CONCLUSIONS: In Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction.
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| 32. |
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| 33. |
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| 34. |
- Lindén, Thomas, 1962, et al.
(författare)
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Protective effect of lesion to the glutamatergic cortico-striatal projections on the hypoglycemic nerve cell injury in rat striatum.
- 1987
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Ingår i: Acta neuropathologica. - 0001-6322. ; 74:4, s. 335-44
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Tidskriftsartikel (refereegranskat)abstract
- In rat striatum severe hypoglycemia causes an irreversible nerve cell injury, which does not become manifest until during the post-insult recovery period. This injury can be ameliorated by lesions of the glutamatergic cortico-striatal pathway, which suggests that an "excitotoxic" effect mediated by the glutamatergic input is the likely cause of the post-hypoglycemic nerve cell destruction. In this paper we further characterize the protective effect of abolishing the glutamatergic innervation to striatum at the ultrastructural level. Two weeks after a unilateral cortical ablation rats were subjected to 30 min of severe hypoglycemia with isoelectric EEG and killed either immediately after the insult or following 60 min of recovery induced by restoring the blood glucose levels. Immediately after the hypoglycemic insult the structure of striatum was similar on both sides (except for the changes attributable to the ablation); i.e., the neurons and their dendrites had pale cytoplasm with condensed mitochondria, sparse RER and pinpoint ribosomes. After 60 min restitution numerous striatal neurons on the non-protected, non-ablated side had turned variably dark and condensed, whereas underneath the ablation they remained similar as immediately after hypoglycemia. This sequence indicates that the most likely cause of nerve cell destruction on the non-protected side is the "excitotoxic" effect mediated by the glutamatergic innervation, which is superimposed on the action of the hypoglycemic insult per se. Furthermore, the primary condensation of neurons and their dendrites indicate existence of another type of acute "excitotoxic" nerve cell injury which differs from the previously described injury characterized by neuronal swelling.
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| 35. |
- Lindén, Thomas, 1962, et al.
(författare)
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Risk of central pontine myelinolysis in the treatment of severe hyponatremia
- 1989
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Ingår i: Läkartidningen. - 0023-7205. ; 86:20, s. 1905-7
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Tidskriftsartikel (refereegranskat)abstract
- Central pontine myelinolysis is a life-threatening condition involving the demyelination of axons in certain areas of the brain. It has been shown almost invariably to occur in connection with hospital care. In recent years, a connection has been noted between the rapid restitution of low serum sodium and the development of the condition. In this review, the most recent scientific information is summarized. It is concluded that the risk should always be considered in treating a hyponatremic patient. The serum sodium level should be raised slowly and the acute treatment ended before normal serum sodium levels are reached, ie when the patient is still slightly hyponatremic.
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| 36. |
- Lindström, Mona, 1961-
(författare)
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Satellite cells in human skeletal muscle : molecular identification quantification and function
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Skeletal muscle satellite cells located between the plasma membrane and the basal lamina of muscle fibres, could for many years, only be studied in situ by electron microscopy. The introduction of immunohistochemistry and the discovery of molecular markers of satellite cells then made them accessible for light microscopic studies and a wealth of information is today available. Satellite cells are myogenic stem cells that can be activated from a quiescent state to proliferate for self-renewal or differentiate into myogenic cells. The satellite cells are involved in muscle growth during fetal and postnatal development and play a key role in repair and regeneration of damaged muscle fibres. The satellite cells are also essential for muscle fibre hypertrophy and maintenance of muscle mass in the adult. When the present thesis was initiated, studies on satellite cells in human skeletal muscle relied on the neuronal cell adhesion molecule (NCAM) as a marker for satellite cell identification. The results from different studies varied markedly. Therefore the aims of the present thesis were i) to develop a highly reliable method using light microscopy for satellite cell identification and quantification in biopsies of human skeletal muscle in normal and pathological conditions. A molecular marker for the myofibre basal lamina or plasma membrane to enhance the reliability of myonuclei and satellite cell identification were to be included. Furthermore unbiased morphometric methods should be used in the quantification process. ii) to evaluate which molecular markers which had been described for satellite cell and stem cell identification in different cell states (quiescence, activated or differentiated) are the most useful for studies on human skeletal muscle. iii) to further explore the function and heterogeneity of satellite cells with respect to different markers in human skeletal muscle by studying the effects of strength-training, intake of anabolic substances and pathological conditions. A new immunofluorescence method was developed where in the same tissue section, two satellite cell markers, the basal lamina and nuclei were monitored. From the evaluation of different markers it was found that both NCAM and Pax7 identified the majority of satellite cells but that both markers were needed for reliable identification. The members of the myogenic regulatory family were evaluated and by using the new method MyoD and myogenin were found to be useful markers to identify activated and differentiated satellite cells. Upon re-examination of biopsies from power-lifters, power-lifters using anabolic substances and untrained subjects it was observed that the new results on satellite cell frequency were significantly different from those obtained when using staining for NCAM and nuclei alone. In addition three subtypes of satellite cells (94.4% NCAM+/Pax7+, 4.2% NCAM+/Pax7– and 1.4% NCAM–/Pax7+) were observed. Thus the multiple marker method gave more information about satellite cells heterogeneity in human muscle and we propose that this is more reliable than previous methods. Low numbers of MyoD or myogenin stained satellite cells were observed in both untrained and strength trained subjects. Other markers such as DLK1/FA1, a member of the EGF-like family and c-Met, the receptor for hepatocyte growth factor showed that satellite cell heterogeneity in human muscle is far greater than previously shown. Furthermore, new evidence is presented for so called fibre splitting observed in hypertrophic muscle fibres to be due to defect regeneration of partially damaged fibres.
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| 37. |
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| 38. |
- Low, W C, et al.
(författare)
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Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL
- 2007
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 130:Part 2, s. 357-367
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Tidskriftsartikel (refereegranskat)abstract
- Several hereditary small vessel diseases (SVDs) of the brain have been reported in recent years. In 1977, Sourander and Wålinder described hereditary multi-infarct dementia (MID) in a Swedish family. In the same year, Stevens and colleagues reported chronic familial vascular encephalopathy in an English family bearing a similar phenotype. These disorders have invariably been suggested to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) but their genetic identities remain unknown. We used molecular, radiological and neuropathological methods to characterize these disorders. Direct DNA sequencing unexpectedly confirmed that affected members of the English family carried the R141C mutation in the NOTCH3 gene diagnostic of CADASIL. However, we did not detect any pathogenic mutations in the entire 8091 bp reading frame of NOTCH3 or find clear evidence for NOTCH3 gene linkage in the Swedish DNA. This was consistent with the lack of hyperintense signals in the anterior temporal pole and external capsule in Swedish subjects upon magnetic resonance imaging. We further found no evidence for granular osmiophilic material in skin biopsy or post-mortem brain samples of affected members in the Swedish family. In addition, there was distinct lack of NOTCH3 N-terminal fragments in the cerebral microvasculature of the Swedish hereditary MID subjects compared to the intense accumulation in the English family afflicted with CADASIL. Several differences in arteriosclerotic changes in both the grey and white matter were also noted between the disorders. The sclerotic index values, density of collagen IV immunoreactivity in the microvasculature and number of perivascular macrophages were greater in the English CADASIL samples compared to those from the Swedish brains. Multiple approaches suggest that the Swedish family with hereditary MID suspected to be CADASIL has a different novel disorder with dissimilar pathological features and belongs to the growing number of genetically uncharacterized familial SVDs.
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| 39. |
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| 40. |
- Melberg, Atle, et al.
(författare)
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Adult course in dynamin 2 dominant centronuclear myopathy with neonatal onset
- 2010
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 20:1, s. 53-56
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Tidskriftsartikel (refereegranskat)abstract
- We report a family with autosomal dominant centronuclear (myotubular) myopathy caused by a novel mutation, p.A618D, in dynamin 2 (DNM2). The 64-year-old mother and 26-year-old daughter had neonatal onset with hypotonia and weak suckling, followed by improvement, then slowly progressive muscle weakness and respiratory restriction. Muscle biopsy showed radial sarcoplasmic strands around the frequent central nuclei. Electrophysiology revealed predominantly myopathic patterns without peripheral nerve involvement. Centronuclear myopathy with neonatal onset caused by a DNM2 mutation in the C-terminal part of the pleckstrin homology domain may have a favorable prognosis and follow a course similar to adult-onset centronuclear myopathy. We advise respiratory follow-up in these patients.
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| 41. |
- Melberg, Atle, et al.
(författare)
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MR characteristics and neuropathology in adult-onset autosomal dominant leukodystrophy with autonomic symptoms
- 2006
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Ingår i: American Journal of Neuroradiology. - 0195-6108 .- 1936-959X. ; 27:4, s. 904-11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Three families with adult-onset autosomal dominant leukodystrophy (ADLD) presenting autonomic dysfunction as the first symptom are reported. We describe detailed MR appearances of the brain in 2 new families and neuropathology in 2 patients and compare the findings with those in other adult-onset leukodystrophies. METHODS: Twenty subjects (12 women and 8 men; age range, 29-70 years) from 2 unrelated families with ADLD were examined with MR. Six subjects were asymptomatic. Fourteen had autonomic dysfunction. Eleven of them also had pyramidal signs and ataxia. The brains of 2 autopsied patients were examined histopathologically. RESULTS: Two subjects manifested no neurologic symptoms, signs, or MR pathology. Eighteen subjects displayed radiologic abnormalities ranging from subtle T2 high-signal-intensity changes in the upper corticospinal tract to extensive confluent white matter changes, predominantly in a frontoparietal distribution, along the corticospinal tracts down to the medulla oblongata and in the upper and middle cerebellar peduncles. Periventricular white matter was spared or less affected than the adjacent white matter. Histopathology revealed marked loss of cerebral and cerebellar myelin without signs of inflammation. Oligodendrocytes were relatively spared, the number of axons not markedly decreased, and reactive gliosis was modest. The number of Purkinje cells in the cerebellum was reduced. CONCLUSIONS: Two families with adult-onset ADLD with the disease entity originally reported by Eldridge et al. (N Engl J Med 1984;311:948-53) were described. We propose naming the disease "adult-onset ADLD with autonomic symptoms." The characteristic radiologic findings, combined with the clinical symptoms and mode of inheritance, enable the diagnosis.
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| 42. |
- Miao, Qing, et al.
(författare)
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Arterioles of the lenticular nucleus in CADASIL
- 2006
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 16, s. S90-S90
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose-In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) the arteriopathy leads to recurrent infarcts in cerebral white matter (WM) and deep gray matter (GM), whereas cortex is spared. To assess the pathogenesis of deep GM infarcts, we analyzed structural changes in arterioles of the lenticular nucleus (LN) in 6 CADASIL patients. Methods-Five elderly and one 32-year-old deceased CADASIL patients were studied. Seven elderly and 4 young deceased persons without cerebrovascular diseases served as controls. In addition to immunohistochemical analysis the external and luminal diameters of arterioles in the LN, cerebral cortex and WM were measured. The thickness of arteriolar wall and sclerotic index were calculated. Results-In CADASIL patients, LN arterioles were immunoreactive for the extracellular domain of Notch3 and collagen 1, whereas a-smooth muscle actin staining was irregular or negative. No major leakage of plasma fibrinogen or fibronectin was observed. Although in patients the walls of LN arterioles were significantly thicker than in controls, definite stenosis was not observed. Arteriolar lumina in the LN were not only significantly larger than in the WM, where most lacunar infarcts in CADASIL occur, but also larger than in cortical GM, where infarcts virtually never exist. Conclusions-Fibrotic thickening of the arteriolar walls without consequent stenosis occurs in the LN of CADASIL patients. The pathogenesis of lacunar infarcts in the WM and LN seem to be different, stenosis in the former and probably hemodynamic disturbances in the latter.
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| 43. |
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| 44. |
- Morris, James H., et al.
(författare)
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Vascular dementias
- 2004
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Ingår i: The neuropathology of dementia. - : Cambridge University Press, Cambridge. - 0 521 81915 6 ; , s. 289-329
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 45. |
- Mykkanen, Kati, et al.
(författare)
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Different Clinical Phenotypes in Monozygotic CADASIL Twins With a Novel NOTCH3 Mutation
- 2009
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 40:6, s. 2215-2218
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose-CADASIL is a hereditary arteriopathy causing recurrent strokes and cognitive decline. Because monozygotic twins have identical genetic background, differences in their environment and lifestyle could reveal factors that may influence CADASIL patients' clinical course, which is highly variable even within the same family. Methods-We describe differences in clinical and imaging findings in a pair of monozygotic CADASIL twins. Results-Twin B experienced his first-ever stroke 14 years earlier than twin A, and his symptoms, signs, and imaging findings were more severe. Distinguishing factors were twin B's smoking as well as twin A's physical activity and earlier statin treatment. Causative NOTCH3 mutation was a novel c.752G>A -substitution (p.Cys251Tyr). Conclusions-The phenotypic differences in these monozygotic twins suggest influence of environmental and lifestyle factors on the clinical course of CADASIL. (Stroke. 2009; 40: 2215-2218.)
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| 46. |
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| 47. |
- Nordfors, K., et al.
(författare)
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Peroxiredoxins and antioxidant enzymes in pilocytic astrocytomas
- 2007
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Ingår i: Clinical Neuropathology. - 0722-5091. ; 26:5, s. 210-218
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Peroxiredoxins are antioxidant enzymes (AOEs), which are redox-regulated thiol proteins with potential effects on the growth, invasion and drug resistance of neoplastic cells. In this study, their biology and clinical significance were examined in pilocytic astrocytomas (PAs). Material and methods: The expression of peroxiredoxins (Prx I-VI) was investigated in 105 PAs by the means of immunohistochemistry and compared with the expression of selected other antioxidant enzymes, cell proliferation, angiogenesis, apoptosis, p53, histopathology and patient survival. Results: Peroxiredoxins were strongly expressed in general suggesting that oxidative damage and consequent defense takes place during the progression of pilocytic astrocytomas. In agreement with this hypothesis, several other AOEs correlated with the degenerative features and angiogenesis possibly associated with reactive oxygen species-derived cellular damage. Moreover, the expression of the AOEs was associated with each other indicating a concurrent activation of the enzymes. With the exception of manganese superoxide dismutase (MnSOD), a strong expression of AOEs was generally associated with higher cell proliferation. Prx VI seemed to have a positive association with a longer recurrence-free interval while other AOEs had no association with patient survival. Many AOEs, such as MnSOD, induce chemo- and radioresistance and are highly elevated in aggressive malignancies. PAs lack this confounding factor, and these tumors are treated only by surgery Conclusions: Taken together, the results of this study on pilocytic astrocytomas suggest that the levels of Prxs and other AOEs and their related thiol proteins are generally strongly expressed in these tumors. At least Prx VI can contribute to tumor behavior which can make it a potential prognostic factor.
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| 48. |
- O'Callaghan, Paul, et al.
(författare)
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Heparan sulfate accumulation with Abeta deposits in Alzheimer's disease and Tg2576 mice is contributed by glial cells
- 2008
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Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 18:4, s. 548-561
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid beta-peptide (Abeta) plaques, one of the major neuropathological lesions in Alzheimer's disease (AD), can be broadly subdivided into two morphological categories: neuritic and diffuse. Heparan sulfate (HS) and HS proteoglycans (HSPGs) are codeposits of multiple amyloidoses, including AD. Although HS has been considered a limiting factor in the initiation of amyloid deposition, the pathological implications of HS in Abeta deposits of AD remain unclear. In this study, immunohistochemistry combined with fluorescence and confocal microscopy was employed to gain deeper insight into the accumulation of HS with Abeta plaques in sporadic and familial AD. Here we demonstrate that HS preferentially accumulated around the Abeta40 dense cores of neuritic plaques, but was largely absent from diffuse Abeta42 plaques, suggesting that Abeta42 deposition may occur independently of HS. A codeposition pattern of HS with Abeta deposits in Tg2576 mice was also examined. We identified the membrane-bound HSPGs, glypican-1 (GPC1) and syndecan-3 (SDC3), in glial cells associated with Abeta deposits, proximal to sites of HS accumulation. In mouse primary glial cultures, we observed increased levels of GPC1 and SDC3 following Abeta stimulation. These results suggest that HS codeposits with Abeta40 in neuritic plaques and is mainly derived from glial cells.
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| 49. |
- Peuralinna, Terhi, et al.
(författare)
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Neurofibrillary tau pathology modulated by genetic variation of alpha-synuclein
- 2008
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 64:3, s. 348-352
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed whether genetic variation of alpha-synuclein modulates the extent of neuropathological changes in a population-based autopsied sample of 272 elderly Finns. None of the 11 markers was associated with the extent of neocortical beta-amyloid pathology. The intron 4 marker rs2572324 was associated with the extent of neurofibrillary pathology (p = 0.0006, permuted p = 0.004; Braak stages IV-VI vs 0-II). The same variant also showed a trend for association with neocortical Lewy-related pathology. These results suggest for the first time that variation of alpha-synuclein modulates neurofibrillary tau pathology and support the recent observations of an interaction of alpha-synuclein and tau in neurodegeneration.
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| 50. |
- Philipson, Ola, et al.
(författare)
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A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice.
- 2009
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 30:9, s. 1393-405
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta (Abeta) is a major drug target in Alzheimer's disease. Here, we demonstrate that deposited Abeta is SDS insoluble in tgAPP-ArcSwe, a transgenic mouse model harboring the Arctic (E693G) and Swedish (KM670/671NL) APP mutations. Formic acid was needed to extract the majority of deposited Abeta in both tgAPP-ArcSwe and Alzheimer's disease brain, but not in a commonly used type of mouse model with the Swedish mutation alone. Interestingly, the insoluble state of Arctic Abeta was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, Abeta plaques displayed a patchy morphology with bundles of Abeta fibrils, whereas amyloid cores in tgAPP-Swe were circular with radiating fibrils. Amyloid was more densely stacked in tgAPP-ArcSwe, as demonstrated with a conformation sensitive probe. A reduced increase in plasma Abeta was observed following acute administration of an Abeta antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma Abeta efflux. TgAPP-ArcSwe, with its insoluble state of deposited Abeta, could serve as a complementary model to better predict the outcome of clinical trials.
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