| 1. |
- Karlsson, Christine, et al.
(författare)
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Genetic intratumour heterogeneity in high-grade brain tumours is associated with telomere-dependent mitotic instability.
- 2007
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Ingår i: Neuropathology & Applied Neurobiology. - : Wiley. - 1365-2990 .- 0305-1846. ; 33:4, s. 440-454
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) and other high-grade brain tumours are typically characterized by complex chromosome abnormalities and extensive intratumour cytogenetic heterogeneity. The mechanisms behind this diversity have been little explored. In this study, we analysed the pattern of chromosome segregation at mitosis in 20 brain tumours. We found an abnormal segregation of chromatids at mitosis through anaphase bridging (10-25% of anaphase cells) in all 10 GBMs. Anaphase bridging was also found in two medulloblastomas (7-15%), one anaplastic astrocytoma (17%) and one oligodendroglioma (6%). These tumours showed a relatively high degree of cytogenetic complexity and heterogeneity. In contrast, cell division abnormalities were not found in low-grade brain tumours with less complex karyotypes, including two pilocytic astrocytomas and two ependymomas. Further analysis of two GBMs by fluorescence in situ hybridization with telomeric repeat probes revealed excessive shortening of TTAGGG repeats, indicating dysfunctional protection of chromosome ends. In xenografts established from these GBMs, there was a gradual reduction in cytogenetic heterogeneity through successive passages as the proportion of abnormally short telomeres was reduced and the frequency of anaphase bridges decreased from >25% to 0. However, bridging could be reintroduced in late-passage xenograft cells by pharmacological induction of telomere shortening, using a small-molecule telomerase inhibitor. Telomere-dependent abnormal segregation of chromosomes at mitosis is thus a common phenomenon in high-grade brain tumours and may be one important factor behind cytogenetic intratumour diversity in GBM.
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| 2. |
- Nordborg, C, et al.
(författare)
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Oedema-related tissue damage after temporary and permanent occlusion of the middle cerebral artery
- 1994
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Ingår i: Neuropathology & Applied Neurobiology. - : Wiley. - 1365-2990 .- 0305-1846. ; 20:1, s. 56-65
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Tidskriftsartikel (refereegranskat)abstract
- Eleven adults spontaneously-hypertensive male rats (SHR) were studied 22 h or 7 days after a 2 h unilateral occlusion of the right middle cerebral artery (MCA). Another 11 SHR were studied after 24 h or 7 days of permanent MCA ligation. The brain infarcts were significantly larger (P < 0.05) after permanent occlusion than after a 2 h occlusion. More extensive and widespread vasogenic oedema, emanating from the infarcts, was visualized immunohistochemically in the temporarily-ligated animals and the relative number of astrocytes in their contralateral hemispheres was greater, thereby indicating that the vasogenic oedema influences the degree of gliosis. An immunopositivity for albumin but not for fibrinogen extended via the white matter into the ipsilateral thalamic nuclei, where cytolytic nerve cell damage, severely shrunken and karyorrhectic nerve cells as well as gliosis were found one week after permanent and temporary MCA ligation. The histological changes in the thalamus indicated a difference in timing between lateral and medial parts of the lesion as well as between temporarily- and permanently-ligated SHR. These findings together with the close spatial correlation with albumin immunoreactivity indicate that the spread of extravasated plasma constituents or degradation products with the oedema bulk flow from the infarct influences the timing, character and extent of thalamic lesions after cerebral infarction.
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| 3. |
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| 4. |
- Alafuzoff, Irina, et al.
(författare)
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Beta-amyloid deposition in brains of subjects with diabetes
- 2009
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 35:1, s. 60-68
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Tidskriftsartikel (refereegranskat)abstract
- AIM:A causative association between diabetes mellitus (DM) and Alzheimer's disease (AD) has been suggested based on clinical and epidemiological studies. One hypothesis is that the link between DM and AD is related to the function of insulin-degrading enzyme (IDE), an enzyme that degrades not only insulin and pancreatic amylin but also beta-amyloid (Abeta). Thus, in diabetics, insulin and Abeta might compete for IDE and this might lead to an increase in Abeta. The objective of this study was to test the hypothesis that hyperinsulinaemia can elevate Abeta levels and thus contribute to AD pathology in humans.METHODS:Neuropathological examination was carried out employing conventional and immunohistochemical (IHC) methods of the brains obtained post mortem from 701 aged subjects.RESULTS:The loads of IHC/Abeta, silver stained neuritic plaques (NP) and neurofibrillary tangles (NFT) were significantly higher in subjects carrying the Apolipoprotein E e4 allele. In contrast, the loads of Abeta, NPs and NFT in the brains were not influenced by hyperglycaemia when comparing 134 diabetic with 567 non-diabetic subjects.CONCLUSIONS:We conclude that the hypothesis that hyperinsulinaemia would significantly elevate the Abeta load and thus increase the extent of AD pathology cannot be supported. Our result challenges the claim that DM is a direct risk factor of developing AD. Thus further studies on pathological lesions in demented diabetics should be conducted.
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| 5. |
- Thornell, Lars-Eric, et al.
(författare)
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Satellite cell dysfunction contributes to the progressive muscle atrophy in myotonic dystrophy type 1
- 2009
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 35:6, s. 529-633
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT Aims: Myotonic Dystrophy type 1 (DM1), one of the most common forms of inherited neuromuscular disorders in the adult, is characterized by progressive muscle weakness and wasting leading to distal muscle atrophy whereas proximal muscles of the same patients are spared during the early phase of the disease. In this report, the role of satellite cell dysfunction in the progressive muscular atrophy has been investigated. Methods: Biopsies were obtained from distal and proximal muscles of the same DM1 patients. Histological and immunohistological analyses were carried out and the past regenerative history of the muscle was evaluated. Satellite cell number was quantified in vivo and proliferative capacity was determined in vitro. Results: The size of the CTG expansion was positively correlated with the severity of the symptoms and the degree of muscle histopathology. Marked atrophy associated with typical DM1 features was observed in distal muscles of severely affected patients whereas proximal muscles were relatively spared. The number of satellite cells was significantly increased (2-fold) in the distal muscles whereas very little regeneration was observed as confirmed by telomere analyses and developmental MyHC staining (0,3% to 3%). The satellite cells isolated from the DM1 distal muscles had a reduced proliferative capacity (36%) and stopped growing prematurely with telomeres longer than control cells (8,4kb vs 7,1kb) indicating that the behaviour of these precursor cells was modified. Conclusions: Our results indicate that alterations in the basic functions of the satellite cells progressively impair the muscle mass maintenance and/or regeneration resulting in gradual muscular atrophy.
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| 7. |
- Dehghani, F., et al.
(författare)
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Inhibition of microglial and astrocytic inflammatory responses by the immunosuppressant mycophenolate mofetil
- 2010
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 36:7, s. 598-611
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Nucleotide depletion induced by the immunosuppressant mycophenolate mofetil (MMF) has been shown to exert neuroprotective effects. It remains unclear whether nucleotide depletion directly counteracts neuronal demise or whether it inhibits microglial or astrocytic activation, thereby resulting in indirect neuroprotection. Methods: Effects of MMF on isolated microglial cells, astrocyte/microglial cell co-cultures and isolated hippocampal neurones were analysed by immunocytochemistry, quantitative morphometry, and elisa. Results: We found that: (i) MMF suppressed lipopolysaccharide-induced microglial secretion of interleukin-1 beta, tumour necrosis factor-alpha and nitric oxide; (ii) MMF suppressed lipopolysaccharide-induced astrocytic production of tumour necrosis factor-alpha but not of nitric oxide; (iii) MMF strongly inhibited proliferation of both microglial cells and astrocytes; (iv) MMF did not protect isolated hippocampal neurones from excitotoxic injury; and (v) effects of MMF on glial cells were reversed after treatment with guanosine. Conclusions: Nucleotide depletion induced by MMF inhibits microglial and astrocytic activation. Microglial and astrocytic proliferation is suppressed by MMF-induced inhibition of the salvage pathway enzyme inosine monophosphate dehydrogenase. The previously observed neuroprotection after MMF treatment seems to be indirectly mediated, making this compound an interesting immunosuppressant in the treatment of acute central nervous system lesions.
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| 10. |
- Kovacs, Gabor G, et al.
(författare)
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Neuropathology of the hippocampus in FTLD-Tau with Pick bodies : A study of the BrainNet Europe Consortium
- 2013
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 39:2, s. 166-178
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurons. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. Methods: We evaluated immunoreactivity for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. Results: Mean age at death was 68.2 years (range 49 to 96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of FTD, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein immunoreactivity was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurons. Aβ immunoreactivity was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. Conclusions: 1) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; 2) even minor deviation from these morphological criteria suggests a different disorder; and 3) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.
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