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Pathological Phenotype (pathological + phenotype)

Distribution by Scientific Domains

Medical Sciences	83%

Selected Abstracts

Role of vascular endothelial growth factor and angiopoietin systems in serum of Crohn's disease patients

INFLAMMATORY BOWEL DISEASES, Issue 1 2008
Inés D. Pousa
Abstract Background: The purposes of this study were to determine soluble angiogenic factors in Crohn's disease (CD) patients and to compare these factors according to the pathological behavior of the disease in order to establish a possible relationship with its evolution in patients with CD. Methods: Blood samples were collected from 70 patients with CD, grouped according to their phenotypic behavior, and from 30 healthy controls. Vascular endothelial growth factor (VEGF), placental growth factor (PlGF), angiopoietin 1 (Ang1), angiopoietin 2 (Ang2), and their cognate receptors [VEGFR1, VEGFR2, and angiopoietin receptor tyrosine kinase (Tie2)] were assayed by ELISA. Results: Circulating levels of VEGF, PlGF, VEGFR1, Ang2, and Tie2 were significantly higher in CD patients than in healthy controls (489 ± 271 versus 335 ± 118 pg/mL, P < 0.001; 31 ± 9 versus 23 ± 9 pg/mL, P < 0.001; 1.7 ± 0.4 versus 1.0 ± 0.3 ng/mL, P < 0.001; 4.8 ± 2.0 versus 3.9 ± 2.0 ng/mL, P < 0.05; and 36 ± 5 versus 22 ± 7 ng/mL, P < 0.001, respectively). Conversely, CD patients showed significantly lower serum levels of Ang1 than healthy controls (40 ± 12 versus 67 ± 22 ng/mL; P < 0.001). No differences between the groups were found in VEGFR2 serum level. The circulating levels of the angiogenic factors did not differ significantly when the CD patients were classified according to pathological phenotype. Conclusions: In comparison with healthy controls, CD patients were found to have an active angiogenic profile, as detected by significant alterations in levels of angiogenesis soluble markers. These patients did not differ in serum levels of angiogenic factors according to phenotypic disease behavior. (Inflamm Bowel Dis 2007) [source]

Frontotemporal lobar degeneration with ubiquitinated tau-negative inclusions and additional ,-synuclein pathology but also unusual cerebellar ubiquitinated p62-positive, TDP-43-negative inclusions

NEUROPATHOLOGY, Issue 4 2009
Andrew King
Mutations in the progranulin (PGRN) gene on chromosome 17 have been shown to be responsible for one non-tauopathy subtype of familial frontotemporal lobar degeneration , frontotemporal lobar degeneration with ubiquitinated, tau-negative inclusions (FTLD-U). Such cases have pathological similarities to sporadic cases with neuronal inclusions positive for ubiquitin, the ubiquitin binding protein, p62 and the newly recognised protein TDP-43 but negative for hyperphosphorylated (HP) tau. There has been a recent report on two families with a novel progranulin mutation where the neuropathology showed not only TDP-43 neuronal positivity but separate tau and/or ,-synuclein pathology. We describe an unusual case with some family history but no mutation in the progranulin gene. The pathological features were typical for FTLD-U but with additional significant ,-synuclein pathology, and unusual ubiquitin-positive, p62-positive, TDP-43-negative inclusions in the cerebellum. This case may represent a further pathological phenotype for familial FTLD-U. It also highlights the need for further investigations on the ubiquitin binding protein p62 as a marker in FTLD-U. It is certainly possible that the presence or absence of these ubiquitinated p62-positive yet TDP-43-negative cerebellar inclusions may act as a useful correlative factor in the future. [source]

APOE,4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A, protein

NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 3 2003
K. Chalmers
The relative amounts of amyloid ,-protein (A,) in cerebral blood vessels and parenchyma vary considerably amongst patients with Alzheimer's disease (AD). Although several mechanisms have been proposed to explain this variability, the underlying genetic and environmental determinants are still unclear, as are the functional consequences. Polymorphisms in APOE, the gene for apolipoprotein E (ApoE), influence the risk of developing AD and of deposition of A, within the brain. We examined the relationship between the APOE genotype and the relative extent of accumulation of A, as plaques within the cerebral parenchyma and in cortical blood vessels in the form of cerebral amyloid angiopathy (CAA), in autopsy brain tissue from 125 AD cases and from 53 elderly, neurologically normal controls of which 19 had CAA without other neuropathological features of AD. In the AD cases, we also assessed whether the severity of CAA was related to the age of onset and duration of dementia, risk factors for atherosclerotic vascular disease, and histologically demonstrable cerebral in-farcts or foci of haemorrhage. The APOE genotype was determined by a standard polymerase chain reaction-based method. Paraffin sections of frontal, temporal and parietal lobes were immunolabelled for A, and the parenchymal A, load (total A, minus vessel-associated A,) was quantified by computer-assisted image analysis. CAA severity was scored for cortical and leptomeningeal vessels. The relevant clinical data were obtained from the database of the South West Brain Bank. In AD, we found the severity of CAA to be strongly associated with the number of ,4 alleles (P < 0.0001) but the parenchymal A, load to be independent of APOE genotype. Cases with severe CAA had a lower parenchymal A, load than had those with moderate CAA (P = 0.003). Neither the severity of CAA nor the parenchymal A, load correlated with age of onset, duration of disease or age at death, and the severity of CAA also did not correlate with the presence of cerebral infarcts or foci of haemorrhage. These findings indicate that possession of the APOE,4 allele favours vascular over parenchymal accumulation of A, in AD. This may influence the pathogenesis of neurodegeneration in ,4-associated AD. [source]

p53/CEP-1 increases or decreases lifespan, depending on level of mitochondrial bioenergetic stress

AGING CELL, Issue 4 2009
Natascia Ventura
Summary Mitochondrial pathologies underlie a number of life-shortening diseases in humans. In the nematode Caenorhabditis elegans, severely reduced expression of mitochondrial proteins involved in electron transport chain-mediated energy production also leads to pathological phenotypes, including arrested development and/or shorter life; in sharp contrast, mild suppression of these same proteins extends lifespan. In this study, we show that the C. elegans p53 ortholog cep-1 mediates these opposite effects. We found that cep-1 is required to extend longevity in response to mild suppression of several bioenergetically relevant mitochondrial proteins, including frataxin , the protein defective in patients with Friedreich's Ataxia. Importantly, we show that cep-1 also mediates both the developmental arrest and life shortening induced by severe mitochondrial stress. These findings support an evolutionarily conserved function for p53 in modulating organismal responses to mitochondrial dysfunction and suggest that metabolic checkpoint responses may play a role in longevity control and in human mitochondrial-associated diseases. [source]

Classical sheep transmissible spongiform encephalopathies: pathogenesis, pathological phenotypes and clinical disease

NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2007
M. Jeffrey
Scrapie is a prion disease or transmissible spongiform encephalopathy (TSE) of sheep, goats and moufflon. As with its human counterparts, pathology consists of vacuolation, gliosis and accumulations of abnormal forms of a host prion protein (PrPd) in the brain of affected individuals. Immunohistochemical methods can be used to identify both the intracellular truncation sites of PrPd in different cell types (PrPd epitope mapping) and the different morphological patterns of accumulation (PrPd profiling). Differences in the inferred truncation sites of PrPd are found for different strains of sheep TSEs and for different infected cell types within individual strains. Immunochemical methods of characterizing strains broadly correspond to PrPd mapping discriminatory results, but distinct PrPd profiles, which provide strain- and source-specific information on both the cell types which sustain infection (cellular tropisms) and the cellular processing of PrPd, have no immunoblotting counterparts. The cause of neurological dysfunction in human is commonly considered to be neuronal loss secondary to a direct or indirect effect of the accumulation of PrPd. However, in sheep scrapie there is no significant neuronal loss, and relationships between different magnitudes, topographical and cytological forms of PrPd accumulation and clinical signs are not evident. PrPd accumulation also occurs in lymphoid tissues, for which there is indirect evidence of a pathological effect, in the peripheral nervous system and in other tissues. It is generally assumed that neuroinvasion results from infection of the enteric nervous system neurones subsequent to amplification of infectivity in lymphoid tissues and later spread via sympathetic and parasympathetic pathways. The evidence for this is, however, circumstantial. Accumulation of PrPd and presence of infectivity in tissues other than the nervous and lymphoreticular systems gives insights on the ways of transmission of infection and on food safety. [source]

4145: Analysis of mouse eye mutants as models for human diseases

ACTA OPHTHALMOLOGICA, Issue 2010
S JADEJA
Purpose The Eumodic (European Mouse Disease Clinic) project screens mouse knockout lines and ENU induced mutants for pathological phenotypes. Initially 2 of the strains identified with an eye defect by the Sanger MGP and a strain from the ENU mutagenesis screen at MRC Harwell have been selected for further investigation. Methods Following the initial primary phenotyping, pathology; histology; and immunohistochemistry was carried out on ocular tissue collected from mutant and control animals to determine defects in eye structure and development. This gave an indication to the underlying cause of the defects seen, enabling further molecular biology analysis. Results Btb/Poz Domain-containing Protein 12 (Btbd12) is a scaffold protein required for the formation of DNA repair complexes. The mouse knockout of this gene shows corneal opacity, dilated pupils and occasional microphthalmia, modelling the phenotypes seen in human diseases of defective DNA repair. The corneas of the mutant animals exhibit increased DNA damage which is likely to be the cause of the opacification. Solute Carrier Family 9 Member 8 (Slc9a8) is a Sodium/ Hydrogen exchanger and has previously been shown to play a role in ion exchange. The Slc9a8 knockout strain appears to have retinal degeneration and the males are infertile. The ENU-induced mutant Pedv128 exhibits defects in the retinal vasculature including defective vascular patterning and increased vascular leakage. Of particular interest is that this vascular phenotype is restricted to the eyes. Conclusion Investigation of mouse eye mutants can result in a better understanding of the pathology and underlying causes of human diseases. [source]