Molecular Genetic Characterisation of Frontotemporal Dementia on Chromosome 3

Ashworth, A.; Lloyd, Sarah L; Brown, JM; Gydesen, Susanne; Sørensen, Søren Freiesleben; Brun, Arne; Englund, Elisabet; Humphreys, Christopher M.; Housman, David E.; Badura, Mary; Stanton, Vincent P.; Taylor, Katarzyna; Cameron, Judy L.; Munroe, D L; Johansson, Jenni; Rossor, Martin N.; Fisher, Elizabeth; Collinge, John

doi:10.1159/000051222

Cited by 55 publications

(30 citation statements)

References 35 publications

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“…Existing data suggest that enhanced apoptosis appears in the progression of CKD and uremic milieu per se is partly responsible for the phenomenon [1,2,3,9,10]. We demonstrated that expression of Bcl-2 decreased significantly in the course of CKD which remained the only independent predictor.…”

Section: Discussionmentioning

confidence: 51%

Mononuclear Leukocyte Apoptosis and Inflammatory Markers in Patients with Chronic Kidney Disease

et al. 2012

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Background/Aim: Increased apoptosis along with enhanced inflammation has been reported in hemodialysis and pre-dialysis patients. However, there is limited information at which stage during the progression of chronic kidney disease (CKD) the balance between pro- and anti-apoptotic mechanisms is disturbed and inflammatory response is activated. The aim of this study was to investigate possible alterations in apoptotic and inflammatory markers during CKD (stages 1–4) progression and the probable interactions between them. Methods: In a cross-sectional study, 152 steady-state CKD outpatients (83 males, 55%) with mean estimated glomerular filtration rate 46 (29–76) ml/min/1.73 m² were studied. Apoptosis was assessed in peripheral blood mononuclear cells by estimating Bcl-2 expression, annexin V-propidium iodine staining and serum soluble Fas (sFas) and Fas-ligand. Serum levels of C-reactive protein, tumor necrosis factor-α (TNF-α), interleukin-6 and plasma levels of fibrinogen were measured as markers of inflammation. Results: Bcl-2 expression was found to decrease significantly in both lymphocytes and monocytes from CKD stage 1 to 4. In contrast, the activity of sFas increased significantly and so did the levels of TNF-α and fibrinogen. The majority of these alterations occurred as soon as patients entered stage 3 of CKD. A multivariate regression analysis demonstrated that CKD remained a significant predictor of the aggregate of the assessed markers. Conclusions: Apoptosis appeared to increase across CKD stages 1–4, and this was associated with increased proinflammatory activity.

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Section: Discussionmentioning

confidence: 51%

Mononuclear Leukocyte Apoptosis and Inflammatory Markers in Patients with Chronic Kidney Disease

et al. 2012

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“…DNA ladders are produced by cleavage of genomic DNA between nucleosomes to generate fragments with lengths corresponding to multiple integers of approximately 180 bp [33]. These morphologic changes represent the classic hallmarks of apoptosis that are distinct from cell necrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Cendoroglo et al [33] reported an increased apoptosis level in PMN isolated from healthy controls and treated with uremic plasma. This is in agreement with the study by Sardenberg et al [36], who showed that in PMN from HD and uremic patients apoptosis was increased compared to PMN from healthy subjects.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Effects of <b><i>p</i></b>-Cresol in Renal Epithelial Tubular Cells

Brocca¹,

Virzì²,

Cal³

et al. 2013

Blood Purif

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Background: The uremic syndrome is characterized by a deterioration of kidney function due to the accumulation of uremic toxins. Currently, 100 different uremic toxins have been identified. Uremic toxins are particularly difficult to remove by conventional dialysis treatments and are the major causes of mortality in patients with chronic kidney disease (CKD). p-Cresol is a well-known uremic toxin which accumulates in uremic serum. Our aim was to evaluate the in vitro effect of p-cresol on apoptosis and necrosis in renal tubular cells (RTCs) to better understand the pathophysiological effect of this toxin on the kidney. Methods: We studied apoptosis and necrosis in RTCs, which were incubated for 24 h with increasing concentrations of p-cresol. A DNA ladder was noted in treated cells as a qualitative marker of the apoptotic process. Furthermore, we performed quantitative analysis of cell viability using a flow cytometer and assessed caspase-3 activity. Results: Incubation with p-cresol for 24 h resulted in a significant reduction in RTC viability. DNA isolated from RTCs incubated with increasing p-cresol concentrations for 24 h showed a ‘ladder' pattern of apoptosis at p-cresol concentrations of 10, 5 and 2.5 mg/l. However, we did not observe any significant changes in apoptosis levels detected by annexin V and caspase-3 compared with untreated cells. Cytofluorimetric analysis of necrosis highlighted significantly higher cell death rates in RTCs incubated with the higher p-cresol concentrations (range 40-10 mg/l) compared with other concentrations (5-2.5 mg/l) and untreated cells (p < 0.05). Necrosis induction was stronger at higher p-cresol concentrations. Conclusion: It is necessary to develop new therapeutic and dialytic strategies to manage p-cresol concentrations in CKD.

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“…Although the lack of analysis of other apoptotic markers is another limitation of our study, it can be speculated that the source of the cfDNA in our study might be apoptosis because of the size of genomic DNA sequences studied. Recent studies suggest that the state of uremia is associated with accelerated apoptosis of lymphocytes, monocytes and neutrophils [17,18,19,20]. Furthermore, caspase-dependent apoptosis of mononuclear cells, neutrophils and mesothelial cells induced by conventional glucose-containing PD solutions with a high glucose degradation product content have been reported [21,22,23,24].…”

Section: Discussionmentioning

confidence: 99%

Plasma Cell-Free DNA Levels in Children on Peritoneal Dialysis

et al. 2009

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Background/Aims: Plasma levels of cell-free DNA (cfDNA) are elevated in various clinical conditions including cancer, stroke, trauma, myocardial infarction, autoimmune disorders, and pregnancy-associated complications. Previously, increased cfDNA levels were reported during hemodialysis. However, there is limited data regarding cfDNA levels in peritoneal dialysis (PD) patients. The aim of this study was to investigate the levels of cfDNA in children on PD. Methods: Twenty-one children on PD (median age: 12; range: 4–18 years) and 21 healthy children (median age: 10; range: 6–16 years) were enrolled into the study. Plasma cfDNA was measured using a real-time quantitative PCR for the beta-globin gene. Results: The median concentrations of cfDNA in the plasma of PD patients and healthy controls were 2,205 genome-equivalents/ml of plasma (range: 39–5,845) and 1,033 genome-equivalents/ml of plasma (range: 254–5,116), respectively (p = 0.026). A significant positive correlation was observed between C-reactive protein levels and plasma cfDNA levels (r: 0.52, p < 0.0001). Conclusion: Our data have demonstrated for the first time that cfDNA is increased in children on PD treatment. However, the mechanism by which the levels of cfDNA is increased and the clinical significance of this finding in PD patients is unclear. Further studies are warranted to clarify the precise mechanism and clinical significance of elevated cfDNA in children on PD.

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Molecular Genetic Characterisation of Frontotemporal Dementia on Chromosome 3

Cited by 55 publications

References 35 publications

Mononuclear Leukocyte Apoptosis and Inflammatory Markers in Patients with Chronic Kidney Disease

Mononuclear Leukocyte Apoptosis and Inflammatory Markers in Patients with Chronic Kidney Disease

Cytotoxic Effects of <b><i>p</i></b>-Cresol in Renal Epithelial Tubular Cells

Plasma Cell-Free DNA Levels in Children on Peritoneal Dialysis

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