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Bartesaghi S.,University College London | Graziano V.,University College London | Graziano V.,University of Chieti Pescara | Galavotti S.,University College London | And 11 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis. Source


Hermanussen M.,Aschauhof | Stec K.,University of Potsdam | Assmann C.,University of Bamberg | Meigen C.,Deutsches Zentrum fur Neurodegenerative Erkrankungen | Van Buuren S.,TNO
American Journal of Human Biology | Year: 2016

Objectives: To reanalyze the between-population variance in height, weight, and body mass index (BMI), and to provide a globally applicable technique for generating synthetic growth reference charts. Methods: Using a baseline set of 196 female and 197 male growth studies published since 1831, common factors of height, weight, and BMI are extracted via Principal Components separately for height, weight, and BMI. Combining information from single growth studies and the common factors using in principle a Bayesian rationale allows for provision of completed reference charts. Results: The suggested approach can be used for generating synthetic growth reference charts with LMS values for height, weight, and BMI, from birth to maturity, from any limited set of height and weight measurements of a given population. Conclusion: Generating synthetic growth reference charts by incorporating information from a large set of reference growth studies seems suitable for populations with no autochthonous references at hand yet. © 2015 Wiley Periodicals, Inc. Source


Schaufele M.,Mannheim University of Applied Sciences | Schaufele M.,University of Heidelberg | Kohler L.,Deutsches Zentrum fur Neurodegenerative Erkrankungen | Kohler L.,University of Heidelberg | And 5 more authors.
Psychiatrische Praxis | Year: 2013

Objective: The study aimed to determine the prevalence of dementia and the degree of medical care among residents of nursing homes based on a nationally representative sample of nursing homes in Germany for the first time. Methods: Based on a probability sample of 609 long-term care institutions in Germany, we drew a sample of 86 facilities by applying a two-stage random procedure. All residents of the participating care facilities were comprehensively assessed by qualified nurses using a standardized Care and Behavior Assessment (CBA). Results: Of the 4,481 residents assessed in 58 care facilities (mean age 82.6 years;78 % female) on average 68.6 % (95 % CI: 67.0 - 69.8) were affected by a dementia-syndrome, 56.6 % by a severe dementia-syndrome. There were frequent contacts between residents and general practitioners, but provision of specialized medical care seemed to be deficient in many aspects. Conclusion: People with dementia form the major group of residents in German nursing homes. The study provides important data on need for care and health care planning. © Georg Thieme Verlag KG Stuttgart New York. Source


Forstl H.,TU Munich | Haass C.,Deutsches Zentrum fur Neurodegenerative Erkrankungen | Hemmer B.,TU Munich | Meyer B.,TU Munich | Halle M.,TU Munich
Deutsches Arzteblatt | Year: 2010

Background: Boxing has received increased public attention and acceptance in recent years. However, this development has not been accompanied by a critical discussion of the early and late health complications. Methods: We selectively review recent studies on the acute, subacute, and chronic neuropsychiatric consequences of boxing. Results: Cerebral concussions ("knock-outs") are the most relevant acute consequence of boxing. The number of reported cases of death in the ring seems to have mildly decreased. Subacute neuropsychological deficits appear to last longer than subjective symptoms. The associated molecular changes demonstrate neuronal and glial injury correlated with the number and severity of blows to the head (altered total tau, beta-amyloid, neurofilament light protein, glial fibrillary acidic protein, and neuron-specific enolase). The risk of a punch-drunk syndrome (boxer's dementia, dementia pugilistica) as a late effect of chronic traumatic brain injury is associated with the duration of a boxer's career and with his earlier stamina. There are similarities (e.g. increased risk with ApoE4-polymorphism, beta-amyloid pathology) and differences (more tau pathology in boxers) compared with Alzheimer's disease. Conclusion: Protective gear has led to a remarkable reduction of risks in amateur boxing. Similar measures can also be used in professional boxing, but may decrease the thrill, which does appeal to many supporters. Source


Kaut O.,University of Bonn | Ramirez A.,University of Bonn | Pieper H.,University of Bonn | Schmitt I.,Deutsches Zentrum fur Neurodegenerative Erkrankungen | And 2 more authors.
Dementia and Geriatric Cognitive Disorders | Year: 2014

Background: The cytokine tumor necrosis factor-alpha (TNF-α) is elevated in the blood of Alzheimer's disease (AD) patients. Epigenetic DNA modifications of the TNF-α promoter may account for the observed upregulation. Methods: We analyzed blood samples of 50 AD patients and 55 controls plus 4 AD and 4 control cortex samples using bisulfite sequencing PCR. Results: A significant hypomethylation of the TNF-α promoter was found in AD patients' brains but not in their blood. Cortical TNF-α promoter DNA was higher methylated than blood-derived DNA, both in AD patients and controls. Conclusion: In AD patients, epigenetic mechanisms of TNF-α gene regulation, like aberrant DNA methylation, are not relevant in blood. © 2014 S. Karger AG, Basel. Source

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