Age-Related Neuronal Degeneration: Complementary Roles of Nucleotide Excision Repair and Transcription-Coupled Repair in Preventing Neuropathology

Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa−/− and Csb−/− CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa−/− and Xpc−/− XP mice, but also occurred in XpdXPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa−/−, Csb−/−) or highly sporadic (Xpa−/−, Xpc−/−) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa−/− and Csb−/− TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR–deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival

Blood pressure and site-specific cancer mortality: evidence from the original Whitehall study

Studies relating blood pressure to cancer risk have some shortcomings and have revealed inconsistent findings. In 17498 middle-aged London-based government employees we related systolic and diastolic blood pressure recorded at baseline examination (1967-1970) to the risk of cancer mortality risk at 13 anatomical sites 25 years later. Following adjustment for potential confounding and mediating factors, inverse associations between blood pressure and mortality due to leukaemia and cancer of the pancreas (diastolic only) were seen. Blood pressure was also positively related to cancer of the liver and rectum (diastolic only). The statistically significant blood pressure-cancer associations seen in this large-scale prospective investigation offering high power were scarce and of sufficiently small magnitude as to be attributable to chance or confounding

Spatial variations in the incidence of breast cancer and potential risks associated with soil dioxin contamination in Midland, Saginaw, and Bay Counties, Michigan, USA

<p>Abstract</p> <p>Background</p> <p>High levels of dioxins in soil and higher-than-average body burdens of dioxins in local residents have been found in the city of Midland and the Tittabawassee River floodplain in Michigan. The objective of this study is threefold: (1) to evaluate dioxin levels in soils; (2) to evaluate the spatial variations in breast cancer incidence in Midland, Saginaw, and Bay Counties in Michigan; (3) to evaluate whether breast cancer rates are spatially associated with the dioxin contamination areas.</p> <p>Methods</p> <p>We acquired 532 published soil dioxin data samples collected from 1995 to 2003 and data pertaining to female breast cancer cases (<it>n </it>= 4,604) at ZIP code level in Midland, Saginaw, and Bay Counties for years 1985 through 2002. Descriptive statistics and self-organizing map algorithm were used to evaluate dioxin levels in soils. Geographic information systems techniques, the Kulldorff's spatial and space-time scan statistics, and genetic algorithms were used to explore the variation in the incidence of breast cancer in space and space-time. Odds ratio and their corresponding 95% confidence intervals, with adjustment for age, were used to investigate a spatial association between breast cancer incidence and soil dioxin contamination.</p> <p>Results</p> <p>High levels of dioxin in soils were observed in the city of Midland and the Tittabawassee River 100-year floodplain. After adjusting for age, we observed high breast cancer incidence rates and detected the presence of spatial clusters in the city of Midland, the confluence area of the Tittabawassee, and Saginaw Rivers. After accounting for spatiotemporal variations, we observed a spatial cluster of breast cancer incidence in Midland between 1985 and 1993. The odds ratio further suggests a statistically significant (<it>α </it>= 0.05) increased breast cancer rate as women get older, and a higher disease burden in Midland and the surrounding areas in close proximity to the dioxin contaminated areas.</p> <p>Conclusion</p> <p>These findings suggest that increased breast cancer incidences are spatially associated with soil dioxin contamination. Aging is a substantial factor in the development of breast cancer. Findings can be used for heightened surveillance and education, as well as formulating new study hypotheses for further research.</p

Collateral circulation: Past and present

Following an arterial occlusion outward remodeling of pre-existent inter-connecting arterioles occurs by proliferation of vascular smooth muscle and endothelial cells. This is initiated by deformation of the endothelial cells through increased pulsatile fluid shear stress (FSS) caused by the steep pressure gradient between the high pre-occlusive and the very low post-occlusive pressure regions that are interconnected by collateral vessels. Shear stress leads to the activation and expression of all NOS isoforms and NO production, followed by endothelial VEGF secretion, which induces MCP-1 synthesis in endothelium and in the smooth muscle of the media. This leads to attraction and activation of monocytes and T-cells into the adventitial space (peripheral collateral vessels) or attachment of these cells to the endothelium (coronary collaterals). Mononuclear cells produce proteases and growth factors to digest the extra-cellular scaffold and allow motility and provide space for the new cells. They also produce NO from iNOS, which is essential for arteriogenesis. The bulk of new tissue production is carried by the smooth muscles of the media, which transform their phenotype from a contractile into a synthetic and proliferative one. Important roles are played by actin binding proteins like ABRA, cofilin, and thymosin beta 4 which determine actin polymerization and maturation. Integrins and connexins are markedly up-regulated. A key role in this concerted action which leads to a 2-to-20 fold increase in vascular diameter, depending on species size (mouse versus human) are the transcription factors AP-1, egr-1, carp, ets, by the Rho pathway and by the Mitogen Activated Kinases ERK-1 and -2. In spite of the enormous increase in tissue mass (up to 50-fold) the degree of functional restoration of blood flow capacity is incomplete and ends at 30% of maximal conductance (coronary) and 40% in the vascular periphery. The process of arteriogenesis can be drastically stimulated by increases in FSS (arterio-venous fistulas) and can be completely blocked by inhibition of NO production, by pharmacological blockade of VEGF-A and by the inhibition of the Rho-pathway. Pharmacological stimulation of arteriogenesis, important for the treatment of arterial occlusive diseases, seems feasible with NO donors

Enriching a biomedical event corpus with meta-knowledge annotation

Background: Biomedical papers contain rich information about entities, facts and events of biological relevance. To discover these automatically, we use text mining techniques, which rely on annotated corpora for training. In order to extract protein-protein interactions, genotype-phenotype/gene-disease associations, etc., we rely on event corpora that are annotated with classified, structured representations of important facts and findings contained within text. These provide an important resource for the training of domain-specific information extraction (IE) systems, to facilitate semantic-based searching of documents. Correct interpretation of these events is not possible without additional information, e.g., does an event describe a fact, a hypothesis, an experimental result or an analysis of results? How confident is the author about the validity of her analyses? These and other types of information, which we collectively term meta-knowledge, can be derived from the context of the event.Results: We have designed an annotation scheme for meta-knowledge enrichment of biomedical event corpora. The scheme is multi-dimensional, in that each event is annotated for 5 different aspects of meta-knowledge that can be derived from the textual context of the event. Textual clues used to determine the values are also annotated. The scheme is intended to be general enough to allow integration with different types of bio-event annotation, whilst being detailed enough to capture important subtleties in the nature of the meta-knowledge expressed in the text. We report here on both the main features of the annotation scheme, as well as its application to the GENIA event corpus (1000 abstracts with 36,858 events). High levels of inter-annotator agreement have been achieved, falling in the range of 0.84-0.93 Kappa.Conclusion: By augmenting event annotations with meta-knowledge, more sophisticated IE systems can be trained, which allow interpretative information to be specified as part of the search criteria. This can assist in a number of important tasks, e.g., finding new experimental knowledge to facilitate database curation, enabling textual inference to detect entailments and contradictions, etc. To our knowledge, our scheme is unique within the field with regards to the diversity of meta-knowledge aspects annotated for each event. © 2011 Thompson et al; licensee BioMed Central Ltd

Plasma, oral fluid and sweat wipe ecstasy concentrations in controlled and real life conditions.

In a double-blind placebo controlled study on psychomotor skills important for car driving (Study 1), a 75 mg dose of 3,4methylenedioxymethamphetamine (MDMA) was administered orally to 12 healthy Volunteers who were known to be recreational MDMA-users. Toxicokinetic data were gathered by analysis of blood, urine. oral fluid and sweat wipes collected during the first 5 h after administration. Resultant plasma concentrations varied from 21 to 295 ng/ml, with an average peak concentration of 178 ng/ml observed between 2 and 4 h after administration. MDA concentrations never exceeded 20 ng/ml. Corresponding MDMA concentrations in oral fluid, as measured with a specific LC-MS/MS method (which required only 50 mul of oral fluid), generally exceeded those in plasma and peaked at an average concentration of 1215 ng/ml. A substantial intra- and inter-subject variability was observed with this matrix, and values ranged from 50 to 6982 ng/ml MDMA. Somewhat even 4-5 h after ingestion, the MDMA levels in sweat only averaged 25 ng/wipe. In addition to this controlled study, data were collected from 19 MDMA-users who participated in a driving simulator study (Study 2), comparing sober non-drug conditions with MDMA-only and multiple drug use conditions. In this particular study, urine samples were used for general drug screening and oral fluid was collected as an alternative to blood sampling. Analysis of oral fluid samples by LC-MS/MS revealed an average MDMA/MDEA concentration of 1121 ng/ml in the MDMA-only condition, with large inter-subject variability. This was also the case in the multiple drug condition, where generally, significantly higher concentrations of MDMA, MDEA and/or amphetamine were detected in the oral fluid samples. Urine screening revealed the presence of combinations such as MDMA, MDEA, amph, cannabis, cocaine, LSD and psilocine in the rnultiple-drug condition. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved