A Model of Cardiovascular Disease Giving a Plausible Mechanism for the Effect of Fractionated Low-Dose Ionizing Radiation Exposure

Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally exposed groups receiving small daily radiation doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and cancer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapolation would be appropriate for this endpoint

Parameter Identifiability and Redundancy in a General Class of Stochastic Carcinogenesis Models

Background Heidenreich et al. (Risk Anal 1997 17 391–399) considered parameter identifiability in the context of the two-mutation cancer model and demonstrated that combinations of all but two of the model parameters are identifiable. We consider the problem of identifiability in the recently developed carcinogenesis models of Little and Wright (Math Biosci 2003 183 111–134) and Little et al. (J Theoret Biol 2008 254 229–238). These models, which incorporate genomic instability, generalize a large number of other quasi-biological cancer models, in particular those of Armitage and Doll (Br J Cancer 1954 8 1–12), the two-mutation model (Moolgavkar et al. Math Biosci 1979 47 55–77), the generalized multistage model of Little (Biometrics 1995 51 1278–1291), and a recently developed cancer model of Nowak et al. (PNAS 2002 99 16226–16231). Methodology/Principal Findings We show that in the simpler model proposed by Little and Wright (Math Biosci 2003 183 111–134) the number of identifiable combinations of parameters is at most two less than the number of biological parameters, thereby generalizing previous results of Heidenreich et al. (Risk Anal 1997 17 391–399) for the two-mutation model. For the more general model of Little et al. (J Theoret Biol 2008 254 229–238) the number of identifiable combinations of parameters is at most less than the number of biological parameters, where is the number of destabilization types, thereby also generalizing all these results. Numerical evaluations suggest that these bounds are sharp. We also identify particular combinations of identifiable parameters. Conclusions/Significance We have shown that the previous results on parameter identifiability can be generalized to much larger classes of quasi-biological carcinogenesis model, and also identify particular combinations of identifiable parameters. These results are of theoretical interest, but also of practical significance to anyone attempting to estimate parameters for this large class of cancer models

Associations between pre-pregnancy obesity and asthma symptoms in adolescents

Background: The high prevalence of children's asthma symptoms, worldwide, is unexplained. We examined the relation between maternal pre-pregnancy weight and body mass index (BMI), and asthma symptoms in adolescents. Methods: Data from 6945 adolescents born within the Northern Finland Birth Cohort 1986 were used. Prospective antenatal and birth outcome data, including maternal pre-pregnancy weight and BMI, and asthma symptoms in adolescent offspring at age 15–16 years, were employed. Logistic regression analyses were performed to examine the associations between relevant prenatal factors and asthma symptoms during adolescence. Results: Current wheeze (within the past year) was reported by 10.6% of adolescents, and physician-diagnosed asthma by 6.0%. High maternal pre-pregnancy BMI was a significant predictor of wheeze in the adolescents (increase per kilogram per square metre unit; 2.7%, 95% CI 0.9 to 4.4 for ever wheeze; 3.5%, 95% CI 1.3 to 5.8 for current wheeze), and adjusting for potential confounders further increased the risk (2.8%, 95% CI 0.5 to 5.1; 4.7%, 95% CI 1.9 to 7.7, respectively). High maternal pre-pregnancy weight, in the top tertile, also significantly increased the odds of current wheeze in the adolescent by 20% (95% CI 4 to 39), and adjusting for potential confounders further increased the risk (OR=1.52, 95% CI 1.19 to 1.95). Results were similar for current asthma. Furthermore, these significant associations were observed only among adolescents without parental history of atopy but not among those with parental history of atopy. Conclusions: The association demonstrated here between maternal pre-pregnancy overweight and obesity, and asthma symptoms in adolescents suggests that increase in asthma may be partly related to the rapid rise in obesity in recent years

Archaeological Excavation of State Circle, Annapolis, Maryland

Other State Circle Site records include: 18AP50, Bordley-Randall Site (area 11), http://hdl.handle.net/1903/11016 ; 18AP55, Donaldson House (area 2), http://hdl.handle.net/1903/11019 ; 18AP61, Public Well Site (area 18), http://hdl.handle.net/1903/11020Archaeological excavations were conducted at State Circle in Annapolis during the fall and winter of 1989-1990 by "Archaeology in Annapolis", a cooperative program between the University of Maryland, College Park and the Historic Annapolis Foundation. Excavation was conducted as part of the undergrounding of public utility wires within State Circle, Francis Street, and School Street. The work was undertaken to satisfy the conditions of compliance as set forth in the Annotated Code of Maryland, Article 83b, sections 5-617 and 5-18. Twenty excavation area were selected for excavation within the project area. Areas were selected based on data gathered during historical background research. Areas were also selected in an attempt to gather information concerning the Baroque town plan designed in 1695 by Royal Governor Francis Nicholson. Three sites previously identified in the project area (18AP22, 18AP28, and 18AP50) were tested. Nine additional sites were discovered during excavation (18AP54, 18AP55, 18AP56, 18AP57, 18AP58, 18AP59, 18AP60, 18AP61, and 18AP62). At least one hand dug 3 ft by 5 ft unit per site was excavated. In all, a total of 23 units were excavated

A novel 4-dimensional live-cell imaging system to study leukocyte-endothelial dynamics in ANCA-associated vasculitis

This work was supported by the Lauren Currie Twilight Foundation, NHS Grampian Renal Endowment Fund and Aberdeen University Development Fund.Peer reviewedPostprintPostprin

A Summary of Archaeological Excavations from 1983-1986 at the Green Family Print Shop, 18AP29, Annapolis, Maryland

18AP29, the Green Family Printshop, also known as the Jonas Green site, was excavated from 1983 to 1986 by Archaeology in Annapolis and Historic Annapolis Foundation. The site is not only the home of a significant figure in colonial Maryland but is also the location of one of the first colonial printing operations in Maryland. This site represents an important pre-industrial business in Annapolis. While this domestic site is complicated and rich, one of the most fascinating aspect of 18AP29 is the discovery of a large quantity of printers' type. Extensive analysis of the printers' type and documentary research on one of the print shop's products, the colonial newspaper, the Maryland Gazette, provides insights into the print culture which was developing during the 18th and 19th centuries. This report summarizes the stratigraphic analysis, minimum vessel counts, and faunal analysis. It provides some description of the printers' type

IL-6 Induced STAT3 Signalling Is Associated with the Proliferation of Human Muscle Satellite Cells Following Acute Muscle Damage

Although the satellite cell (SC) is a key regulator of muscle growth during development and muscle adaptation following exercise, the regulation of human muscle SC function remains largely unexplored. STAT3 signalling mediated via interleukin-6 (IL-6) has recently come to the forefront as a potential regulator of SC proliferation. The early response of the SC population in human muscle to muscle-lengthening contractions (MLC) as mediated by STAT3 has not been studied.Twelve male subjects (21±2 y; 83±12 kg) performed 300 maximal MLC of the quadriceps femoris at 180°•s(-1) over a 55° range of motion with muscle samples (vastus lateralis) and blood samples (antecubital vein) taken prior to exercise (PRE), 1 hour (T1), 3 hours (T3) and 24 hours (T24) post-exercise. Cytoplasmic and nuclear fractions of muscle biopsies were purified and analyzed for total and phosphorylated STAT3 (p-STAT3) by western blot. p-STAT3 was detected in cytoplasmic fractions across the time course peaking at T24 (p<0.01 vs. PRE). Nuclear total and p-STAT3 were not detected at appreciable levels. However, immunohistochemical analysis revealed a progressive increase in the proportion of SCs expressing p-STAT3 with ∼60% of all SCs positive for p-STAT3 at T24 (p<0.001 vs. PRE). Additionally, cMyc, a STAT3 downstream gene, was significantly up-regulated in SCs at T24 versus PRE (p<0.05). Whole muscle mRNA analysis revealed induction of the STAT3 target genes IL-6, SOCS3, cMyc (peaking at T3, p<0.05), IL-6Rα and GP130 (peaking at T24, p<0.05). In addition, Myf5 mRNA was up-regulated at T24 (p<0.05) with no appreciable change in MRF4 mRNA.We demonstrate that IL-6 induction of STAT3 signaling occurred exclusively in the nuclei of SCs in response to MLC. An increase in the number of cMyc+ SCs indicated that human SCs were induced to proliferate under the control of STAT3 signaling