No abstract

On the basis of simulation results, adding dapagliflozin to currently available treatment options is projected to further decrease the CV and microvascular complications associated with T2DM.

An immunoaffinity column is described that facilitates the analysis of oxidative DNA damage. DNA adducts excised from DNA are excreted in urine and can be assayed as a measure of DNA damage in individuals. Polyclonal antibodies that recognize 8-hydroxy-2'-deoxyguanosine (oh8dG), a biomarker of oxidative damage to DNA, have been produced and their binding properties characterized. The antibodies, raised in rabbits following immunization with protein carrier-hapten conjugates prepared by covalently linking periodate-treated 8-hydroxyguanosine (oh8G) to bovine serum albumin (BSA) or casein, bind oh8dG with high affinity and selectivity, as measured by a competitive radioimmunoassay (RIA). Antibodies obtained from the rabbits immunized with the casein conjugate exhibited a binding affinity for oh8dG of 6.9 x 10(8) M-1. Studies on the relative binding affinities of these polyclonal antibodies for oh8dG, unmodified nucleosides, or derivatives of guanine indicate that the antibodies are suitable for the preparation of immunoaffinity columns that permit us to rapidly isolate oh8dG and 8-hydroxyguanine (oh8Gua) from urine. The high selectivity of the antibodies for oh8dG and oh8G reduces the amount of urinary contaminants previously observed in samples prepared by solid phase extraction, thus greatly facilitating the isolation of these damage products from urine. The relative binding affinity of these antibodies for oh8Gua and 2'-deoxyguanosine were approximately 7.6 x 10(3) and 7.4 x 10(4) fold lower respectively, than the binding affinity for oh8dG. The antibody can be used to quantitate oh8dG in enzymatic hydrolyzates of DNA with values comparable to those obtained by HPLC with electrochemical detection (HPLC-EC).

No abstract

Folate deficiency in Swiss mice increased the incidence of micronuclei in peripheral blood erythrocytes, indicating increased chromosomal damage in nucleated erythrocyte precursors. Caffeine enhanced the incidence of micronuclei in blood and bone marrow by up to 5-fold in folatedeficient mice at doses that did not significantly alter the micronucleus frequency in the presence of adequate dietary folate. The lower dose of caffeine used in this study (75 mg/kg) approaches doses received by humans who consume large amounts of caffeinated beverages. Since folate deficiency and caffeine consumption are highly prevalent in the human population, the potential for a similar interaction in man should be evaluated.The occurrence of micronuclei in peripheral blood and bone marrow erythrocytes has been used as an indicator of cytogenetic damage in laboratory animals and man (1-3). Two recent studies indicate that folate deficiency and caffeinatedbeverage consumption may elevate the frequency of micronucleated erythrocytes in man. Caffeinated-coffee consumption was associated with an elevated frequency of micronucleated erythrocytes in a cross-sectional study of genotoxic risk factors (4), and folate supplementation lowered micronucleus frequency to normal in an individual with a marginal folate deficiency and an abnormally high micronucleus frequency (5). These studies suggest that folate status and caffeinated-beverage consumption may be risk factors for cytogenetic damage in man.Mild-to-moderate folate deficiency (6-9) and caffeinatedbeverage consumption (10) are both highly prevalent in the general population. Folate deficiency affects up to 60% of low-income and elderly persons (8,11) and is also common in subpopulations, such as alcoholics (12) Folate deficiency in pregnant women has been reported to range from 2% to 50%, depending on the population studied (25). Folate deficiency during pregnancy is associated with an elevated incidence of birth defects (26).Severe folate deficiency induced by antifolate drugs has been shown to increase the frequency of micronuclei in mouse bone marrow erythrocytes (27, 28), but we are not aware of previous reports of increased micronucleus frequencies induced by dietary folate deficiency in laboratory animals.Fragile-site expression induced in vitro by conditions of limiting folate is known to be strongly enhanced by caffeine, leading to micronucleus formation and increased frequencies of chromosome breaks (18,29). Under these conditions, caffeine increases folate-related breakage events, often by more than an order of magnitude. There appear to be no data indicating whether a similar interaction occurs in mammals in vivo. Although earlier studies of caffeine effects in animals and man have failed to demonstrate significant genotoxic effects in vivo at doses near those that would result from the consumption of caffeinated beverages (30-33), the recent report by Chen et al. (34) that chromosomal fragility in human lymphocytes cultured under low-folate conditions is linearly ...

BackgroundNo clinical trials have assessed the effects or cost-effectiveness of health check strategies to detect and manage vascular disease. We used a mathematical model to estimate the cost-effectiveness of several health check strategies in six European countries.MethodsWe used country-specific data from Denmark, France, Germany, Italy, Poland, and the United Kingdom to generate simulated populations of individuals aged 40–75 eligible for health checks in those countries (e.g. individuals without a previous diagnosis of diabetes, myocardial infarction, stroke, or serious chronic kidney disease). For each country, we used the Archimedes model to compare seven health check strategies consisting of assessments for diabetes, hypertension, lipids, and smoking. For patients diagnosed with vascular disease, treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, major adverse cardiovascular events (MACE), and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY).ResultsCompared with current care, health checks reduced the incidence of MACE (6–17 events prevented per 1000 people screened) and diabetes related microvasular complications (5–11 events prevented per 1000 people screened), and increased QALYs (31–59 discounted QALYs) over 30 years, in all countries. The cost per QALY of offering a health check to all individuals in the study cohort ranged from €14903 (France) to cost saving (Poland). Pre-screening the population and offering health checks only to higher risk individuals lowered the cost per QALY. Pre-screening on the basis of obesity had a cost per QALY of €10200 (France) or less, and pre-screening with a non-invasive risk score was similar.ConclusionsA vascular disease health check would likely be cost effective at 30 years in Denmark, France, Germany, Italy, Poland, and the United Kingdom.

BackgroundPatients with type 2 diabetes (T2DM) are at risk of long-term vascular complications. In trials, exenatide once weekly (ExQW), a GLP-1R agonist, improved glycemia, weight, blood pressure (BP), and lipids in patients with T2DM. We simulated potential effects of ExQW on vascular complications, survival, and medical costs over 20 years versus standard therapies.Patients and methodsThe Archimedes model was used to assess outcomes for ~25,000 virtual patients with T2DM (NHANES 1999–2006 [metformin ± sulfonylureas, age 57 years, body mass index 33 kg/m2, weight 94 kg, duration T2DM 9 years, hemoglobin A1c [A1C] 8.1%]). The effects of three treatment strategies were modeled and compared to moderate-adherence insulin therapy: advancement to high-adherence insulin at A1C ≥ 8% (treat to target A1C < 7%) and addition of pioglitazone (PIO) or ExQW from simulation start. ExQW effects on A1C, weight, BP, and lipids were modeled from clinical trial data. Costs, inflated to represent 2010 $US, were derived from Medicare data, Drugstore.com, and publications. As ExQW was investigational, we omitted ExQW, PIO, and insulin pharmacy costs.ResultsBy year 1, ExQW treatment decreased A1C (~1.5%), weight (~2 kg), and systolic BP (~5 mmHg). PIO and high-adherence insulin decreased A1C by ~1%, increased weight, and did not affect systolic BP. After 20 years, A1C was ~7% with all strategies. ExQW decreased rates of cardiovascular and microvascular complications more than PIO or high-adherence insulin versus moderate-adherence insulin. Over 20 years, ExQW treatment resulted in increased quality-adjusted life-years (QALYs) of ~0.3 years/person and cost savings of $469/life-year versus moderate adherence insulin. For PIO or high-adherence insulin, QALYs were virtually unchanged, and costs/life-year versus moderate-adherence insulin increased by $69 and $87, respectively.ConclusionsThis long-term simulation demonstrated that ExQW treatment may decrease rates of cardiovascular and some microvascular complications of T2DM. Increased QALYs, and decreased costs were also projected.

This study found that rosuvastatin 20 mg and 40 mg lowers the risk of MACE more than atorvastatin 40 mg and atorvastatin 80 mg. While simulation models cannot replace real-world clinical trials, this study bridges gaps in the evidence, and identifies high risk cohorts that would likely see additional benefit from treatment with rosuvastatin rather than atorvastatin.