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Increased oxidative stress generated nucleoside damage seems to play a crucial role in bipolar disorder (BD) pathophysiology. It may contribute to accelerated ageing and reduced life expectancy in patients with BD.In the five-year prospective "Bipolar Illness Onset study", we investigated repeated measurements of oxidative stress generated RNA and DNA damage in 357 patients with newly diagnosed/first-episode BD (880 visits), 132 of their unaffected first-degree relatives (236 visits) and 198 healthy age- and sex-matched control persons with no personal or first-degree family history of affective disorder (432 visits). Amongst patients with BD, we further investigated associations of oxidative stress generated RNA- and DNA damage with affective phases and measures of illness load.Patients newly diagnosed with BD and their unaffected relatives had higher levels of oxidative stress generated RNA damage than healthy control individuals and these differences persisted over time, whereas DNA damage was less consistently elevated. Neither illness load nor affective phase impacted the levels in patients with BD.Our findings support elevated oxidative stress generated RNA damage being a trait phenomenon in BD as indicated by persistent increase in RNA damage over time in patients newly diagnosed with BD and in their unaffected first-degree relatives compared with healthy control individuals. We did not detect state alterations in levels of oxidative stress.

Nucleic acid damage from oxidative stress (NA-OXS) may be a molecular mechanism driving the severely increased morbidity and mortality from somatic causes in adults with psychiatric disorders.To systematically retrieve and analyze data on NA-OXS across the psychiatric disorder diagnostic spectrum.The PubMed, Embase, and PsycINFO databases were searched from inception to November 16, 2021. A hand search of reference lists of relevant articles was also performed.Key study inclusion criteria in this meta-analysis were as follows: adult human study population, measurement of any marker of DNA or RNA damage from oxidative stress, and either a (1) cross-sectional design comparing patients with psychiatric disorders (any diagnosis) with a control group or (2) prospective intervention. Two authors screened the studies, and 2 senior authors read the relevant articles in full and assessed them for eligibility.The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two authors performed data extraction independently, and a senior coauthor was consulted in cases of disagreement. Data were synthesized with random-effects and multilevel meta-analyses.The predefined hypothesis was that individuals with psychiatric disorders have increased NA-OXS levels. The main outcome was the standardized mean differences (SMDs) among patients and controls in nucleic acid oxidation markers compared across diagnostic groups. Analyses were divided into combinations of biological matrices and nucleic acids.Eighty-two studies fulfilled the inclusion criteria, comprising 205 patient vs control group comparisons and a total of 10 151 patient and 10 532 control observations. Overall, the data showed that patients with psychiatric disorders had higher NA-OXS levels vs controls across matrices and molecules. Pooled effect sizes ranged from moderate for urinary DNA markers (SMD = 0.44 [95% CI, 0.20-0.68]; P .001) to very large for blood cell DNA markers (SMD = 1.12 [95% CI, 0.69-1.55; P .001). Higher NA-OXS levels were observed among patients with dementias followed by psychotic and bipolar disorders. Sensitivity analyses excluding low-quality studies did not materially alter the results. Intervention studies were few and too heterogenous for meaningful meta-analysis.The results of this meta-analysis suggest that there is an association with increased NA-OXS levels in individuals across the psychiatric disorder diagnostic spectrum. NA-OXS may play a role in the somatic morbidity and mortality observed among individuals with psychiatric disorders.

Oxidative stress generated nucleoside damage seems to represent key pathophysiological mechanisms of bipolar disorder (BD). Likewise, mood and activity are core features of BD and can be reliably monitored using smartphone-based applications. The aim was to investigate whether oxidative stress generated nucleoside damage could reflect psychopathology in BD using easily available and non-invasive patient-reported smartphone-based symptoms. We included 223 patients newly diagnosed with BD and employed linear mixed-effect regression models to associate baseline measurements of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) levels with patient-reported smartphone measures of mood, activity, anxiety, stress and sleep duration monitored three days prior to and 30 days after the baseline visit in the longitudinal Bipolar Illness Onset Study. In patients newly diagnosed with BD higher 8-oxoGuo levels were inversely associated with the patient-reported activity level (B = 0.953, 95%CI = 0.909;0.99, p = 0.043) and positively associated with patient-reported anxiety (B = 1.104, 95%CI = 1.022;1.161, p=0.012), perceived stress (B = 1.092, 95%CI = 1.009;1.183, p = 0.014) and sleep duration (B = 1.000, 95%CI = 1.000;1.001, p = 0.001), respectively, in analyses, adjusted for sex and age. The associations between 8-oxoGuo levels and anxiety, perceived stress and sleep duration, respectively, withstood adjustment for sex, age, smoking, BMI and alcohol intake. No associations between 8-oxodG levels and patient-reported smartphone-based data were found and mood was not associated with 8-oxoGuo. Oxidative stress was associated with patient-reported smartphone-based data on activity, anxiety, stress and sleep duration pointing towards that oxidative stress generated nucleoside damage may reflect ongoing psychopathology in BD.

A substantial part of mortality during the COVID-19-pandemic occurred among nursing home residents which caused alarm in many countries. We investigate nursing home mortality in relation to the expected mortality prior to the pandemic. This nationwide register-based study included all 135,501 Danish nursing home residents between 2015 until October 6, 2021. All-cause mortality rates were calculated using a standardization method on sex and age distribution of 2020. Survival probability and lifetime lost for 180 days was calculated using Kaplan Meier estimates. Of 3,587 COVID-19 related deaths, 1137 (32%) occurred among nursing home residents. The yearly all-cause mortality rates per 100,000 person-years in 2015, 2016, and 2017 were 35,301 (95% CI: 34,671–35,943), 34,801 (95% CI: 34,180–35,432), and 35,708 (95% CI: 35,085–36,343), respectively. Slightly elevated mortality rates per 100,000 person-years were seen in 2018, 2019, 2020, and 2021 of 38,268 (95% CI: 37,620–38,929), 36,956 (95% CI: 36,323–37,600), 37,475 (95% CI: 36,838–38,122), and 38,536 (95% CI: 37,798–39,287), respectively. For SARS-CoV-2-infected nursing home residents, lifetime lost difference was 42 days (95% CI: 38–46) in 2020 versus non-infected in 2018. Among vaccinated in 2021, lifetime lost difference was 25 days (95% CI: 18–32) for SARS-CoV-2-infected versus non-infected. Even though a high proportion of COVID-19 fatalities took place in nursing homes and SARS-CoV-2-infection increased the risk of individual death, the annual mortality was only slightly elevated. For future epidemics or pandemics reporting numbers of fatal cases in relation to expected mortality is critical. A substantial part of mortality during the COVID-19-pandemic occurred among nursing home residents which caused alarm in many countries. We investigate nursing home mortality in relation to the expected mortality prior to the pandemic. This nationwide register-based study included all 135,501 Danish nursing home residents between 2015 until October 6, 2021. All-cause mortality rates were calculated using a standardization method on sex and age distribution of 2020. Survival probability and lifetime lost for 180 days was calculated using Kaplan Meier estimates. Of 3,587 COVID-19 related deaths, 1137 (32%) occurred among nursing home residents. The yearly all-cause mortality rates per 100,000 person-years in 2015, 2016, and 2017 were 35,301 (95% CI: 34,671–35,943), 34,801 (95% CI: 34,180–35,432), and 35,708 (95% CI: 35,085–36,343), respectively. Slightly elevated mortality rates per 100,000 person-years were seen in 2018, 2019, 2020, and 2021 of 38,268 (95% CI: 37,620–38,929), 36,956 (95% CI: 36,323–37,600), 37,475 (95% CI: 36,838–38,122), and 38,536 (95% CI: 37,798–39,287), respectively. For SARS-CoV-2-infected nursing home residents, lifetime lost difference was 42 days (95% CI: 38–46) in 2020 versus non-infected in 2018. Among vaccinated in 2021, lifetime lost difference was 25 days (95% CI: 18–32) for SARS-CoV-2-infected versus non-infected. Even though a high proportion of COVID-19 fatalities took place in nursing homes and SARS-CoV-2-infection increased the risk of individual death, the annual mortality was only slightly elevated. For future epidemics or pandemics reporting numbers of fatal cases in relation to expected mortality is critical.

Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients’ cognitive outcomes. Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients’ cognitive outcomes.

IMPORTANCE: Thyroid eye disease (TED) is a serious condition that can cause proptosis and strabismus and, in rare cases, lead to blindness. Incidence data for TED and strabismus and surgical interventions after TED are sparce. OBJECTIVE: To investigate the nationwide incidence of TED, strabismus, and surgical interventions associated with TED. DESIGN, SETTING, AND PARTICIPANTS: A Danish nationwide registry-based cohort study between 2000, which marks the beginning of uniform coding for the decompression surgery nationwide, and 2018. The cohort consisted of a mean 4.3 million people aged 18 to 100 years with no prior TED diagnosis each year. Total observation time was 8.22 × 10(7) person-years (women, 4.18 × 10(7) person-years; men, 4.04 × 10(7) person-years). MAIN OUTCOME MEASURES: The annual numeric and age-standardized incidence of hospital-treated TED and cumulative incidence of strabismus, strabismus surgery, and orbital decompression surgery in patients with TED. The incidence was stratified by sex, thyroid diagnosis, and age. RESULTS: A total of 4106 incident diagnoses of TED were identified during 19 years among 3344 women (81.4%) and 762 men (18.6%). The mean numeric annual nationwide incidence rate of TED was 5.0 per 100 000 person-years overall, 8.0 per 100 000 person-years in women, and 1.9 per 100 000 person-years in men, resulting in a 4:1 ratio of women to men with TED. The age-standardized incidence was similar. The mean (SD) age at onset was 51.3 (14.5) years. At the time of TED diagnosis, 611 patients (14.9%) were euthyroid, 477 (11.6%) were hypothyroid, and 3018 (73.5%) were hyperthyroid. In patients with TED who were euthyroid, the 4-year cumulative incidence was 41% for antithyroid medication and 13% for L-thyroxine. In patients with TED, the 4-year cumulative incidence for strabismus was 10%. The 4-year cumulative incidence of surgical interventions after TED was 8% for strabismus surgery and 5% for orbital decompression. At 4 years, strabismus surgery was more common in men (13.3%; 95% CI, 10.75-15.86) than in women (7.2%; 95% CI, 6.24-8.08), and the absolute difference was 6.1% (95% CI, 3.42-8.14; P

Oxidatively generated DNA damage is of paramount importance in a wide range of physiological and pathophysiological processes. Urinary 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) is often used as an outcome marker in studies on the role of oxidatively generated DNA damage, but its exact relation to intracellular damage levels and variations in DNA repair have been unclear. Using a new approach of quantitative kinetic modeling inspired by pharmacokinetics, we find evidence that in steady state - i.e. when systemic consequences of given change in damage or cellular removal rates have stabilized - the urinary excretion of 8-oxodG is closely correlated to rates of damage and intracellular 8-oxodG levels, but independent of the rate of cellular removal. Steady state was calculated to occur within approximately 12 h. A similar pattern was observed in a model of the corresponding RNA marker 8-oxo-7,8-dihydroguanosine (8-oxoGuo), but with steady-state occurring slower (up to 5 d). These data have significant implications for the planning of studies and interpretation of data involving urinary 8-oxodG/8-oxoGuo excretion as outcome.HighlightsThe kinetics of 8-oxodG/8-oxoGuo formation, removal and excretion were simulated

Background: Between 30 and 50% of patients with major depressive disorder (MDD) do not respond sufficiently to antidepressant regimens. The conventional pharmacological treatments predominantly target serotonergic brain signaling but better tools to predict treatment response and identify relevant subgroups of MDD are needed to support individualized and mechanistically targeted treatment strategies. The aim of this study is to investigate antidepressant-free patients with MDD using neuroimaging, electrophysiological, molecular, cognitive, and clinical examinations and evaluate their ability to predict clinical response to SSRI treatment as individual or combined predictors. Methods: We will include 100 untreated patients with moderate to severe depression (>17 on the Hamilton Depression Rating Scale 17) in a non-randomized open clinical trial. We will collect data from serotonin 4 receptor positron emission tomography (PET) brain scans, functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), cognitive tests, psychometry, and peripheral biomarkers, before (at baseline), during, and after 12 weeks of standard antidepressant treatment. Patients will be treated with escitalopram, and in case of non-response at week 4 or intolerable side effects, offered to switch to a second line treatment with duloxetine. Our primary outcome (treatment response) is assessed using the Hamilton depression rating subscale 6-item scores at week 8, compared to baseline. In a subset of the patients (n = ~40), we will re-assess the neurobiological response (using PET, fMRI, and EEG) 8 weeks after initiated pharmacological antidepressant treatment, to map neurobiological signatures of treatment responses. Data from matched controls will either be collected or is already available from other cohorts. Discussion: The extensive investigational program with follow-up in this large cohort of participants provides a unique possibility to (a) uncover potential biomarkers for antidepressant treatment response, (b) apply the findings for future stratification of MDD, (c) advance the understanding of pathophysiological underpinnings of MDD, and (d) uncover how putative biomarkers change in response to 8 weeks of pharmacological antidepressant treatment. Our data can pave the way for a precision medicine approach for optimized treatment of MDD and also provides a resource for future research and data sharing. Clinical Trial Registration: The study was registered at clinicaltrials.gov prior to initiation (NCT02869035; 08.16.2016, URL: https://clinicaltrials.gov/ct2/results?cond=&term=NCT02869035&cntry=&state=&city=&dist=)

Aims To compare the hazard of all-cause, chronic obstructive pulmonary disease (COPD) and heart failure (HF) hospitalization in carvedilol vs. metoprolol/bisoprolol/nebivolol users with COPD and concurrent HF from 2009 to 2012, and to evaluate the use and persistence in treatment of these β-blockers, their impact on the risk of COPD-related hospitalization, and the factors important for their selection. Methods and results Cox and logistic regression were used for both unadjusted and adjusted analyses. Carvedilol users had a higher hazard of being hospitalized for HF compared with metoprolol/bisoprolol/nebivolol users in both the unadjusted [hazard ratio (HR) 1.74; 95% confidence interval (CI) 1.65-1.83] and adjusted (HR 1.61; 95% CI 1.52-1.70) analyses. No significant differences were found for all-cause and COPD hospitalization between the two groups. Carvedilol users had a significant lower restricted mean persistence time than metoprolol/bisoprolol/nebivolol users. Patients exposed to carvedilol had an odds ratio (OR) of 1.38 (95% CI 1.23-1.56) for being hospitalized due to COPD within 60 days after redeeming the first carvedilol prescription, which was similar to that observed in metoprolol/bisoprolol/nebivolol users (OR 1.37; 95% CI 1.27-1.48). Patients with concurrent chronic kidney disease had a higher probability of receiving carvedilol (OR 1.16; 95% CI 1.04-1.29). Conclusion Carvedilol prescription carried an increased hazard of HF hospitalization and lower restricted mean persistence time among patients with COPD and concurrent HF. Additionally, we found a widespread phenomenon of carvedilol prescription at variance with the European Society of Cardiology guidelines and potential for improving the proportion of patients treated with β-blockers.

Background: The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography. Methods: 1599 individuals (mean age 64 years [min-max 29–96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010–2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies. Results: Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, pConclusions: Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a “missing heritability” in early-onset CAD warrants more research.

Aims To compare the hazard of all-cause, chronic obstructive pulmonary disease (COPD) and heart failure (HF) hospitalization in carvedilol vs. metoprolol/bisoprolol/nebivolol users with COPD and concurrent HF from 2009 to 2012, and to evaluate the use and persistence in treatment of these β-blockers, their impact on the risk of COPD-related hospitalization, and the factors important for their selection. Methods and results Cox and logistic regression were used for both unadjusted and adjusted analyses. Carvedilol users had a higher hazard of being hospitalized for HF compared with metoprolol/bisoprolol/nebivolol users in both the unadjusted [hazard ratio (HR) 1.74; 95% confidence interval (CI) 1.65-1.83] and adjusted (HR 1.61; 95% CI 1.52-1.70) analyses. No significant differences were found for all-cause and COPD hospitalization between the two groups. Carvedilol users had a significant lower restricted mean persistence time than metoprolol/bisoprolol/nebivolol users. Patients exposed to carvedilol had an odds ratio (OR) of 1.38 (95% CI 1.23-1.56) for being hospitalized due to COPD within 60 days after redeeming the first carvedilol prescription, which was similar to that observed in metoprolol/bisoprolol/nebivolol users (OR 1.37; 95% CI 1.27-1.48). Patients with concurrent chronic kidney disease had a higher probability of receiving carvedilol (OR 1.16; 95% CI 1.04-1.29). Conclusion Carvedilol prescription carried an increased hazard of HF hospitalization and lower restricted mean persistence time among patients with COPD and concurrent HF. Additionally, we found a widespread phenomenon of carvedilol prescription at variance with the European Society of Cardiology guidelines and potential for improving the proportion of patients treated with β-blockers.

Leg cramps are common in patients with heart failure. Quinine is frequently prescribed in low doses to these patients, but safety of this practice is unknown. We studied the outcomes associated with use of quinine in a nationwide cohort of patients with heart failure.Through individual-level-linkage of Danish national registries, we identified patients discharged from first-time hospitalization for heart failure in 1997-2010. We estimated the risk of mortality associated with quinine treatment by time-dependent Poisson regression models.A total of 135 529 patients were included, with 14 510 patients (11%) using quinine at some point. During a median time of follow-up of 989 days (interquartile range 350-2004) 88 878 patients (66%) died. Patients receiving quinine had slightly increased mortality risk, adjusted incidence rate ratio (IRR) 1.04 (95% confidence interval [CI] 1.01 to 1.07). The risks differed according to concomitant β-blocker treatment. For patients treated with both quinine and β-blockers IRR was 1.15 (95% CI 1.09 to 1.21) vs. 0.99 (95% CI 0.96 to 1.03) for patients treated with quinine but not β-blockers. The risks were highest shortly after initiation of therapy: for the first 14 days of treatment IRR was 2.12 (95% CI 1.54 to 2.93) for patients in treatment with β-blockers and 1.17 (95% CI 0.86 to 1.59) for patients not treated with β-blockers.Use of quinine was common and associated with increased mortality in heart failure, especially if administered together with β-blockers and shortly after treatment initiation. Mechanisms underlying the findings remain to be established.

To compare survival on different beta-blockers in heart failure.We identified all Danish patients ≥35 years of age who were hospitalized with a first admission for heart failure and who initiated treatment with a beta-blocker within 60 days of discharge. The study period was 1995-2011. The main outcome was all-cause mortality and all-cause hospitalization. Cox proportional hazard models were used to compare survival. The study included 58 634 patients of whom 30.121 (51.4%) died and 46.990 (80.1%) were hospitalized during follow-up. The mean follow-up time was 4.1 years. In an unadjusted model carvedilol was associated with a lower mortality [hazard ratio (HR) 0.737, 0.714-0.761] compared with metoprolol (reference) while bisoprolol was not associated with an increased mortality (HR 1.020, 0.973-1.069). In a model adjusted for possible confounders and stratified according to beta-blocker dosages, patients that received high-dose carvedilol (≥50 mg daily) had a lower all-cause mortality risk (HR 0.873, 0.789-0.966) than patients receiving high-dose (≥200 mg daily) metoprolol (reference). High-dose bisoprolol (≥10 mg daily) was associated with a greater risk of death (HR 1.125, 1.004-1.261). High-dose carvedilol was associated with significantly lower all-cause hospitalization risk (HR 0.842, 0.774-0.915) than high-dose metoprolol (reference), while high-dose bisoprolol had insignificantly lower risk than high-dose metoprolol (HR 0.948, 0.850-1.057).Heart failure patients receiving high-dose carvedilol (≥50 mg daily) showed significantly lower all-cause mortality risk and hospitalization risk, compared with other beta-blockers.

Accumulating evidence supports the popular notion that psychological stress states may accelerate aging. Stress has been shown to influence cellular systems known to be involved in the aging process. Furthermore, stress is associated with an increased risk of various age-related medical disorders. These effects are likely mediated by the secretion of stress hormones. In this short review we focus on biochemical and epidemiological evidence for a link between stress and aging.

Of the DNA-derived biomarkers of oxidative stress, urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is the most frequently measured. However, there is significant discrepancy between chromatographic and immunoassay approaches, and intratechnique agreement among all available chromatography-based assays and ELISAs is yet to be established. This is a significant obstacle to their use in large molecular epidemiological studies. To evaluate the accuracy of intra/intertechnique and interlaboratory measurements, samples of phosphate buffered saline and urine, spiked with different concentrations of 8-oxoG, together with a series of urine samples from healthy individuals were distributed to ESCULA members. All laboratories received identical samples, including 2 negative controls that contained no added 8-oxodG. Data were returned from 17 laboratories, representing 20 methods, broadly classified as mass spectrometric (MS), electrochemical detection (EC), or enzyme-linked immunosorbant assay (ELISA). Overall, there was good within-technique agreement, with the majority of laboratories' results lying within 1 sd of their consensus mean. However, ELISA showed more within-technique variation than did the chromatographic techniques and, for the urine samples, reported higher values. Bland-Altman plots revealed good agreement between MS and EC methods but concentration-dependent deviation for ELISA. All methods ranked urine samples according to concentration similarly. Creatinine levels are routinely used as a correction factor for urine concentration, and therefore we also conducted an interlaboratory comparison of methods for urinary creatinine determination, in which the vast majority of values lay within 1 sd of the consensus value, irrespective of the analysis procedure. This study reveals greater consensus than previously expected, although concern remains over ELISA.-ESCULA [European Standards Committee on Urinary (DNA) Lesion Analysis], Evans, M. D., Olinski, R., Loft, S., Cooke, M. S. Toward consensus in the analysis of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine as a noninvasive biomarker of oxidative stress. Some of the authors of this paper are partners in, and this work was partly supported by, ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a Network of Excellence operating within the European Union 6th Framework Program, Priority 5: Food Quality and Safety (contract 513943)

Inflammation and endothelial activation are associated with an increased risk of CVD and epidemiological evidence suggests an association between levels of markers of inflammation or endothelial activation and the intake of fruit. Also, vitamin E, a fat-soluble antioxidant, has anti-inflammatory properties. We performed a randomised 2 × 2 factorial, crossover trial to determine the effect of orange and blackcurrant juice (500 ml/d) and vitamin E (15 mg RRR-α-tocopherol/d) supplementation on markers of inflammation and endothelial activation in forty-eight patients with peripheral arterial disease. Patients were randomly allocated to two dietary supplements from the four possible combinations of juice and vitamin E: juice+vitamin E; juice+placebo; reference beverage (sugar drink)+vitamin E; and reference beverage+placebo. The supplementations were given for 28 d, separated by a 4-week wash-out period. Analysis of main effects showed that juice decreased C-reactive protein (CRP) by 11 % and fibrinogen by 3 % while the reference drink increased CRP by 13 % and fibrinogen by 2 % (P P

The medication history among hospitalized patients often relies on patients' self-reports due to insufficient communication between health care professionals. The aim of the present study was to estimate the reliability of patients' self-reported medication use. Five hundred patients admitted to an acute medical department at a Danish university hospital were interviewed on the day of admission about their recent medication use. Blood samples drawn immediately after admission were screened for contents of 5 drugs (digoxin, bendroflumethiazide, amlodipine, simvastatin, glimepiride), and the results were compared to the patients' self-reported medication history. Information on prescribed drugs dispensed from any Danish pharmacy was collected from nationwide real-time pharmacy records. The authors performed home visits in a subgroup of 115 patients 4 weeks after their discharge. Stored drugs were inspected, and patients were interviewed about their drug use. Additional blood samples were drawn for drug analysis. The median age of included patients was 72 years, and 298 patients (60%) were women. Patients reported use of 3 (median) prescription-only medications (range, 0-14) during the structured interview. The congruence between self-report and drug analysis was high for all 5 drugs measured (all kappa0.8). However, 9 patients (2%) reported use of drugs that were not detected in their blood samples. In 29 patients (6%), the blood samples contained drugs not reported during the structured interview, but 14 of these drugs were registered in either hospital files or pharmacy records. Overall, the sensitivity of information from hospital files, structured interviews, and pharmacy records in identifying drug users was 87% to 93%, with no significant differences between methods. In conclusion, patients' self-reports are reliable when estimating recent use of cardiovascular and antidiabetic drugs.

Associations between genotypes of phase 2 enzymes and cancer risk are extracted from epidemiological studies, namely case-control studies. Variant alleles in glutathione S-transferase (GST), UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and N-acetyltransferase (NAT) have been used as molecular genetic biomarkers of risk. GSTM(my)1 has been associated with an increased risk of colorectal cancer, lung cancer, and bladder cancer and GSTP(pi)1 with prostate cancer. UGT1A1*28 and *37 are both associated with an increased risk of breast cancer as is SULT1A1*2. The presence of UGT1A1*28 results in an increased risk of ovarian cancer and NAT2 of colorectal and lung cancer. A high frequency of SULT1A1*1 has been identified in patients with breast cancer; the role in colorectal cancer is more controversial. This chapter discusses the balance between carcinogen activation and detoxification in relation to phase 2 enzymes.

Exclusively private companies do drug development. The State contributes with education of academics and basic research constituting the basis of half of the drugs developed by the private companies. The Danish private drug research amounts to six billion DKK per year, corresponding to the estimated price of the development of one new drug. The development shows a negative tendency. There are doubts about the scientific credibility, the number of new drugs is declining, drug development costs are rising, and the competitiveness in Europe is declining compared with the one of The United States. Continued improvement of Danish drug development can be achieved by stimulation of the public research related to drug development.

The aim of this study was to determine by multivariate analysis how alcohol and other factors affect the clinical course and outcome in patients with acetaminophen (paracetamol) poisoning. A total of 645 consecutive patients admitted from 1994 to 2000 with single-dose acetaminophen poisoning were studied, giving special attention to alcohol history, time between overdose and intravenous N-acetylcysteine (NAC) treatment ("time to NAC"), and other data available at the time of admittance. Up until 72 hours after ingestion, time to NAC was the single most important independent risk factor. With a time to NAC less than 12 hours, the mortality rate was 0.42% (95% CI, 0.05-2.7). When time to NAC exceeded 12, 24, and 48 hours, the mortality rate increased to 6.1%, 13%, and 19%, respectively. Chronic alcohol abuse was an independent risk factor of mortality (odds ratio [OR], 3.52; 95% CI, 1.78-6.97). Acute alcohol ingestion was an independent protective factor regarding mortality in alcoholic patients (OR, 0.08; 95% CI, 0.01-0.66) but not in nonalcoholic patients (OR, 0.21; 95% CI, 0.03-1.67). Patient age and quantity of acetaminophen were independent risk factors. In conclusion, time to NAC was confirmed as the major risk factor in acetaminophen-induced hepatotoxicity and mortality. Chronic alcohol abuse was an independent risk factor that could be counteracted by concomitant acute alcohol ingestion. We suggest that patients with chronic alcoholism and suspected acetaminophen poisoning due to an increased risk of developing hepatotoxicity should be treated with NAC regardless of risk estimation.

Restriction of energy intake (ER), without malnutrition of essential nutrients, has repeatedly been demonstrated to increase longevity in rodents. In the antioxidant theory of aging the lack of balance between the generation of free radicals and free radical scavenging was thought to be a main causal agent, in the aging process. From this point of view the antiaging effect induced by ER might be due to the lower rate of free-radical production and related damage induced by a lower metabolic rate. The antiaging effects of ER might also occur in humans. This study explored the effects of a 10-week moderately energy-restricted diet (80% of habitual) in 24 non-obese middle-aged men (16 ER subjects, 8 controls) on resting metabolic rate (RMR) and indicators of the primary antioxidant defense system, oxidative stress and genotoxicity. RMR decreased significantly in both groups, even when adjustments were made for the change in body composition. The increase in blood vitamin C concentration correlated with the increase in urinary 8-hydroxydeoxyguanosine (80HdG) excretion. The change in urinary 80HdG excretion also correlated with the change in RMR per kg fat-free mass. No differences between groups were found for changes in indicators of genotoxicity, erythrocyte catalase, glutathione peroxidase and superoxide dismutase activity and in plasma vitamin E, A or beta-carotene concentrations. We conclude that 10 weeks of moderate ER did not affect indicators of antioxidative capacity, oxidative stress and genotoxicity of humans. Since subjects were not in energy balance at the end of the study, no conclusions can be made with respect to long-term effects.

Reactive free oxygen radicals are formed in the reactions involved in normal cell metabolism. This formation is closely regulated e.g. by dietary antioxidants. Present knowledge suggests that an imbalance, with surplus of free radicals, can play a role in the pathogenesis of certain types of cancer, atherosclerosis, and cataract. A number of epidemiological studies have demonstrated a reduced risk of developing these diseases in persons who consume a diet with a high content of vegetables and fruit, which contains large quantities of the antioxidants: beta-carotene, vitamins C and E. Intervention studies, using supplements of these antioxidants, have so far not been able to show a beneficial effect. The apparently protective effect of fruit and vegetables may be due to other active ingredients. In Denmark the average intake of vegetables and fruit is low, and it is estimated that an increased consumption of these foods could reduce the occurrence of certain cancer types and atherosclerosis. In contrast, there is no evidence that antioxidant supplements would provide protection against disease, and their safety remains to be established.

Nitroglycerin and other organic nitrates are beneficial in ischaemic heart disease and myocardial infarction and as adjunctive therapy in congestive heart failure. The nitrates are inactive prodrugs, and their vascular effects depend on metabolic conversion to vasoactive intermediates like nitric oxide and/or nitrosothiols with subsequent stimulation of guanylate cyclase causing increased formation of cyclic GMP. The compounds relax vascular smooth muscle producing venous dilatation at low concentrations and at higher concentrations dilation of coronary arteries and collaterals and systemic arterial vessels. Nitrate tolerance is, however, a problem with continuous nitrate therapy. Tolerance is most likely to occur with frequent dosing or with the use of long-acting nitrates or transdermal applications resulting in constant plasma concentrations. Therapeutic strategies should be designed to provide a daily low-nitrate period or nitrate-free period to obviate the development of tolerance and thus maintain the antianginal effects.

Reduced glutathione (GSH) is the main intracellular non-protein thiol compound. GSH is important in a variety of reactions including reductive processes, protection of cells against oxidative stress, free oxygen species and other toxic compounds of endogenous and exogenous origin. In the cardiovascular field, thiol compounds may protect against ischaemia-reperfusion injuries, regulate enzyme activities and modify the function of organic nitrates and vascular tone. Metabolic manipulation with thiol compounds (i.e. by treatment with N-acetylcysteine or oxothiazolidine) may provide a safe method for protecting cells against ischaemia and may be a relevant supplement to current cardiovascular therapy.