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In Hungary, N-ethyl-hexedrone (NEH) was the most frequently seized stimulant designer drug in 2017, while among synthetic cannabinoids ADB-FUBINACA and AB-FUBINACA were the most popular. Symptoms of intoxication by these substances are well known but less is known about the pathology of overdose-related death. NEH-induced fatal intoxication has not been described in the literature and knowledge surrounding the particular circumstances of death could be useful better public education of risk and more adequate treatment of overdose patients. In this report, we characterize the case of a 23-year-old male regular drug user who died a few hours after NEH and ADB-FUBINACA consumption. His medical history showed arrhythmia in childhood, and some seizures. Autopsy found he had a BMI of 42.9, a hypertrophic and dilated heart, severe atherosclerosis of the valves, coronaries and the arteries, and edema of the internal organs. Histology confirmed those findings. Postmortem blood levels of NEH were 285 ng/ml, along with 0.08 ng/ml ADB-FUBINACA and five ADB-FUBINACA metabolites. Based on the blood concentrations measured in suspected drug users (≤83.9 ng/ml) we hypothesize that NEH intoxication was the cause of death in this case, with heart disease being a co-factor and that the synthetic cannabinoid effect might have been accompaniment. This case also offered the opportunity to identify the metabolites of ADB-FUBINACA in the blood. We identified metabolites in the post-mortem blood by comparing them to human liver microsomal enzyme metabolites in vitro. Three major and two minor metabolites were found in the blood, of which two could only be derived from ADB-FUBINACA, as opposed to other cannabinoids. The case highlights the importance of the complex analysis of drug related deaths by medico-legal autopsy, histopathology and toxicology.

Background Persons with a lower socioeconomic position spend more years with disability, despite their shorter life expectancy, but it is unknown what the important determinants are. This study aimed to quantify the contribution to educational inequalities in years with disability of eight risk factors: father’s manual occupation, low income, few social contacts, smoking, high alcohol consumption, high body-weight, low physical exercise and low fruit and vegetable consumption. Methods We collected register-based mortality and survey-based disability and risk factor data from 15 European countries covering the period 2010–14 for most countries. We calculated years with disability between the ages of 35 and 80 by education and gender using the Sullivan method, and determined the hypothetical effect of changing the prevalence of each risk factor to the prevalence observed among high educated (‘upward levelling scenario’), using Population Attributable Fractions. Results Years with disability among low educated were higher than among high educated, with a difference of 4.9 years among men and 5.5 years among women for all countries combined. Most risk factors were more prevalent among low educated. We found the largest contributions to inequalities in years with disability for low income (men: 1.0 year; women: 1.4 year), high body-weight (men: 0.6 year; women: 1.2 year) and father’s manual occupation (men: 0.7 year; women: 0.9 year), but contributions differed by country. The contribution of smoking was relatively small. Conclusions Disadvantages in material circumstances (low income), circumstances during childhood (father’s manual occupation) and high body-weight contribute to inequalities in years with disability.

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by ductal obstructions, tissue fibrosis, atrophy and exocrine and endocrine pancreatic insufficiency. However, our understanding is very limited concerning the disease’s progression from a single acute inflammation, via recurrent acute pancreatitis (AP) and early CP, to the late stage CP. Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor enzyme activated mostly by oxidative DNA damage. As a co-activator of inflammatory transcription factors, PARP1 is a central mediator of the inflammatory response and it has also been implicated in acute pancreatitis. Here, we set out to investigate whether PARP1 contributed to the pathogenesis of CP. We found that the clinically used PARP inhibitor olaparib (OLA) had protective effects in a murine model of CP induced by multiple cerulein injections. OLA reduced pancreas atrophy and expression of the inflammatory mediators TNFα and interleukin-6 (IL-6), both in the pancreas and in the lungs. Moreover, there was significantly less fibrosis (Masson’s trichrome staining) in the pancreatic sections of OLA-treated mice compared to the cerulein-only group. mRNA expression of the fibrosis markers TGFβ, smooth muscle actin (SMA), and collagen-1 were markedly reduced by OLA. CP was also induced in PARP1 knockout (KO) mice and their wild-type (WT) counterparts. Inflammation and fibrosis markers showed lower expression in the KO compared to the WT mice. Moreover, reduced granulocyte infiltration (tissue myeloperoxidase activity) and a lower elevation of serum amylase and lipase activity could also be detected in the KO mice. Furthermore, primary acinar cells isolated from KO mice were also protected from cerulein-induced toxicity compared to WT cells. In summary, our data suggest that PARP inhibitors may be promising candidates for repurposing to treat not only acute but chronic pancreatitis as well.

Purpose To study the trends of smoking-attributable mortality among the low and high educated in consecutive birth cohorts in 11 European countries. Methods Register-based mortality data were collected among adults aged 30 to 79 years in 11 European countries between 1971 and 2012. Smoking-attributable deaths were estimated indirectly from lung cancer mortality rates using the Preston-Glei-Wilmoth method. Rate ratios and rate differences among the low and high-educated were estimated and used to estimate the contribution of inequality in smoking-attributable mortality to inequality in total mortality. Results In most countries, smoking-attributable mortality decreased in consecutive birth cohorts born between 1906 and 1961 among low- and high-educated men and high-educated women, but not among low-educated women among whom it increased. Relative educational inequalities in smoking-attributable mortality increased among both men and women with no signs of turning points. Absolute inequalities were stable among men but slightly increased among women. The contribution of inequality in smoking-attributable mortality to inequality in total mortality decreased in consecutive generations among men but increased among women. Conclusions Smoking might become less important as a driver of inequalities in total mortality among men in the future. However, among women, smoking threatens to further widen inequalities in total mortality.

Wound healing is a complex multiphase process which can be hampered by many factors including impaired local circulation, hypoxia, infection, malnutrition, immunosuppression, and metabolic dysregulation in diabetes. Redox dysregulation is a common feature of many skin diseases demonstrated by virtually all cell types in the skin with overproduction of reactive oxygen and nitrogen species. The objective of this study was to characterize the redox environment in wound fluids and sera from patients suffering from chronic leg ulcers (n=19) and acute wounds (bulla fluids from second degree burns; n=11) with serum data also compared to those from healthy volunteers (n=7). Significantly higher concentrations of TNF-α, interleukine-8, vascular endothelial growth factor, and lactate dehydrogenase (measure of cell damage) were found in fluids from chronic wounds compared to acute ones. The extent of protein carbonylation (measure of protein oxidation), lipid peroxidation, and tyrosine nitration (indicator of peroxynitrite production) was similar in acute and chronic wound fluids, while radical scavenging activity and glutathione (GSH) levels were elevated in chronic wound fluids compared to acute wounds. Sera were also assessed for the same set of parameters with no significant differences detected. Nitrotyrosine (the footprint of the potent oxidant peroxynitrite) and poly(ADP-ribose) (the product of the DNA damage sensor enzyme PARP-1) could be detected in wound biopsies. Our data identify multiple signs of redox stress in chronic wounds with notable differences. In chronic wounds, elevations in antioxidant levels/activities may indicate compensatory mechanisms against inflammation. The presence of nitrotyrosine and poly(ADP-ribose) in tissues from venous leg ulcers indicate peroxynitrite production and PARP activation in chronic wounds.

International audience; The magnitude of socioeconomic inequalities in mortality differs importantly between countries, but these variations have not been satisfactorily explained. We explored the role of behavioral and structural determinants of these variations, by using a dataset covering 17 European countries in the period 1970-2010, and by conducting multilevel multivariate regression analyses. Our results suggest that between-country variations in inequalities in current mortality can partly be understood from variations in inequalities in smoking, excessive alcohol consumption, and poverty. Also, countries with higher national income, higher quality of government, higher social transfers, higher health care expenditure and more self-expression values have smaller inequalities in mortality. Finally, trends in behavioral risk factors, particularly smoking and excessive alcohol consumption, appear to partly explain variations in inequalities in mortality trends. This study shows that analyses of variations in health inequalities between countries can help to identify entry-points for policy.

Socioeconomic inequalities in mortality are a challenge for public health around the world, but appear to be resistant to policy-making. We aimed to identify European countries which have been more successful than others in narrowing inequalities in mortality, and the factors associated with narrowing inequalities. We collected and harmonised mortality data by educational level in 15 European countries over the last 25 years, and quantified changes in inequalities in mortality using a range of measures capturing different perspectives on inequality (e.g., ‘relative’ and ‘absolute’ inequalities, inequalities in ‘attainment’ and ‘shortfall’). We determined which causes of death contributed to narrowing of inequalities, and conducted country- and period-fixed effects analyses to assess which country-level factors were associated with narrowing of inequalities in mortality. Mortality among the low educated has declined rapidly in all European countries, and a narrowing of absolute, but not relative inequalities was seen in many countries. Best performers were Austria, Italy (Turin) and Switzerland among men, and Spain (Barcelona), England and Wales, and Austria among women. Ischemic heart disease, smoking-related causes (men) and amenable causes often contributed to narrowing inequalities. Trends in income inequality, level of democracy and smoking were associated with widening inequalities, but rising health care expenditure was associated with narrowing inequalities. Trends in inequalities in mortality have not been as unfavourable as often claimed. Our results suggest that health care expansion has counteracted the inequalities widening effect of other influences. Electronic supplementary material The online version of this article (10.1007/s10654-019-00580-9) contains supplementary material, which is available to authorized users.

Purpose Diabetes is accompanied by fundamental rearrangements in redox homeostasis. Hyperglycemia triggers the production of reactive oxygen and nitrogen species which contributes to tissue damage in various target organs. Proliferative diabetic retinopathy (PDR) is a common manifestation of diabetic complications but information on the possible role of reactive intermediates in this condition with special regard to the involvement of the vitreous in PDR-associated redox alterations is scarce. The aim of the study was to determine key parameters of redox homeostasis [advanced glycation endproducts (AGE); protein carbonyl and glutathione (GSH)] content in the vitreous in PDR patients. Methods The study population involved 10 diabetic patients undergoing surgery for complications of proliferative diabetic retinopathy and 8 control (non-diabetic) patients who were undergoing surgery for epiretinal membranes. Vitreal fluids were assayed for the above biochemical parameters. Results We found elevated levels of AGE in the vitreous of PDR patients (812.10 vs 491.69 ng AGE/mg protein). Extent of protein carbonylation was also higher in the samples of diabetic patients (2.08 vs 0.67 A/100 μg protein). The GSH content also increased in the vitreous of PDR patients as compared to the control group (4.54 vs 2.35 μmol/μg protein), respectively. Conclusion The study demonstrates that diabetes-associated redox alterations also reach the vitreous with the most prominent changes being increased protein carbonylation and increased antioxidant levels., Graphical abstract fx1, Highlights • Vitreal AGE levels are elevated in PDR patients. • Extent of protein carbonylation is higher in the vitreal samples of PDR patients. • The glutathione content is increased in the vitreous of PDR patients.

BACKGROUND: Socioeconomic inequalities in longevity have been found in all European countries. We aimed to assess which determinants make the largest contribution to these inequalities.METHODS: We did an international comparative study of inequalities in risk factors for shorter life expectancy in Europe. We collected register-based mortality data and survey-based risk factor data from 15 European countries. We calculated partial life expectancies between the ages of 35 years and 80 years by education and gender and determined the effect on mortality of changing the prevalence of eight risk factors-father with a manual occupation, low income, few social contacts, smoking, high alcohol consumption, high bodyweight, low physical exercise, and low fruit and vegetable consumption-among people with a low level of education to that among people with a high level of education (upward levelling scenario), using population attributable fractions.FINDINGS: In all countries, a substantial gap existed in partial life expectancy between people with low and high levels of education, of 2·3-8·2 years among men and 0·6-4·5 years among women. The risk factors contributing most to the gap in life expectancy were smoking (19·8% among men and 18·9% among women), low income (9·7% and 13·4%), and high bodyweight (7·7% and 11·7%), but large differences existed between countries in the contribution of risk factors. Sensitivity analyses using the prevalence of risk factors in the most favourable country (best practice scenario) showed that the potential for reducing the gap might be considerably smaller. The results were also sensitive to varying assumptions about the mortality risks associated with each risk factor.INTERPRETATION: Smoking, low income, and high bodyweight are quantitatively important entry points for policies to reduce educational inequalities in life expectancy in most European countries, but priorities differ between countries. A substantial reduction of inequalities in life expectancy requires policy actions on a broad range of health determinants.FUNDING: European Commission and Network for Studies on Pensions, Aging, and Retirement.

Background: Bulky DNA adducts reflect genotoxic exposures, have been associated with lower birth weight, and may predict cancer risk. Objective: We selected factors known or hypothesized to affect in utero adduct formation and repair and examined their associations with adduct levels in neonates. Methods: Pregnant women from Greece, Spain, England, Denmark, and Norway were recruited in 2006–2010. Cord blood bulky DNA adduct levels were measured by the 32P-postlabeling technique (n = 511). Diet and maternal characteristics were assessed via questionnaires. Modeled exposures to air pollutants and drinking-water disinfection by-products, mainly trihalomethanes (THMs), were available for a large proportion of the study population. Results: Greek and Spanish neonates had higher adduct levels than the northern European neonates [median, 12.1 (n = 179) vs. 6.8 (n = 332) adducts per 108 nucleotides, p < 0.001]. Residence in southern European countries, higher maternal body mass index, delivery by cesarean section, male infant sex, low maternal intake of fruits rich in vitamin C, high intake of dairy products, and low adherence to healthy diet score were statistically significantly associated with higher adduct levels in adjusted models. Exposure to fine particulate matter and nitrogen dioxide was associated with significantly higher adducts in the Danish subsample only. Overall, the pooled results for THMs in water show no evidence of association with adduct levels; however, there are country-specific differences in results with a suggestion of an association in England. Conclusion: These findings suggest that a combination of factors, including unknown country-specific factors, influence the bulky DNA adduct levels in neonates. Citation: Pedersen M, Mendez MA, Schoket B, Godschalk RW, Espinosa A, Landström A, Villanueva CM, Merlo DF, Fthenou E, Gracia-Lavedan E, van Schooten FJ, Hoek G, Brunborg G, Meltzer HM, Alexander J, Nielsen JK, Sunyer J, Wright J, Kovács K, de Hoogh K, Gutzkow KB, Hardie LJ, Chatzi L, Knudsen LE, Anna L, Ketzel M, Haugen M, Botsivali M, Nieuwenhuijsen MJ, Cirach M, Toledano MB, Smith RB, Fleming S, Agramunt S, Kyrtopoulos SA, Lukács V, Kleinjans JC, Segerbäck D, Kogevinas M. 2015. Environmental, dietary, maternal, and fetal predictors of bulky DNA adducts in cord blood: a European mother–child study (NewGeneris). Environ Health Perspect 123:374–380; http://dx.doi.org/10.1289/ehp.1408613

Hypertension and dyslipidemia belong to the most prevalent modifiable risk factors for cerebrovascular and cardiovascular diseases. Hereby, we aimed to examine the combined effects of newly diagnosed hypertension and hyperlipidemia on the characteristics of the arterial wall and on cognitive function. We examined 72 hypertensive and 85 apparently healthy individuals. Based on serum lipid levels, four subgroups were created ranging from normotensive-normolipidemic to hypertensive-hyperlipidemic subjects. Carotid intima-media thickness (IMT), arterial stiffness, and cognitive function were assessed. IMT of controls was the lowest, whereas that of patients with both risk factors the highest. Stiffness parameters increased when both risk factors were present, whereas subjects with only one risk factor exhibited intermediate values. Hypertensive patients performed worse when memory, attention, reaction time, and trait anxiety were assessed. Significant worsening of IMT, arterial stiffness, and sum of neuropsychological scores was observed along with increasing mean arterial pressure. Generally, hyperlipidemia combining with hypertension resulted in further worsening of all examined parameters. Subclinical changes of the vascular wall and cognitive performance are already present in recently diagnosed hypertensive patients. Combination of hyperlipidemia and hypertension results in more severe impairments, therefore, early and intensive treatment may be crucial to prevent further deterioration.

Objectives We aimed to assess whether trends in inequalities in mortality during the period 1970–2010 differed between Finland, Norway, England and Wales, France, Italy (Turin) and Hungary. Methods Total and cause-specific mortality data by educational level and, if available, occupational class were collected and harmonized. Both relative and absolute measures of inequality in mortality were calculated. Results In all countries except Hungary, all-cause mortality declined strongly over time in all socioeconomic groups. Relative inequalities in all-cause mortality generally increased, but more so in Hungary and Norway than elsewhere. Absolute inequalities often narrowed, but went up in Hungary and Norway. As a result of these trends, Hungary (where inequalities in mortality where almost absent in the 1970s) and Norway (where inequalities in the 1970s were among the smallest of the six countries in this study) now have larger inequalities in mortality than the other four countries. Conclusions While some countries have experienced dramatic setbacks, others have made substantial progress in reducing inequalities in mortality. Electronic supplementary material The online version of this article (doi:10.1007/s00038-016-0922-9) contains supplementary material, which is available to authorized users.

This study examined the relationship between autonomic nervous system dysfunction, anxiety and depression in untreated hypertension.86 newly diagnosed hypertensive patients and 98 healthy volunteers were included in the study. The psychological parameters were assessed with Spielberger State-Trait Anxiety Inventory and Beck Depression Inventory by a skilled psychologist. Autonomic parameters were examined during tilt table examination (10min lying position, 10min passive tilt). Heart rate variability (HRV) was calculated by autoregressive methods. Baroreflex sensitivity (BRS) was calculated by non-invasive sequence method from the recorded beat to beat blood pressure values and RR intervals.Significantly higher state (42.6±9.3 vs. 39.6±10.7 p=0.05) and trait (40.1±8.9 vs. 35.1±8.6, p0.0001) anxiety scores were found in the hypertension group. There was no statistically significant difference in the depression level. LF-RRI (Low Frequency-RR interval) of HRV in passive tilt (377.3±430.6 vs. 494.1±547, p=0.049) and mean BRS slope (11.4±5.5 vs. 13.2±6.4, p=0.07) in lying position were lower in hypertensives. Trait anxiety score correlates significantly with sympatho/vagal balance (LF/HF-RRI) in passive tilt position (Spearman R=-0.286, p=0.01).Anxiety could play a more important role than depression in the development of hypertension. Altered autonomic control of the heart could be one of the pathophysiological links between hypertension and psychological factors.

Background Hypertensive (HT) patients are at higher risk of cognitive decline than normotensive individuals, because high blood pressure is a risk factor for mild cognitive deterioration. In this study cardio- and cerebrovascular reactivity along with cognitive performance was assessed on newly diagnosed HT patients. Methods Diagnosis of hypertension was based on international recommendations. None of the patients had diabetes, and all of them had normal cerebral CT scan. Eighty-one patients (43.5 ± 10.2 years, male/female ratio: 42/39) were compared with 94 healthy controls (44 ± 9.4 years, male/female ratio: 50/44). In both groups continuous, non-invasive and simultaneous monitoring of cerebral and cardiac hemodynamical parameters were recorded during head-up tilt table testing (HUTT). Reaction time, attention and memory skills, anxiety and depression rate were determined by neuropsychological tests. Results During HUTT significant differences were found in certain cardiovascular parameters (blood pressure, total peripheral resistance index, stroke index), but no differences were detected in cerebral blood flow velocity . While there was no significant difference in reaction time between the two groups, tests estimating short-term memory (Digit Span Test) differed significantly. Moreover, sum of standardized test scores was significantly lower, while anxiety level was significantly increased in HT patients compared to controls. Conclusion Decrease in neuropsychological performance along with alterations of cardiovascular parameters is an early manifestation of hypertension. Aim for an early intervention and accurate treatment is crucial for preventing further impairments.

Lung cancer rate in Hungary is one of the highest in the world among men and also very high among women, for reasons not clearly understood yet. The aim of the study was to explore characteristics of DNA damage and TP53 gene mutations in lung cancer from Hungary. Tissue samples from 104 lung resections for lung cancer patients, both men and women, operated on for non-small cell lung cancer, specifically, primary squamous cell carcinoma or adenocarcinoma were studied. Of the cases, 37% smoked up to the surgery, 24% stopped smoking within 1 year before the surgery, 26% stopped smoking more than a year before the surgery and 13% never smoked. TP53 mutations were detected by denaturant gradient gel electrophoresis, automated capillary electrophoresis single-strand conformation polymorphism and sequencing. Bulky DNA adduct levels were determined by (32)P-post-labelling in non-tumorous lung tissue. In total, 45% (47/104) of the cases carried TP53 mutation. The prevalence of TP53 mutations was statistically significantly associated with duration of smoking, tumour histology and gender. Smokers had approximately twice as high bulky adduct level as the combined group of former- and never-smokers (10.9 +/- 6.5 versus 5.5 +/- 3.4 adducts/10(8) nucleotides). The common base change G --> T transversion (8/43; 19%) was detected exclusively in smokers. For the first time, we demonstrate that most carriers of G --> T transversions had also a high level of bulky DNA adducts in their non-tumourous lung tissue. Our study provides evidence for a high burden of molecular alterations occurring concurrently in the lung of lung cancer patients.

Suicide and alcohol-related mortality are often linked to each other in recent times, especially in the unfavourable mortality trends detected in Russia. Recent study has aimed to investigate suicide and alcohol-related mortality in Hungary between 1986 and 2005. This paper is based on the concept of social anomie and expects to find more favourable trends for both causes of death among those who were less exposed to unfavourable economic and social trends in the last two decades.In a cross-sectional design sex, age- and education-specific mortality rates were calculated.We found falling suicide rates in all socio-demographic groups, except well-educated middle aged men. Suicide has fallen more among women than men, more among the elderly than the young and more among the more educated than the less educated. Alcohol-related mortality has risen by 5-10 %, and its occurrence in different socio-demographic groups was found to be changing entirely proportionally.Developments in suicide mortality are generally in accordance with the hypothesis based on the concept of social anomie while those of alcohol-related mortality showed no relation with this concept.

The objective of this study was to estimate the effect of the thyroglobulin (TG) locus on beef quality traits in some beef cattle breeds and to investigate the effect of the DGAT1 locus on milk production traits in the Hungarian Holstein Friesian population. TG and DGAT1 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. At the TG locus TT bulls showed the highest fat percentage values in the longissimus dorsi muscle (m. longissimus dorsi); the difference between CC and TT genotypes was significant. DGAT1 GC/GC cows had the highest milk, fat and protein yield values. Due to the relatively small number of GC/GC cows the difference proved to be significant only between AA/AA and AA/GC genotypes.

International audience; ackground: Smoking contributes to socioeconomic inequalities in mortality, but the extent to which this contribution has changed over time and driven widening or narrowing inequalities in total mortality remains unknown. We studied socioeconomic inequalities in smoking-attributable mortality and their contribution to inequalities in total mortality in 1990-1994 and 2000-2004 in 14 European countries.Methods: We collected, harmonised and standardised population-wide data on all-cause and lung-cancer mortality by age, gender, educational and occupational level in 14 European populations in 1990-1994 and 2000-2004. Smoking-attributable mortality was indirectly estimated using the Preston-Glei-Wilmoth method.Results: In 2000-2004, smoking-attributable mortality was higher in lower socioeconomic groups in all countries among men, and in all countries except Spain, Italy and Slovenia, among women, and the contribution of smoking to socioeconomic inequalities in mortality varied between 19% and 55% among men, and between -1% and 56% among women. Since 1990-1994, absolute inequalities in smoking-attributable mortality and the contribution of smoking to inequalities in total mortality have decreased in most countries among men, but increased among women.Conclusions: In many European countries, smoking has become less important as a determinant of socioeconomic inequalities in mortality among men, but not among women. Inequalities in smoking remain one of the most important entry points for reducing inequalities in mortality.

Background Socioeconomic inequalities are increasingly recognised as an important public health issue, although their role in the leading causes of mortality in urban areas in Europe has not been fully evaluated. In this study, we used data from the INEQCITIES study to analyse inequalities in cause-specific mortality in 15 European cities at the beginning of the 21st century. Methods A cross-sectional ecological study was carried out to analyse 9 of the leading specific causes of death in small areas from 15 European cities. Using a hierarchical Bayesian spatial model, we estimated smoothed Standardized Mortality Ratios, relative risks and 95% credible intervals for cause-specific mortality in relation to a socioeconomic deprivation index, separately for men and women. Results We detected spatial socioeconomic inequalities for most causes of mortality studied, although these inequalities differed markedly between cities, being more pronounced in Northern and Central-Eastern Europe. In the majority of cities, most of these causes of death were positively associated with deprivation among men, with the exception of prostatic cancer. Among women, diabetes, ischaemic heart disease, chronic liver diseases and respiratory diseases were also positively associated with deprivation in most cities. Lung cancer mortality was positively associated with deprivation in Northern European cities and in Kosice, but this association was non-existent or even negative in Southern European cities. Finally, breast cancer risk was inversely associated with deprivation in three Southern European cities. Conclusions The results confirm the existence of socioeconomic inequalities in many of the main causes of mortality, and reveal variations in their magnitude between different European cities, Background Socioeconomic inequalities are increasingly recognised as an important public health issue, although their role in the leading causes of mortality in urban areas in Europe has not been fully evaluated. In this study, we used data from the INEQ-CITIES study to analyse inequalities in cause-specific mortality in 15 European cities at the beginning of the 21st century. Methods A cross-sectional ecological study was carried out to analyse 9 of the leading specific causes of death in small areas from 15 European cities. Using a hierarchical Bayesian spatial model, we estimated smoothed Standardized Mortality Ratios, relative risks and 95% credible intervals for cause-specific mortality in relation to a socioeconomic deprivation index, separately for men and women. Results We detected spatial socioeconomic inequalities for most causes of mortality studied, although these inequalities differed markedly between cities, being more pronounced in Northern and Central-Eastern Europe. In the majority of cities, most of these causes of death were positively associated with deprivation among men, with the exception of prostatic cancer. Among women, diabetes, ischaemic heart disease, chronic liver diseases and respiratory diseases were also positively associated with deprivation in most cities. Lung cancer mortality was positively associated with deprivation in Northern European cities and in Kosice, but this association was non-existent or even negative in Southern European cities. Finally, breast cancer risk was inversely associated with deprivation in three Southern European cities. Conclusions The results confirm the existence of socioeconomic inequalities in many of the main causes of mortality, and reveal variations in their magnitude between different European cities.

Thrombolysis by intravenous recombinant tissue plasminogen activator (rt-PA) is an effective therapy in acute ischemic stroke (AIS). Thrombin generation test (TGT) is a global hemostasis test providing information about the speed and amount of generated thrombin in plasma. Here we aimed to find out whether results of this test before the initiation of thrombolysis might predict outcomes. Study population included 120 consecutive AIS patients, all within 4.5 hours of their symptom onset, who underwent thrombolysis by rt-PA. Blood samples were collected from all patients upon admission and TGT was performed using platelet poor plasma. Clinical data of patients including the NIHSS were registered at admission, day 1 and 7 after therapy. The ASPECT score was assessed using CT images taken before and 24 hours after thrombolysis. Long-term functional outcome was defined 3 months after the event by the modified Rankin Scale. Endogenous Thrombin Potential (ETP) and Peak Thrombin were significantly lower in patients with cardioembolic IS. Symptomatic intracranial hemorrhage (SICH) was found in 6 patients and was significantly associated with low ETP and Peak Thrombin levels. A multiple logistic regression model revealed that an ETP result in the lower quartile is an independent predictor of mortality within the first two weeks (OR: 6.03; 95%CI: 1.2-30.16, p

Poly(ADP-ribosyl)ation (PARylation) is a protein modification reaction regulating various diverse cellular functions ranging from metabolism, DNA repair and transcription to cell death. We set out to investigate the role of PARylation in wound healing, a highly complex process involving various cellular and humoral factors. We found that topically applied poly(ADP-ribose) polymerase (PARP) inhibitors 3-aminobenzamide and PJ-34 accelerated wound closure in a mouse model of excision wounding. Moreover, wounds also closed faster in PARP-1 knockout mice as compared with wild-type littermates. Immunofluorescent staining for poly(ADP-ribose) (PAR) indicated increased PAR synthesis in scattered cells of the wound bed. Expression of interleukin (IL)-6, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase and matrix metalloproteinase-9 was lower in the wounds of PARP-1 knockout mice as compared with control, and expression of IL-1 β, cyclooxygenase-2, TIMP-1 and -2 also were affected. The level of nitrotyrosine (a marker of nitrating stress) was lower in the wounds of PARP-1 knockout animals as compared with controls. In vitro scratch assays revealed significantly faster migration of keratinocytes treated with 3-aminobenzamide or PJ34 as compared with control cells. These data suggest that PARylation by PARP-1 slows down the wound healing process by increasing the production of inflammatory mediators and nitrating stress and by slowing the migration of keratinocytes.

Aims: To explore inequalities in total mortality between small areas of 16 European cities for men and women, as well as to analyse the relationship between these geographical inequalities and their socioeconomic indicators. Methods: A cross-sectional ecological design was used to analyse small areas in 16 European cities (26,229,104 inhabitants). Most cities had mortality data for a period between 2000 and 2008 and population size data for the same period. Socioeconomic indicators included an index of socioeconomic deprivation, unemployment, and educational level. We estimated standardised mortality ratios and controlled for their variability using Bayesian models. We estimated relative risk of mortality and excess number of deaths according to socioeconomic indicators. Results: We observed a consistent pattern of inequality in mortality in almost all cities, with mortality increasing in parallel with socioeconomic deprivation. Socioeconomic inequalities in mortality were more pronounced for men than women, and relative inequalities were greater in Eastern and Northern European cities, and lower in some Western (men) and Southern (women) European cities. The pattern of excess number of deaths was slightly different, with greater inequality in some Western and Northern European cities and also in Budapest, and lower among women in Madrid and Barcelona. Conclusions: In this study, we report a consistent pattern of socioeconomic inequalities in mortality in 16 European cities. Future studies should further explore specific causes of death, in order to determine whether the general pattern observed is consistent for each cause of death.

Background: Health and inequalities in health among inhabitants of European cities are of major importance for European public health and there is great interest in how different health care systems in Europe perform in the reduction of health inequalities. However, evidence on the spatial distribution of cause-specific mortality across neighbourhoods of European cities is scarce. This study presents maps of avoidable mortality in European cities and analyses differences in avoidable mortality between neighbourhoods with different levels of deprivation. Methods: We determined the level of mortality from 14 avoidable causes of death for each neighbourhood of 15 large cities in different European regions. To address the problems associated with Standardised Mortality Ratios for small areas we smooth them using the Bayesian model proposed by Besag, York and Mollie. Ecological regression analysis was used to assess the association between social deprivation and mortality. Results: Mortality from avoidable causes of death is higher in deprived neighbourhoods and mortality rate ratios between areas with different levels of deprivation differ between gender and cities. In most cases rate ratios are lower among women. While Eastern and Southern European cities show higher levels of avoidable mortality, the association of mortality with social deprivation tends to be higher in Northern and lower in Southern Europe. Conclusions: There are marked differences in the level of avoidable mortality between neighbourhoods of European cities and the level of avoidable mortality is associated with social deprivation. There is no systematic difference in the magnitude of this association between European cities or regions. Spatial patterns of avoidable mortality across small city areas can point to possible local problems and specific strategies to reduce health inequality which is important for the development of urban areas and the well-being of their inhabitants.

Background Over the last decades of the 20th century, a widening of the gap in death rates between upper and lower socioeconomic groups has been reported for many European countries. For most countries, it is unknown whether this widening has continued into the first decade of the 21st century. Methods We collected and harmonised data on mortality by educational level among men and women aged 30–74 years in all countries with available data: Finland, Sweden, Norway, Denmark, England and Wales, Belgium, France, Switzerland, Spain, Italy, Hungary, Lithuania and Estonia. Results Relative inequalities in premature mortality increased in most populations in the North, West and East of Europe, but not in the South. This was mostly due to smaller proportional reductions in mortality among the lower than the higher educated, but in the case of Lithuania and Estonia, mortality rose among the lower and declined among the higher educated. Mortality among the lower educated rose in many countries for conditions linked to smoking (lung cancer, women only) and excessive alcohol consumption (liver cirrhosis and external causes). In absolute terms, however, reductions in premature mortality were larger among the lower educated in many countries, mainly due to larger absolute reductions in mortality from cardiovascular disease and cancer (men only). Despite rising levels of education, population-attributable fractions of lower education for mortality rose in many countries. Conclusions Relative inequalities in premature mortality have continued to rise in most European countries, and since the 1990s, the contrast between the South (with smaller inequalities) and the East (with larger inequalities) has become stronger. While the population impact of these inequalities has further increased, there are also some encouraging signs of larger absolute reductions in mortality among the lower educated in many countries. Reducing inequalities in mortality critically depends upon speeding up mortality declines among the lower educated, and countering mortality increases from conditions linked to smoking and excessive alcohol consumption such as lung cancer, liver cirrhosis and external causes.

Background— Pulmonary vein isolation has increasingly been used to cure atrial fibrillation, but concerns have recently been raised that subclinical brain damage may occur because of microembolization during these procedures. We compared the occurrence of bubble formation seen on intracardiac echocardiography and the microembolic signals (MESs) detected by transcranial Doppler on the use of different ablation techniques and anticoagulation strategies. Methods and Results— This prospective study included 35 procedures in 34 consecutive patients (age, 52; SD, 12.8 years; female:male 9:25). Pulmonary vein isolation was performed with a cryoballoon and the conventional anticoagulation protocol (activated clotting time >250 s) in 10 procedures (group 1), with a multipolar duty-cycled radiofrequency pulmonary group 2), and with regime a pulmonary vein ablation catheter with an aggressive anticoagulation (activated clotting time >320 s) in 13 procedures (group 3). The mean total numbers of MESs detected during the procedures were 833.7 (SD, 727.4) in group 1, 3142.6 (SD, 1736.4) in group 2, and 2204.6 (SD, 1078.1) in group 3 ( P =0.0005). MESs were detected mostly during energy delivery in the pulmonary vein ablation catheter groups, whereas a relatively even distribution of emboli formation was seen during cryoballoon ablations. A significant correlation was found in all groups between the degree of bubble formation on intracardiac echocardiography and the number of MESs ( P =0.0000). Conclusions— Duty-cycled radiofrequency ablation is associated with significantly more MESs, even when more aggressive anticoagulation is applied. With both techniques most of these microemboli are gaseous in nature.

This study analysed socioeconomic inequalities in mortality due to injuries in small areas of 15 European cities, by sex, at the beginning of this century. A cross-sectional ecological study with units of analysis being small areas within 15 European cities was conducted. Relative risks of injury mortality associated with the socioeconomic deprivation index were estimated using hierarchical Bayesian model. The number of small areas varies from 17 in Bratislava to 2666 in Turin. The median population per small area varies by city (e.g. Turin had 274 inhabitants per area while Budapest had 76,970). Socioeconomic inequalities in all injury mortality are observed in the majority of cities and are more pronounced in men. In the cities of northern and western Europe, socioeconomic inequalities in injury mortality are found for most types of injuries. These inequalities are not significant in the majority of cities in southern Europe among women and in the majority of central eastern European cities for both sexes. The results confirm the existence of socioeconomic inequalities in injury related mortality and reveal variations in their magnitude between different European cities. This paper has been partially funded by the project INEQ-CITIES, “Socioeconomic inequalities in mortality: evidence and policies of cities of Europe”; project funded by the Executive Agency for Health and Consumers (Commission of the European Union), project no. 2008 12 13.

Silent brain infarction is a cerebral ischaemic event evident on brain imaging without any clinical symptom. Silent brain infarction is often detected in apparently healthy, elderly people and in different selected patient groups as well. Lately, several studies were carried out in order to identify the clinical conditions leading to silent brain infarction. A large number of clinical and paraclinical parameters were found to increase silent brain infarction prevalence, and the continuously growing list of risk factors revealed that the majority of them are similar to those related to stroke. Accordingly, some consider silent brain infarction the preclinical stage of clinically overt stroke. This point of view emphasizes the early recognition and management of silent brain infarction-related risk factors, and a great need for comparative studies, which could elicit the most sensitive indicators of the increased silent brain infarction risk, especially the ones that could be cost-effectively screened in the large populations as well.

We have developed and validated a sandwich chemiluminescence immunoassay (SCIA) which measures polycyclic aromatic hydrocarbon (PAH)-DNA adducts combining high throughput and adequate sensitivity, appropriate for evaluation of adduct levels in human population studies. Fragmented DNA is incubated with rabbit antiserum elicited against DNA modified with r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and subsequently trapped by goat anti-rabbit IgG bound to a solid surface. Anti-single-stranded (ss) DNA antibodies binds in a quantity proportional to the adduct levels and is detected by chemiluminescence. The BPDE-DNA SCIA has a limit of detection of 3 adducts per 10(9) nucleotides with 5 μg DNA per well. We have validated the BPDE-DNA SCIA using DNA modified in vitro, DNA from benzo[a]pyrene (BP)-exposed cultured cells and mice. The levels of adduct measured by SCIA were lower (30-60%) than levels of bulky DNA adducts measured in the same samples by (32)P-postlabelling. The BPDE-DNA SCIA also detected adducts produced in vivo by PAHs other than BP. When blood DNA samples from maternal/infant pairs were assayed by BPDE-DNA SCIA, the adduct levels obtained were significantly correlated. However, there was no correlation between (32)P-postlabelling and SCIA values for the same samples. The SCIA can be extended to any DNA adduct and is expected to provide, when fully automated, a valuable high-throughput approach in large-scale population studies. This work was supported by contracts from the European Union (to S.A.K): Network of Excellence ECNIS—‘Environmental cancer risk, nutrition and individual susceptibility’ and Integrated Project NewGeneris—‘Newborns and genotoxic exposure risks’ (contract numbers FOOD-CT-2005-513943, FOOD-CT-2005-016320). The work was also supported in part by the intramural program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA (to M.C.P.).

Recent research has suggested that violent mortality may be socially patterned and a potentially important source of health inequalities within and between countries. Against this background the current study assessed socioeconomic inequalities in homicide mortality across Europe. To do this, longitudinal and cross-sectional data were obtained from mortality registers and population censuses in 12 European countries. Educational level was used to indicate socioeconomic position. Age-standardized mortality rates were calculated for post, upper and lower secondary or less educational groups. The magnitude of inequalities was assessed using the relative and slope index of inequality. The analysis focused on the 35-64 age group. Educational inequalities in homicide mortality were present in all countries. Absolute inequalities in homicide mortality were larger in the eastern part of Europe and in Finland, consistent with their higher overall homicide rates. They contributed 2.5 % at most (in Estonia) to the inequalities in total mortality. Relative inequalities were high in the northern and eastern part of Europe, but were low in Belgium, Switzerland and Slovenia. Patterns were less consistent among women. Socioeconomic inequalities in homicide are thus a universal phenomenon in Europe. Wide-ranging social and inter-sectoral health policies are now needed to address the risk of violent victimization that target both potential offenders and victims.

This report presents a fatal case related to the consumption of methylone, a relatively new cathinone type designer drug. A 16-year-old boy suddenly lost his consciousness in a party. Resuscitation had been continued for about 1.5 hours at the intensive care unit, but it was unsuccessful. His previous history included cardiac malformation detected at infancy and bronchial asthma had been diagnosed one year before his death. Signs of sudden cardiac death were observed during autopsy. Methylone intake was proved in blood and liver extract using gas chromatography/mass spectrometry; its concentration was 272 ng/ml in the blood, and 387 ng/g in the liver. Pathohistology revealed microvascular steatosis in the liver, which raised the possibility of chronic use of toxic substances. In addition, striated heart muscle damage was observed, which could be due to the use of an amphetamine-like substance. The authors presume that steatosis of the heart muscle, congenital heart disease and bronchial asthma could be predisposing factors for sudden cardiac death that occurred in the presence of relatively low levels of methylone. Access to various designer drugs is easy, fast and broad. Consequently, the potential abuse or overdose should be taken into consideration in the emergency practice. The use of “non-illicit” drugs does not require formal intervention by the authorities, but the medical service must alarm the stakeholders. Orv. Hetil., 2012, 153, 271–276.

Tobacco smoke contains many alkylating agents that can react with DNA to produce O(4)-ethylthymidine (O(4)-etT) and several other types of promutagenic base modifications. Our aims were (i) to confirm results of a pilot study (Godschalk, R., Nair, J., Schooten, F. J., Risch, A., Drings, P., Kayser, K., Dienemann, H. and Bartsch, H. (2002) Comparison of multiple DNA adduct types in tumor adjacent human lung tissue: effect of cigarette smoking. Carcinogenesis, 23, 2081-2086) on the formation of O(4)-etT in smokers' lung; (ii) to explore associations between levels of O(4)-etT and smoking status and (iii) to investigate whether a correlation exists between levels of O(4)-etT and bulky (polycyclic aromatic hydrocarbons-derived) DNA adducts. Archived DNA samples originated from histologically normal peripheral lung tissues of 64 Hungarian lung cancer patients, who underwent lung resection. O(4)-etT was determined by an immunoenriched (32)P-postlabelling-high-performance liquid chromatography method. Levels of bulky DNA adducts were determined by the nuclease P1 adduct-enriched (32)P-postlabelling. O(4)-etT levels ranged from 0.01 to 3.91 adducts/10(8) thymidines. In the combined group of subjects who smoked until surgery or gave up smoking at most 1 year before it, the mean level of O(4)-etT was 1.7-fold (P = 0.015) and of bulky DNA adducts 2.2-fold (P < 0.0001) higher than in long-term ex-smokers (LES) and never-smokers (NS) combined. We found no significant correlation between the individual levels of the two DNA adduct types. No dose-response was detected between O(4)-etT formation and smoking dose. In one-third of LES, O(4)-etT levels were above the 2.0-fold mean level of adducts found in NS, indicating its high persistence. Our results confirm the smoking-related formation of O(4)-etT in human lung DNA that should be explored as biomarker. Its long persistence in target tissue implicates a role of this potentially miscoding lesion in tobacco smoking-associated cancers. The technical assistance by Mayura Meerang (DKFZ) is gratefully appreciated. L. Anna was the recipient of an Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS) Exchange fellowship within ECNIS.

Authors draw attention to their own experience about the occurrence and epidemic measures of tuberculosis in two micro-regions of Hungary, Fadd and Józsefváros situated far from each other. According to data from the National Statistical Office of Hungary, tuberculosis does not belong to the most significant causes of morbidity and mortality. However, it still represents a notable factor in national healthcare and public health. Currently, tuberculosis is not an important issue to be regulated by health care decision makers or at the level of legislation. Based on their own experience, authors suggest reconsidering the possibility of epidemic measures for the prevention of tuberculosis. Orv. Hetil., 2011, 152, 481–484.

Carcinomatous meningitis is a serious complication of advanced stage solid tumours, which may become more common with improved survival.A 53-year-old woman with a recent history of breast cancer (pT2pN2M0) had been treated by mastectomy and adjuvant chemotherapy and radiotherapy. She presented with weakness, diplopia and vertigo raising the possibility of vertebrobasilar ischaemia or an intracranial mass. In another patient, a 62-year-old man with hypertension, a stenotic common bile duct had been diagnosed when examined for abdominal complaints. When he presented with a high blood pressure value accompanied by intensive headache, vomiting and bilateral hearing loss, he was thought to have a hypertensive crisis. The rapidly progressive neurological symptoms and the history of breast cancer and findings suggesting pancreatic head tumour, respectively, led to the clinical diagnosis of carcinomatous meningitis in both cases, despite any evidence on CT scans or a negative MR scan, though of limited value, in the first case. This diagnosis was confirmed by the laboratory and cytological findings of the cerebrospinal fluid, and also by the post mortem examination, since both patients died within a month after the onset of the symptoms. The primary tumour in the second patient proved to be a widely metastasizing diffuse type gastric cancer.Carcinomatous meningitis has a varying but characteristic presentation which generally makes it easy to diagnose, but it can sometimes present differential diagnostic problems. What we can learn from these two cases may help in recognizing this complication.

BACKGROUND: Post-communist transition has had a huge impact on mortality in Eastern Europe. We examined how educational inequalities in mortality changed between 1990 and 2000 in Estonia, Lithuania, Poland and Hungary. METHODS: Cross-sectional data for the years around 1990 and 2000 were used. Age-standardized mortality rates and mortality rate ratios (for total mortality only) were calculated for men and women aged 35-64 in three educational categories, for five broad cause-of-death groups and for five (seven among women) specific causes of death. RESULTS: Educational inequalities in mortality increased in all four countries but in two completely different ways. In Poland and Hungary, mortality rates decreased or remained the same in all educational groups. In Estonia and Lithuania, mortality rates decreased among the highly educated, but increased among those of low education. In Estonia and Lithuania, for men and women combined, external causes and circulatory diseases contributed most to the increasing educational gap in total mortality. CONCLUSIONS: Different trends were observed between the two former Soviet republics and the two Central Eastern European countries. This divergence can be related to differences in socioeconomic development during the 1990s and in particular, to the spread of poverty, deprivation and marginalization. Alcohol and psychosocial stress may also have been important mediating factors

The somatostatin-like (SLI), the neuropeptide Y-like (NPY-LI), and the betaendorphin-like (BE-LI) immunoreactivities of cerebrospinal fluid (CSF) obtained by suboccipital puncture, or plasma from patients suffering from common migraine or other neuropsychiatric disorders were analysed. The SLI concentration was tendentiously decreased in the migraine patients during the attack-free period compared to that of a ‘mixed neuropsychiatric group’. During the migraine attack the level of SLI was further decreased. Similar alteration was found in the CSF BE-LI, while the BE-LI in the plasma showed only a tendentious decrease in common migraine patients. The NPY-LI did not change during the attack period in the CSF or plasma. These findings may indicate the possible role of somatostatin in the pathogenesis of common migraine, and support earlier observations that beta-endorphin is involved in the development in this disorder.

Platelet aggregation induced by ADP, collagen and platelet-activating factor was studied in common (migraine without aura) and classical migraine (migraine with aura) patients during and between attacks. The EC 50 * values for ADP and platelet-activating factor were significantly higher, whilst that for collagen was significantly lower in classical migraine patients during headache-free intervals compared to healthy volunteers. The EC50 values obtained for common migraine sufferers during symptom-free periods were similar to those of controls. During attacks, the EC 50 value for ADP, but not for collagen and platelet-activating factor, was significantly higher than that of the controls. In healthy subjects a positive correlation was found between ADP and collagen-induced aggregation. In contrast, there was a U-shaped correlation matrix in classical migraine patients. The present observations show that platelet aggregation is altered in migraine patients and this raises the possibility that platelet-activating factor may be involved in the pathogenesis of migraine.