The German CPU registry: Comparison of smokers and nonsmokers.

BACKGROUND: Chest pain is a major reason for admission to an internal emergency department, and smoking is a well-known risk factor for coronary artery disease (CAD) and acute coronary syndrome (ACS). The aim of this analysis is to illustrate the differences between smokers and nonsmokers presenting to German chest pain units (CPU) in regard to patient characteristics, CAD manifestation, treatment strategy, and prognosis. METHODS: From December 2008 to March 2014, 13,902 patients who had a complete 3­month follow-up were enrolled in the German CPU registry. The analysis comprised 5796 patients with ACS and documented smoking status. RESULTS: Of all the patients in the CPU registry, 35.2% were smokers. Compared with nonsmokers, they were 13.5 years younger (58.2 vs. 71.7 years, p < 0.001), predominantly men (77.1% vs. 65.2%, p < 0.001), and were more frequently diagnosed with single-vessel disease (32.1% vs. 25.2%) as well as ST-elevation myocardial infarction (STEMI; 23.8% vs. 15.5%, p < 0.001). Although the Global Registry of Acute Coronary Events (GRACE) Risk Score for hospital mortality was lower in the group of smokers (106.1 vs. 123.3, p < 0.001), we did not observe any differences in CPU death (0.4% vs. 0.4%, p = 0.69) and CPU major adverse cardiac event (MACE) rates (3.8% vs 2.9%, p = 0.073) between the groups. In the 3­month follow-up, we documented higher mortality rates in the nonsmoker group (1.9% vs. 2.9%, p = 0.035) in correlation with the GRACE Risk Score (80.3 vs. 105.2, p < 0.001). MACE rates were similar during the follow-up (3.1% vs. 4.1%, p = 0.065). CONCLUSION: Observations from the German CPU registry demonstrate that smoking is a strong predictor of acute CAD manifestation early in life, especially STEMI. In spite of a lower GRACE Risk Score and fewer comorbidities, smokers had a rate of hospital mortality similar to the older group of nonsmokers.

European guidelines on lifestyle changes for management of hypertension : Awareness and implementation of recommendations among German and European physicians.

BACKGROUND: In the 2013 European Society of Hypertension (ESH) and European Society of Cardiology (ESC) guidelines for the management of arterial hypertension, six lifestyle changes for treatment are recommended for the first time with class I, level of evidence A. We initiated a survey among physicians to explore their awareness and consideration of lifestyle changes in hypertension management. METHODS: The survey included questions regarding demographics as well as awareness and implementation of the recommended lifestyle changes. It was conducted at two German and two European scientific meetings in 2015. RESULTS: In all, 1064 (37.4% female) physicians participated (806 at the European and 258 at the German meetings). Of the six recommended lifestyle changes, self-reported awareness was highest for regular exercise (85.8%) followed by reduction of weight (66.2%). The least frequently self-reported lifestyle changes were the advice to quit smoking (47.3%) and moderation of alcohol consumption (36.3%). Similar frequencies were observed for the lifestyle changes implemented by physicians in their care of patients. CONCLUSION: A close correlation between awareness of guideline recommendations and their implementation into clinical management was observed. European physicians place a stronger emphasis on regular exercise and weight reduction than on the other recommended lifestyle changes. Moderation of alcohol consumption is the least emphasized lifestyle change.

[Cannabis--Position Paper of the German Respiratory Society (DGP)]. / Cannabis--Positionspapier der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e.V. (DGP).

In this position paper, the adverse health effects of cannabis are reviewed based on the existing scientific literature; in addition possible symptom-relieving effects on some diseases are depicted. In Germany, cannabis is the most widely used illicit drug. Approximately 600,000 adult persons show abusive or addictive cannabis consumption. In 12 to 17 year old adolescents, cannabis use increased from 2011 to 2014 from 2.8 to 6.4%, and the frequency of regular use from 0.2 to 1.5%. Currently, handling of cannabinoids is much debated in politics as well as in general public. Health aspects have to be incorporated into this debate. Besides analysing mental and neurological side effects, this position paper will mainly focus on the influences on the bronchopulmonary and cardiovascular system. There is strong evidence for the induction of chronic bronchitis. Allergic reactions including asthma are known, too. Associations with other diseases like pulmonary emphysema, lung cancer and pneumonia are not sufficiently proven, however cannot be excluded either. In connection with the use of cannabis cardiovascular events such as coronary syndromes, peripheral vascular diseases and cerebral complications have been noted. Often, the evidence is insufficient due to various reasons; most notably, the overlapping effects of tobacco and cannabis use can frequently not be separated adequately. Empirically, early beginning, high-dosed, long-lasting and regular cannabis consumption increase the risk of various psychological and physical impairments and negatively affect age-based development. Concerns therefore relate especially to children and adolescents. There is only little scientific evidence for medical benefits through cannabis as a remedy; systematic research of good quality, in particular prospective, randomised, placebo-controlled double-blinded studies are rare. The medical societies signing this position paper conclude that cannabis consumption is linked to adverse health effects which have to be taken into consideration in the debate about the social attitude towards cannabinoids. The societies agree that many aspects regarding health effects of cannabis are still uncertain and need clarification, preferably through research provided by controlled studies.

[European guidelines on cardiovascular disease prevention. What has changed in 2012?]. / Europäische Leitlinien zur Prävention kardiovaskulärer Erkrankungen. Was hat sich 2012 geändert?

The new European Guidelines on Cardiovascular Disease Prevention (version 2012) are supported by nine medical societies. They are newly structured, shorter and more readable. Each subchapter starts with key messages and recommendations are labeled with an evidence level. The subchapter ends with "most important newest information" and "persisting gaps of evidence" for further research. Smoking and passive smoking are to be avoided, even a small amount of regular physical activity is beneficial, the Mediterranean type diet is recommended and a body mass index (BMI) between 22 and 25 is associated with the lowest mortality. A blood pressure target of <140/90 mmHg is appropriate for the vast majority of hypertensive patients. Aspirin is not recommended for primary prevention even not for diabetics without vascular disease. Cardiovascular risk is now categorized into four levels: low (<1%), medium (1% to <5%), high (5% to <10%) and very high risk (≥10%). All patients with cardiovascular disease are in the very high risk group with the corresponding treatment goals, e. g. a low density lipoprotein (LDL) cholesterol goal of <70 mg/dl (<1.8 mmol/l). Treatment adherence and behavioral changes can best be achieved by motivational interviews which demand some time. It is emphasized that the physician has the responsibility for clear recommendations in the discharge summaries after hospitalization and for offering help and feed back in the implementation phase of behavioral changes.

[Primary prevention of coronary artery disease: is there a role for risk scores?]. / Primärprävention der koronaren Herzerkrankung: Was nützen die Risiko-Scores?

Primary prevention of coronary artery disease is becoming increasingly important due to treatment costs. The assessment of overall cardiovascular risk in Germany is usually performed using the PROCAM algorithm or the ESC score. If the 10-year risk of myocardial infarction or cardiovascular death exceeds 20% or 5%, respectively, intensive risk intervention is cost effective and the number needed to treat (NNT) is usually <200. An NNT of <200 can also be achieved by treating a single pronounced risk factor. The CARRISMA system uses lifestyle factors in addition to conventional factors to improve risk stratification and also supports lifestyle modification. During the last two decades average life expectancy has increased by 6 years and possibilities for prevention have improved. Risk stratification for prevention should therefore be offered up to the age of 70, as in the Framingham risk score. Risk scores support evidence-based and cost-effective prevention even in higher age groups.

Statistical potentials and scoring functions applied to protein-ligand binding.

In virtual screening, small-molecule ligands are docked into protein binding sites and their binding affinity is predicted. Knowledge-based, regression-based and first-principle-based methods have been developed to rank computer-generated binding modes. As a result of still existing deficiencies, a best compromise might be the combination of several scoring schemes into a consensus scoring approach.

Minimal methylation classifier (MIMIC): A novel method for derivation and rapid diagnostic detection of disease-associated DNA methylation signatures.

Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of minimal methylation classifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality samples remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis. Using this approach, we identify critical DNA methylation patterns from previously inaccessible cohorts, and reveal novel survival differences between the medulloblastoma disease subgroups with significant potential for clinical exploitation.

Rational design and diversity-oriented synthesis of peptoid-based selective HDAC6 inhibitors.

A mini library of HDAC inhibitors with peptoid-based cap groups was synthesized using an efficient multicomponent approach. Four compounds were identified as potent HDAC6 inhibitors with a selectivity over other HDAC isoforms. The most potent HDAC6 inhibitor revealed remarkable chemosensitizing properties and completely reverted the cisplatin resistance in Cal27 CisR cells.

Chalcone-based Selective Inhibitors of a C4 Plant Key Enzyme as Novel Potential Herbicides.

Weeds are a challenge for global food production due to their rapidly evolving resistance against herbicides. We have identified chalcones as selective inhibitors of phosphoenolpyruvate carboxylase (PEPC), a key enzyme for carbon fixation and biomass increase in the C4 photosynthetic pathway of many of the world's most damaging weeds. In contrast, many of the most important crop plants use C3 photosynthesis. Here, we show that 2',3',4',3,4-Pentahydroxychalcone (IC50 = 600 nM) and 2',3',4'-Trihydroxychalcone (IC50 = 4.2 µM) are potent inhibitors of C4 PEPC but do not affect C3 PEPC at a same concentration range (selectivity factor: 15-45). Binding and modeling studies indicate that the active compounds bind at the same site as malate/aspartate, the natural feedback inhibitors of the C4 pathway. At the whole plant level, both substances showed pronounced growth-inhibitory effects on the C4 weed Amaranthus retroflexus, while there were no measurable effects on oilseed rape, a C3 plant. Growth of selected soil bacteria was not affected by these substances. Our chalcone compounds are the most potent and selective C4 PEPC inhibitors known to date. They offer a novel approach to combat C4 weeds based on a hitherto unexplored mode of allosteric inhibition of a C4 plant key enzyme.

Knowledge-based scoring function to predict protein-ligand interactions.

The development and validation of a new knowledge-based scoring function (DrugScore) to describe the binding geometry of ligands in proteins is presented. It discriminates efficiently between well-docked ligand binding modes (root-mean-square deviation <2.0 A with respect to a crystallographically determined reference complex) and those largely deviating from the native structure, e.g. generated by computer docking programs. Structural information is extracted from crystallographically determined protein-ligand complexes using ReLiBase and converted into distance-dependent pair-preferences and solvent-accessible surface (SAS) dependent singlet preferences for protein and ligand atoms. Definition of an appropriate reference state and accounting for inaccuracies inherently present in experimental data is required to achieve good predictive power. The sum of the pair preferences and the singlet preferences is calculated based on the 3D structure of protein-ligand binding modes generated by docking tools. For two test sets of 91 and 68 protein-ligand complexes, taken from the Protein Data Bank (PDB), the calculated score recognizes poses generated by FlexX deviating <2 A from the crystal structure on rank 1 in three quarters of all possible cases. Compared to FlexX, this is a substantial improvement. For ligand geometries generated by DOCK, DrugScore is superior to the "chemical scoring" implemented into this tool, while comparable results are obtained using the "energy scoring" in DOCK. None of the presently known scoring functions achieves comparable power to extract binding modes in agreement with experiment. It is fast to compute, regards implicitly solvation and entropy contributions and produces correctly the geometry of directional interactions. Small deviations in the 3D structure are tolerated and, since only contacts to non-hydrogen atoms are regarded, it is independent from assumptions of protonation states.

Fine mapping and single nucleotide polymorphism association results of candidate genes for asthma and related phenotypes.

Several genome-wide screens for asthma and related phenotypes have been published to date but data on fine-mapping are scarce. For higher resolution we performed a fine-mapping study with 2 cM average spacing in often discussed asthma candidate regions (2p, 5q, 6p, 7p, 9q, 11p, and 12q) to narrow down the regions of interest. All participants of a Caucasian family study (97 families with at least two affected sib pairs) were genotyped for 49 supplementary polymorphic dinucleotide markers. Our results indicate increased evidence for linkage on chromosome 6p, 9q, and 12q. These candidate regions were further analyzed with SNP polymorphisms in the endothelin 1 (EDN1), lymphotoxin alpha (LTA), and neuronal nitric oxide synthase (NOS1) genes. In addition, IL4 -590C>T and IL10 -592C>A, localized on chromosomes 5q and 1q, respectively, have been analyzed for SNP association. Of the six SNPs tested, four revealed weak association with the examined phenotypes. These are the IL10 -592C>A SNP in the interleukin 10 gene (p=0.036 for eosinophil cell counts), the 4124T>C SNP in EDN1 (p=0.044 for asthma), the 3391C>T SNP in NOS1 with eosinophil cell counts (p=0.0086), and the 5266C>T polymorphism, also in the NOS1 gene, for high IgE levels (p=0.022). In summary, fine mapping data enable us to confine asthma candidate regions, while variants of EDN1 and NOS1, or nearby genes, may play an important role in this context.

Linkage but lack of association for blood pressure and the alpha-adducin locus in normotensive twins.

BACKGROUND: alpha-adducin is a cytoskeletal protein involved with sodium-pump activity in the renal tubule. The alpha-adducin gene locus has been linked to hypertension and a polymorphism identified which is associated with hypertension; however, the role of the alpha-adducin gene locus in normal blood pressure regulation is not defined. We performed a combined linkage and association study in normotensive monozygotic (MZ) and dizygotic (DZ) twins and their parents to address this issue. METHODS: We studied 126 MZ and 70 DZ twin pairs and parents of DZ twins. Blood pressure values and responses to a cold pressor test were obtained. Cardiac dimensions were measured echocardiographically. Three microsatellites adjacent to the alpha-adducin gene were studied as well as the 460 Trp mutation in the alpha-adducin gene. RESULTS: We obtained strong evidence for linkage (P< 0.001) between the alpha-adducin gene locus and systolic blood pressure. However, we were not able to associate the 460 Trp mutation with higher blood pressures, cold pressor responses or cardiac dimensions. CONCLUSIONS: The alpha-adducin gene locus is relevant to blood pressure regulation in normal subjects. Failure to find an association between higher blood pressures and the 460 Trp mutation suggests that this mutation may become important only when hypertension is triggered, or that other variations in alpha-adducin are present which have not yet been discovered.

Prognostic importance of collateral flow and residual coronary stenosis of the myocardial infarct artery after anterior wall Q-wave acute myocardial infarction.

Residual high-grade coronary stenosis and collateral flow are frequent findings in the chronic phase after a Q-wave acute myocardial infarction (AMI). The prognostic importance of a residual stenosis of the infarct artery and of collateral flow to the infarct area was analyzed in a group of 102 young patients (mean age 35 years, range 22 to 39) who had survived an anterior wall Q-wave AMI. Patients whose only significant lesion (greater than 50% luminal diameter reduction) was in the proximal portion of the left anterior descending artery were enrolled in the study. A 50 to 74% diameter stenosis was present in 33 of 102 patients (32%), 43 (42%) had a 75 to 99% stenosis and 26% had a total occlusion of the infarct vessel. Collateral vessels, which were evaluated by a scoring system, were present in 52 of 102 patients (51%). Four percent had only faint (score 1), 17 of 102 patients (17%) had moderate and 32 patients (31%) had good collateral flow (score greater than 4). The 8-year cumulative mortality was 15.2%--an eightfold increase compared with the age-matched general population. No patient with less than 75% stenosis died during follow-up, whereas the cumulative 8-year mortality was 23 and 17% in patients with a 75 to 99% stenosis or total occlusion, respectively (p less than 0.01). Patients with at least moderate collateral flow had a mortality rate of 21%, versus 8% for patients without or with faint collateral flow (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Serial exercise testing up to 6 years after coronary bypass surgery: behavior of exercise parameters in groups with different degrees of revascularization determined by postoperative angiography.

To evaluate the behavior of exercise parameters in patients with different angiographically defined degrees of revascularization, serial exercise tests were analyzed in 435 patients 1 to 6 years after coronary artery bypass grafting (CABG). All patients had undergone postoperative angiography 2 to 12 months after CABG to determine the degree of revascularization achieved. Revascularization was complete in 182 patients (all significantly stenosed arteries had patent grafts), sufficient in 176 patients (at least the dominant artery supplying the left ventricle had a patent graft) and incomplete in 57 patients (the dominant artery supplying the left ventricle had a closed graft). Twenty patients had all grafts occluded. Exercise tolerance, angina-free exercise tolerance (angina threshold), maximal double product, prevalence of greater than or equal to 0.1 mV exercise-induced S-T segment depression, and the prevalence of the combination of S-T segment depression plus angina pectoris were determined in serial exercise tests (average of 3.0 postoperative exercise tests per patient for a mean follow up of 3.5 years). Patients with complete, sufficient, and incomplete revascularization showed improvement of all exercise parameters for 6, 4, and 1 year after CABG, respectively. Patients with all grafts occluded had improvement of only some exercise parameters. Five years after CABG, exercise tolerance was improved by 24 W (p less than 0.0005) and 21 W (p less than 0.005) in patients with complete and sufficient revascularization, respectively, and not improved in patients with incomplete revascularization or with all grafts occluded. The angiographically determined completeness of revascularization correlates with the extent and the duration of improvement of exercise parameters after CABG.

Exercise tolerance and working capacity after valve replacement.

Between 1978 and 1987, 1270 patients who survived single aortic or mitral valve replacement at the Rehabilitation Center in Bad Krozingen, Germany, underwent a comprehensive rehabilitation program. The preoperative diagnosis was isolated aortic stenosis in 425, isolated aortic regurgitation in 159, mixed aortic lesion in 211, isolated mitral stenosis in 208, isolated mitral insufficiency in 137 and mixed mitral lesion in 130 cases. Follow up examinations were carried out one and six months after surgery, and at yearly intervals thereafter. Exercise testing was performed with an electrically braked bicycle ergometer in the supine position, and the load was increased by 25 or 50 watts every two minutes until fatigue, severe angina, more than 0.3 mV ST-segment depression, or 80% of the age predicted maximum heart rate was achieved. Patients after aortic valve replacement had a better exercise performance one month after operation than did those after mitral valve replacement. Those with mitral stenosis showed more severe impairment of exercise tolerance than did the mitral insufficiency group. There was a steady increase in exercise tolerance between one and six months postoperatively, both in patients with aortic and those with mitral valve replacement, but the difference in performance between the two groups was still present (72% versus 57% of normal). The results of univariate and multivariate analyses showed that the preoperative employment status was the most important factor for postoperative return to work, followed by gender (male > female), exercise tolerance and valualar lesion (aortic > mitral).(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of the LDL-/HDL-cholesterol quotient on progression and regression of arteriosclerotic lesions. An analysis of controlled angiographic intervention studies]. / Der Einfluss des LDL-/HDL-Cholesterin-Quotienten auf die Progression und Regression von arteriosklerotischen Läsionen. Eine Analyse kontrollierter angiographischer Interventionsstudien.

The importance of hypercholesterolemia for the development of atherosclerotic lesions is undebatable. It is less evident, however, whether the progression of established lesions can be influenced by modifying lipid levels. The review of seven controlled angiographic intervention trials shows that different criteria are used to define progression of lesions. The relation of progression to regression (progression/regression ratio), however, is a useful marker for the activity of coronary artery disease. Patients with familial hypercholesterolemia have a progression/regression ratio of between 3 and 7. There is a consistent relationship between the progression/regression ratio and the LDL-/HDL-cholesterol ratio in both control and intervention groups in these trials. Groups with a LDL-/HDL-cholesterol ratio of 5 have six times more progression than regression. If the LDL-/HDL-cholesterol ratio is less than 2.5 regression occurs more often than progression (i.e. progression/regression ratio less than 1). Thus, in the management of hyperlipidemic patients a LDL-/HDL-cholesterol ratio of less than 2.5 should be achieved if regression of atherosclerotic lesions is desired.

[Benefits and risks of physical activity in patient with coronary heart disease]. / Nutzen und Risiken der körperlichen Aktivität bei Patienten mit koronarer Herzerkrankung.

Endurance training after myocardial infarction results in increased fitness and favours regression of coronary arteriosclerosis if the intensity of the training programme results in an expenditure of at least 2200 Kcalories per week. During physical exercise the risk of sudden death is increased, however the net effect of endurance training results in a decreased risk of sudden cardiac death and also of reinfarction. Very intense physical activity may trigger a myocardial infarction and should be avoided by patients with coronary artery disease. Patients with uncomplicated myocardial infarction benefit from a structured exercise programme lasting 6 months or longer. After a large anterior myocardial infarction moderate physical activity does not have an apparent effect on left ventricular size or remodelling. In patients with a low ejection fraction and borderline compensation, physical activity should be delayed until a better degree of cardiac compensation is achieved. The intensity of exercise most be closely supervised to avoid cardiac decompensation. Regular physical activity is an important component of secondary preventive measures in virtually all patients with established coronary artery disease.

[Comparative pharmacokinetic studies on the relative biologic availability of two propranolol preparations in patients with steady state essential hypertension]. / Vergleichende pharmakokinetische Untersuchungen zur relativen Bioverfügbarkeit von zwei Propranolol-Präparaten bei Patienten mit essentieller Hypertonie im steady-state.

Plasma propranolol concentrations were analyzed after Obsidan (VEB Isis-Chemie, Zwickau, GDR) (= preparation A) and another propranolol-preparation (= preparation B) in 10 patients with arterial hypertension of clinical stage I-II in a cross-over design. The concentration-time-curves (AUC0----infinity) were investigated up to 24 h after the oral intake of 40 mg of both preparations of propranolol and were nearly identical. In comparison with preparation B the relative bioavailability F was 104% for preparation A. The steady-state plasma concentrations of propranolol were within the therapeutic range of 50-100 ng/ml. They showed only interindividual variations about the factor 2-3. Peak plasma concentrations were observed 1,5-2 h after the oral application. There were no statistical differences in the pharmacokinetic parameters between the both preparations. The rate of elimination constants of 0,065 to 0,073 h-1 after preparation A and B explain the long duration of the therapeutic efficacy during chronic treatment.