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During the 1st millennium before the Common Era (BCE), nomadic tribes associated with the Iron Age Scythian culture spread over the Eurasian Steppe, covering a territory of more than 3,500 km in breadth. To understand the demographic processes behind the spread of the Scythian culture, we analysed genomic data from eight individuals and a mitochondrial dataset of 96 individuals originating in eastern and western parts of the Eurasian Steppe. Genomic inference reveals that Scythians in the east and the west of the steppe zone can best be described as a mixture of Yamnaya-related ancestry and an East Asian component. Demographic modelling suggests independent origins for eastern and western groups with ongoing gene-flow between them, plausibly explaining the striking uniformity of their material culture. We also find evidence that significant gene-flow from east to west Eurasia must have occurred early during the Iron Age., The Scythian culture was widespread throughout the Eurasian Steppe during the 1st millennium BCE. This study provides genetic evidence for two independent origins for the Scythians in the eastern and western steppe with varying proportions of Yamnaya and East Asian ancestry, and gene flow among them.

Objectives We sought to evaluate the relationship of blood transfusion after transcatheter aortic valve implantation (TAVI) and mid-term outcome to improve patient selection and periprocedural treatment. Background Increasing evidence suggests a negative influence of blood transfusion on outcomes of patients with cardiovascular diseases. While the adverse impact of bleeding events on survival has been documented after TAVI, data on the impact of postoperative blood transfusions are scarce. Methods TAVI was performed in 700 consecutive patients; 14.7% of TAVI patients suffered from bleeding or access site complications and were excluded from analysis to minimize confounding. Outcomes were analyzed with emphasis on blood transfusions and according to the Valve Academic Research Consortium definitions. Median follow-up duration was 364 days. Multivariable analyses were performed to identify predictors for transfusion and 1-year mortality. Results 33.0% of patients received blood transfusions after TAVI, irrespective of access choice. Blood transfusions were associated with a higher baseline risk profile (median logistic EuroSCORE 21.0 vs. 17.0%), increased rates of postoperative complications and impaired survival (21.2 vs. 36.1% all-cause 1-year mortality). Transfusion was an independent predictor of mortality at 1 year (OR 2.78 [CI 1.59–4.86]). Low body mass index (OR 0.94 [0.89–1.0]), low baseline hemoglobin (OR 0.39 [0.33–0.47]) and combined anticoagulation/antiplatelet therapy were identified as independent predictors of blood transfusion after TAVI. Conclusions Blood transfusions were frequently required after TAVI even in the absence of overt bleeding or access site complications and were identified as an independent predictor of impaired mid-term outcome. Optimization of baseline factors, strict blood conservation strategies, and individualized antiplatelet or anticoagulant regimens may improve outcome after TAVI. © 2014 Wiley Periodicals, Inc.

Objectives We aimed at identifying predictors of renal impairment and its impact on long-term outcome after transcatheter aortic valve implantation (TAVI). Background Renal impairment is common in mostly elderly, multimorbid patients undergoing TAVI. The risk of periprocedural renal function impairment and its association with outcome is incompletely understood. Methods In 458 consecutive patients (mean age, 80.6 ± 7.0 years, 52.2% women) who underwent routine TAVI procedures, we assessed estimated glomerular filtration rate (eGFR) at baseline, during 72-hr postprocedure and at discharge. Over a median follow-up of 0.96 years, we observed 142 deaths. Results: In multivariable-adjusted models, predictors of renal function deterioration within 72 hr were baseline eGFR (β = 0.83, 95% confidence interval [CI] = 0.76/0.91; P

Transcatheter aortic valve implantation (TAVI) is an increasingly common procedure in elderly and multimorbid patients with aortic stenosis. We aimed at developing a pre-procedural risk evaluation scheme beyond current surgical risk scores. We developed a risk algorithm for 1-year mortality in two cohorts consisting of 845 patients undergoing routine TAVI procedures by commercially available devices, mean age 80.9 ± 6.5, 51 % women. Clinical variables were determined at baseline. Multivariable Cox regression related clinical data to mortality (n = 207 deaths). To account for variability related to age and sex and by enrolment site we forced age, sex, and cohort into the score model. Body mass index, estimated glomerular filtration rate, hemoglobin, pulmonary hypertension, mean transvalvular gradient and left ventricular ejection fraction at baseline were most strongly associated with mortality and entered the risk prediction algorithm [C-statistic 0.66, 95 % confidence interval (CI) 0.61–0.70, calibration χ 2-statistic = 6.51; P = 0.69]. Net reclassification improvement compared to existing surgical risk predication schemes was positive. The score showed reasonable model fit and calibration in external validation in 333 patients, N = 55 deaths (C-statistic 0.60, 95 % CI 0.52–0.68; calibration χ 2-statistic = 16.2; P = 0.06). Additional measurement of B-type natriuretic peptide and troponin I did not improve the C-statistic. Frailty increased the C-statistic to 0.71, 95 % CI 0.65–0.76. We present a new risk evaluation tool derived and validated in routine TAVI cohorts that predicts 1-year mortality. Biomarkers only marginally improved risk prediction. Frailty increased the discriminatory ability of the score and needs to be considered. Risk algorithms specific for TAVI may help to guide decision-making when patients are evaluated for TAVI.

Significance Eye, hair, and skin pigmentation are highly variable in humans, particularly in western Eurasian populations. This diversity may be explained by population history, the relaxation of selection pressures, or positive selection. To investigate whether positive natural selection is responsible for depigmentation within Europe, we estimated the strength of selection acting on three genes known to have significant effects on human pigmentation. In a direct approach, these estimates were made using ancient DNA from prehistoric Europeans and computer simulations. This allowed us to determine selection coefficients for a precisely bounded period in the deep past. Our results indicate that strong selection has been operating on pigmentation-related genes within western Eurasia for the past 5,000 y.

Kardiovaskulare Erkrankungen gehoren weltweit zu den haufigsten Todesursachen und fuhren bei vielen Patienten zu signifikanten Einschrankungen im Berufsleben. Risikopatienten konnen uber einfache klinische Risikoalgorithmen wie den Risikoscore der Europaischen Gesellschaft fur Kardiologie oder den Framingham Risikoscore erfasst werden. Die Risikoalgorithmen zeigen jedoch Unscharfen in der Diskriminierung von Gesunden und Individuen mit Risiko fur kardiovaskulare Erkrankungen. Mit neuen Erkenntnissen zur Pathogenese der Atherosklerose sind zahlreiche neue Blutbiomarker zur Risikostratifikation untersucht worden. Die Atherosklerose ist mit ausgepragter lokaler und systemischer inflammatorischer Aktivitat verbunden. Hoch sensitive Testsysteme zur Messung des Akute-Phase-Proteins C-reaktives Protein, die relative Stabilitat des Analyts unter diversen Bedingungen sowie seine geringe intraindividuelle Variabilitat auserhalb von akuten Erkrankungen lassen das hochsensitive C-reaktive Protein (hsCRP) als nutzlichen und relevanten Inflammationsmarker erscheinen. HsCRP korreliert mit kardiovaskularen Erkrankungen und Mortalitat, aber es ist kein kardiospezifischer Marker. In der JUPITER Studie (Justification for Use of Statins in Prevention, an Intervention Trial Evaluating Rosuvastatin) konnte gezeigt werden, dass in der Primarpravention, nach Nachweis von erhohtem hsCRP, Statine effektiv in der globalen kardiovaskularen Risikoreduktion sind. Ein moglicher kausaler Zusammenhang mit dem Atheroskleroseprozess wird weiter untersucht. Die aktuellen Leitlinien der Fachgesellschaften sprechen sich nicht fur ein generelles Screening mit hsCRP aus.

Wahrend fortgeschrittene Atherosklerose, mit ihren Folgeerkrankungen Herzinfarkt und Schlaganfall, sich klinisch durch Gefasstenosen und -verschlusse manifestiert sind die fruhen Stadien gekennzeichnet durch eine noch reversible Storung der Gefasfunktion und erhohte Steifigkeit ohne wesentliche Lumeneinengung des Gefases. Regulator der Gefashomoostase ist das Endothel. Die Endotheldysfunktion ist einer der ersten Schritte bei der Entwicklung der Atherosklerose. Individuen mit einer manifesten Atherosklerose haben eine eingeschrankte Endothelfunktion. Daneben wird die Endothelfunktion durch unterschiedlichste Faktoren beeinflusst wie u. a. Alter, Geschlecht, Blutdruck. Um fruhzeitig Gefasfunktionsstorungen im Screening wie z. B. im arbeitsmedizinischen Setting, zu erkennen, erscheinen nicht-invasive Verfahren zur Bestimmung der Gefasreagibilitat und Steifigkeit attraktiv. In Studien eingesetzte Methoden zur Endothelfunktionsbestimmung (Fluss-mediierte Dilatation [FMD], periphere Pulsamplitudenbestimmung) und Steifigkeitsmessung sind allerdings verhaltnismasig personalaufwendig, untersucherabhangig und ergeben valide Aussagen nur unter standardisiert durchgefuhrten Untersuchungsbedingungen. Die Einflussfaktoren auf die Messung von Probandenseite wie beispielsweise korperliche Aktivitat, Rauchen, Nahrungsaufnahme sind vielfaltig und sollten kontrolliert werden. Es gibt bisher nur verhaltnismasig wenig prospektive Daten, die einen Nutzen der Untersuchung zur Risikostratifizierung belegen. Der Vergleich zu klassischen Risikoalgorithmen fur inzidente kardiovaskulare Ereignisse wie dem Framingham Risikoscore oder dem Risikoscore der Europaischen Gesellschaft fur Kardiologie liegt nur in wenigen Untersuchungen vor. Es zeigen sich keine wesentlichen Verbesserungen der Risikoklassifizierung. Auch in prospektiven Daten der alteren Allgemeinbevolkerung zeigte die Bestimmung der FMD zusatzlich zum Framingham Risikoscore keine signifikante Verbesserung der C-Statistik (Diskriminierung). Eine FMD Bestimmung schien aber die Klassifizierung der Individuen in niedriges, intermediares und hohes Risiko leicht zu verbessern. Ob dies einer Kosten-Nutzen-Rechnung standhalt, bleibt aktuell offen, so dass derzeit ein Einsatz der Methoden nur in Studien gerechtfertigt erscheint. Auch gibt es aktuell noch keine klaren Empfehlungen in Leitlinien der Fachgesellschaften, die Endothelfunktionsmessung breit im Screening einzusetzen.

Vascular reactivity is reflected by blood biomarkers and noninvasive vascular function measurement. The relation of biomarkers to flow-mediated dilation and peripheral arterial tonometry in the general population is little understood. In 5000 individuals (mean age, 56±11 years; age range, 35–74 years; 49% women) of the population-based Gutenberg Health Study we simultaneously assessed 6 biomarkers of cardiovascular function (midregional proadrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro B-type natriuretic peptide, copeptin, C-terminal proendothelin 1, and neopterin) in relation to flow-mediated dilation and peripheral arterial tonometry. Strongest partial correlations (adjusted for age and sex) were observed for baseline pulse amplitude with MR-proADM ( r =0.13) and MR-proANP ( r =−0.13); hyperemic response variables showed the highest correlation for MR-proADM and peripheral arterial tonometry ratio ( r =−0.14). In multivariable linear regression models, strongest associations with baseline vascular function were observed for MR-proANP with baseline pulse amplitude (β per SD increase [99.17%], −0.080 [−0.115 to −0.044]; P P P =0.0017) and N-terminal pro B-type natriuretic peptide (−0.027 [−0.051 to −0.003]; P =0.015) with brachial artery diameter. For hyperemic response variables, highest associations were seen for peripheral arterial tonometry ratio with MR-proADM (−0.022 [−0.043 to −0.004]; P =0.043), MR-proANP (0.016 [−0.0034 to 0.035]; P =0.18), and C-terminal proendothelin 1 (−0.025 [−0.043 to −0.008]; P =0.00094]. In our large, population-based study, we identified MR-proADM and MR-proANP as circulating biomarkers of vascular function most strongly related to noninvasive measures of conduit artery and peripheral arterial performance. Whether determination of blood biomarkers helps to better understand vascular pathology and may provide prognostic information needs to be investigated in future studies.

Background— eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results— In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P −3 . Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene ( P =3.7×10 −8 ; odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript ( P =1.3×10 −96 ). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function ( P =4.4×10 −3 ). Conclusions— The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA , located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.

Differentiation of pluripotent embryonic stem (ES) cells through multipotent neural stem (NS) cells into differentiated neurons is accompanied by wholesale changes in transcriptional programs. One factor that is present at all three stages and a key to neuronal differentiation is the RE1-silencing transcription factor (REST/NRSF). Here, we have used a novel chromatin immunoprecipitation-based cloning strategy (SACHI) to identify 89 REST target genes in ES cells, embryonic hippocampal NS cells and mature hippocampus. The gene products are involved in all aspects of neuronal function, especially neuronal differentiation, axonal growth, vesicular transport and release, and ionic conductance. Most target genes are silent or expressed at low levels in ES and NS cells, but are expressed at much higher levels in hippocampus. These data indicate that the REST regulon is specific to each developmental stage and support the notion that REST plays distinct roles in regulating gene expression in pluripotent ES cells, multipotent NS cells, and mature neurons.

We sought to evaluate the relationship of blood transfusion after transcatheter aortic valve implantation (TAVI) and mid-term outcome to improve patient selection and periprocedural treatment.Increasing evidence suggests a negative influence of blood transfusion on outcomes of patients with cardiovascular diseases. While the adverse impact of bleeding events on survival has been documented after TAVI, data on the impact of postoperative blood transfusions are scarce.TAVI was performed in 700 consecutive patients; 14.7% of TAVI patients suffered from bleeding or access site complications and were excluded from analysis to minimize confounding. Outcomes were analyzed with emphasis on blood transfusions and according to the Valve Academic Research Consortium definitions. Median follow-up duration was 364 days. Multivariable analyses were performed to identify predictors for transfusion and 1-year mortality.33.0% of patients received blood transfusions after TAVI, irrespective of access choice. Blood transfusions were associated with a higher baseline risk profile (median logistic EuroSCORE 21.0 vs. 17.0%), increased rates of postoperative complications and impaired survival (21.2 vs. 36.1% all-cause 1-year mortality). Transfusion was an independent predictor of mortality at 1 year (OR 2.78 [CI 1.59-4.86]). Low body mass index (OR 0.94 [0.89-1.0]), low baseline hemoglobin (OR 0.39 [0.33-0.47]) and combined anticoagulation/antiplatelet therapy were identified as independent predictors of blood transfusion after TAVI.Blood transfusions were frequently required after TAVI even in the absence of overt bleeding or access site complications and were identified as an independent predictor of impaired mid-term outcome. Optimization of baseline factors, strict blood conservation strategies, and individualized antiplatelet or anticoagulant regimens may improve outcome after TAVI.

Female gender has recently been suggested to predict a beneficial outcome and lower mortality following transcatheter aortic valve implantation (TAVI). The study aim was to address gender differences in outcome following TAVI and potentially to replicate these findings.The present single-center prospective registry of 326 patients with severe aortic stenosis treated by TAVI between 2008 and 2011 consisted of 181 women and 145 men.The procedural risk was not significantly different between men and women at baseline. For all-cause mortality no difference was observed at 30 days and at 12 months after TAVI.While several baseline characteristics between men and women treated by TAVI were shown to be different among the study population, no difference was observed in survival between both genders.

BACKGROUND: Different biological pathways have been related to atrial fibrillation (AF). Novel biomarkers capturing inflammation, oxidative stress, and neurohumoral activation have not been investigated comprehensively in AF. METHODS AND RESULTS: In the population-based Gutenberg Health Study (n = 5000), mean age 56 ± 11 years, 51% males, we measured ten biomarkers representing inflammation (C-reactive protein, fibrinogen), cardiac and vascular function (midregional pro adrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro-B-type natriuretic peptide [Nt-proBNP], sensitive troponin I ultra [TnI ultra], copeptin, and C-terminal pro endothelin-1), and oxidative stress (glutathioneperoxidase-1, myeloperoxidase) in relation to manifest AF (n = 161 cases). Individuals with AF were older, mean age 64.9 ± 8.3, and more often males, 71.4%. In Bonferroni-adjusted multivariable regression analyses strongest associations per standard deviation increase in biomarker concentrations were observed for the natriuretic peptides Nt-proBNP (odds ratio [OR] 2.89, 99.5% confidence interval [CI] 2.14-3.90; P13%. CONCLUSIONS: In conclusion, in our large, population-based study, we identified novel biomarkers reflecting vascular function, MR-proADM, inflammation, and myocardial damage, TnI ultra, as related to AF; the strong association of natriuretic peptides was confirmed. Prospective studies need to examine whether risk prediction of AF can be enhanced beyond clinical risk factors using these biomarkers.

We aimed at identifying predictors of renal impairment and its impact on long-term outcome after transcatheter aortic valve implantation (TAVI).Renal impairment is common in mostly elderly, multimorbid patients undergoing TAVI. The risk of periprocedural renal function impairment and its association with outcome is incompletely understood.In 458 consecutive patients (mean age, 80.6 ± 7.0 years, 52.2% women) who underwent routine TAVI procedures, we assessed estimated glomerular filtration rate (eGFR) at baseline, during 72-hr postprocedure and at discharge. Over a median follow-up of 0.96 years, we observed 142 deaths.In multivariable-adjusted models, predictors of renal function deterioration within 72 hr were baseline eGFR (β = 0.83, 95% confidence interval [CI] = 0.76/0.91; P 0.0001), body mass index (β = -1.20, 95% CI = 1.77/-0.62; P 0.0001), and major access site complications (β = -14.82, 95% CI = -26.52/-3.11; P = 0.013) including bleeding (β = -11.97, 95% CI = -21.05/-2.89; P = 0.0099). Strongest renal function predictor of 1-year mortality in risk factor adjusted analyses was the change of eGFR within 72 hr (odds ratio, 0.97; 95% CI = 0.96/0.98; P 0.0001). The addition of information on the change of eGFR increased the C-statistic of the logistic EuroSCORE (P = 0.021).In our routine TAVI sample, baseline eGFR, body mass index, and major access site complications mainly owing to bleeding were correlates of acute kidney injury after TAVI. Acute renal impairment was a risk factor for mortality and adverse cardiovascular events which provided risk information beyond the EuroSCORE.

OBJECTIVE The relation of noninvasive vascular function to sex, sex hormones, and reproductive history in the general population is little understood. METHODS We simultaneously assessed flow-mediated dilation (FMD) and peripheral arterial tonometry in 454 women (mean age 40.4±16.1 years, age range 19-78 years) and 100 men (mean age 44.7±15.3 years) in a community-based cohort. Plasma estradiol, progesterone, luteinizing hormone, and follicle stimulating hormones were measured, and menstrual cycle and reproductive history were recorded. RESULTS Vascular function was blunted in men as compared to women irrespective of menopausal status and adjustment for classical cardiovascular risk factors and hormones. Vascular reactivity changed during the menstrual cycle and correlated with estradiol concentrations for FMD, r=0.13 and inversely with progesterone for pulse amplitude, r=-0.14, and brachial artery diameter, r=-0.10. Multivariable-adjusted regressions showed a relation of estradiol with FMD, β 0.658, 95% confidence interval (CI) 0.084/1.232, P=0.025 in women. Age at menarche (β 0.070, 95% CI 0.039/0.101, P

Objectives We report the results of a large single-center study evaluating predictors and outcomes after transcatheter aortic valve implantation (TAVI) with different devices and access routes according to the Valve Academic Research Consortium (VARC). Background The widespread adoption of TAVI warrants a systematic analysis of outcomes. Only few comprehensive data exist comparing different approaches as selected by a heart team. Methods TAVI was performed in 326 consecutive patients (mean age 80.6 ± 7.1 years, 55.5% female) at high risk for surgery with balloon-expandable and self-expanding devices through transfemoral or transapical access. Data were analyzed according to VARC endpoints; predictors of mortality were identified. Results All-cause mortality was 10.1% (30 days) and 29.9% (1 year) overall and comparable with regard to valve or access choice (P = 0.295) despite different risk profiles at baseline. Device success and 30-day safety endpoints were achieved in 87.1 and 21.2%. Myocardial infarction [hazard ratio (HR) 6.52], stage-2 and −3 acute kidney injury (HR 2.52 and 6.80) and major access site complications (HR 1.96) were independent predictors of 1-year all-cause mortality. Device success had a protective effect (HR 0.58). Baseline predictors included body mass index

We report the results of a large single-center study evaluating predictors and outcomes after transcatheter aortic valve implantation (TAVI) with different devices and access routes according to the Valve Academic Research Consortium (VARC).The widespread adoption of TAVI warrants a systematic analysis of outcomes. Only few comprehensive data exist comparing different approaches as selected by a heart team.TAVI was performed in 326 consecutive patients (mean age 80.6 ± 7.1 years, 55.5% female) at high risk for surgery with balloon-expandable and self-expanding devices through transfemoral or transapical access. Data were analyzed according to VARC endpoints; predictors of mortality were identified.All-cause mortality was 10.1% (30 days) and 29.9% (1 year) overall and comparable with regard to valve or access choice (P = 0.295) despite different risk profiles at baseline. Device success and 30-day safety endpoints were achieved in 87.1 and 21.2%. Myocardial infarction [hazard ratio (HR) 6.52], stage-2 and -3 acute kidney injury (HR 2.52 and 6.80) and major access site complications (HR 1.96) were independent predictors of 1-year all-cause mortality. Device success had a protective effect (HR 0.58). Baseline predictors included body mass index20 kg/m(2) (HR 3.20), NYHA class IV (HR 1.87), left ventricular ejection-fraction30% (HR 2.30), higher STS-PROM scores (HR 1.05 per percent), and age (group 75-85 years, HR 0.47).Comparable results were achieved with different devices and access routes in a heart team approach. Baseline and perioperative predictors of all-cause mortality were identified, contributing to the refinement of patient and device selection criteria for TAVI.

Background Atrial fibrillation (AF) is an increasingly common problem in primary care, but little is known about its prevalence and the distribution of AF risk factors in the general population.

Atrial fibrillation (AF) is an increasingly common problem in primary care, but little is known about its prevalence and the distribution of AF risk factors in the general population.We determined the prevalence of AF and the distribution of known AF risk factors among persons participating in the population-based Gutenberg Health Study. To this end, we used interview data about the medical diagnosis of AF and electrocardiograms (ECGs) that were performed for the study in 5000 persons aged 35 to 74. The response rate was 60.4%.There were 5000 persons in the study sample (age 52.2 ± 11 years; 50.6% were women). The prevalence of AF, weighted for the age and sex distribution of the general population, was 2.5%. AF was found to be more common in older persons, with a more pronounced increase in men: whereas its prevalence was 0.7% in 35- to 44-year-old men, the corresponding figure for the age group 65- to 74 was as high as 10.6%. Twenty five participants (15.5% of AF cases) received their initial diagnosis of AF on the basis of the study ECG. Compared to persons without AF, persons with AF were older and more commonly male, and they had a higher burden of cardiovascular risk factors. 14.3% of persons with AF had none of the well-established risk factors for AF (systolic blood pressure, antihypertensive medication, increased body-mass-index, heart failure). 42.7% of persons with AF were not taking either anticoagulants or platelet inhibitors.These data indicate that the prevalence of AF in the middle-aged general population is 2.5% overall, and higher in the elderly. AF is thus a significant public health problem, and greater awareness of it is needed.

Background— Several methods of noninvasive vascular function testing have been suggested for cardiovascular risk screening in the community. A direct comparison of the different methods and their relation to classical cardiovascular risk factors in a large cohort is missing. Methods and Results— In 5000 individuals (mean age, 55.5±10.9 years; age range, 35 to 74 years; women, 49.2%) of the population-based Gutenberg Heart Study, we performed simultaneous measurement of flow-mediated dilation (FMD) and peripheral arterial volume pulse determined by infrared photo (reflection index) and pneumatic plethysmography (PAT) and explored their associations. All function measures were recorded at baseline and after reactive hyperemia induced by 5-minute brachial artery occlusion. Correlations between different measures of vascular function were statistically significant but moderate. The strongest association for hyperemic response variables was observed for PAT ratio and FMD (Spearman r =0.17; age- and sex-adjusted partial correlation, 0.068). Classical risk factors explained between 15.8% (baseline reflection index) and 58.4% (brachial artery diameter) of the baseline values but only accounted for 3.2% (reflection index), 15.4% (FMD), and 13.9% (PAT ratio) of the variability of reflective hyperemic response. Regression models varied in their relations to classical risk factors for the individual vascular function measures. Consistently associated with different vascular function methods were age, sex, body mass index, and indicators of hypertension. Peripheral tonometry also showed a relation to fasting glucose concentrations. Conclusions— Noninvasive measures of conduit artery and peripheral arterial function are modestly correlated, differ in their relation to classical cardiovascular risk factors, and may thus reflect different pathologies.

The objectives of this study were to describe gender differences in intima-media thickness (IMT) in a community-based population study and to define normal IMT values for healthy men and women. In total, 4,814 participants (aged 35 to 74 years; 2,433 men, 2,381 women) from the Gutenberg-Heart Study (GHS) were included. IMT was measured at both common carotid arteries using an edge detection system. Median IMT was 0.62 mm (25th percentile 0.55, 75th percentile 0.70) in women and 0.65 mm (25th percentile 0.57, 75th percentile 0.75) in men and was significantly associated with age (p0.0001). On multivariate analysis, advanced age, smoking, and arterial hypertension were positively associated with higher IMT in men and women. A subgroup of 1,025 subjects without cardiovascular risk factors or previous cardiovascular disease was analyzed to define normal IMT values. Nomograms were calculated according to age and gender. For each age group, IMT95th percentile was defined as abnormal. In this subgroup, gender differences in IMT became nonsignificant at older ages. At the age of 35 years, IMT was 0.71 mm in men and 0.61 mm in women at the 95th percentile. In comparison, at the age of 74 years, IMT at the 95th percentile was 0.90 mm in men and 0.89 mm in women. In conclusion, men had higher carotid IMT than women, but predictors of early carotid atherosclerosis were similar across genders. In young subjects without cardiovascular risk factors, normal values for IMT were lower in women compared with men. In contrast, in older subjects, gender differences in IMT became nonsignificant.

Background— Echocardiography, the dominant imaging modality for quantification of left ventricular metrics, has undergone continuing development in the past few decades. However, given the lack of population-based data, current guidelines are still based on restricted and small data sets analyzed with methods including expert opinion. This work presents empirically derived reference values from a large-scale, epidemiologic study conducted with state-of-the-art imaging technology and methods. Methods and Results— The distribution of echocardiographic measurements of the left ventricle was analyzed in a population-based sample of 5000 mid-Europeans from the Gutenberg Heart Study in Germany. The randomly selected, noninstitutionalized sample provides data on apparently healthy individuals, as well as on those with prevalent disease. Standardized echocardiograms were recorded in a comprehensive data set at a single site with centralized training and certification of sonographers. Sex-specific reference limits and categories indicating the grade of deviation from the reference were calculated, and nomograms were created by quantile regression. Detailed information is given on the association between left ventricular geometry and age. Conclusions— The rapidly evolving echocardiographic technology with persistent improvements in image quality and new measurement conventions require the evaluation of new reference limits for left ventricular metrics. The present investigation formulates reference limits and nomograms from state-of-the-art technology and methods based on a large population-based data set. The distribution of echocardiographic measures of left ventricular geometry presents, in part, nonlinear associations with age, which should be the subject of future investigations.

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea 60 ml/min/1.73 m 2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P 5 × 10 8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney. © 2010 Nature America, Inc. All rights reserved.

Carey, a first-grade student, had just finished learning through the exploration of cardboard “pizzas” that fractions with I in the numerator get smaller as the denominators increase.

This article critiques elementary school spelling textbooks on four grounds: the memorizationof lists of words as a model for learning spelling, the use of spelling rules and generalizations, questionable activities that extend beyond spelling itself into other areas of language arts, and occasional inaccuracies and inappropriate activities. It suggests that these textbooks continue to be used because of the weight of tradition, their claims to be scientific, and the orderly control of learning that they seem to represent. The article concludes with suggestions for future research.

Recent research about children's invented spelling has not, for the most part, changed spelling curriculum and instruction in American schools. Although children are often encouraged to use their own spellings when they write, widely used spelling textbooks continue to follow a model emphasizing the memorization of lists of words. A spelling curriculum grounded in a newer view of how written language is learned would emphasize creating competent independent spellers, helping them to learn a complex language system largely through tacit learning and at their own pace. Classroom practice would emphasize wide reading and writing, strategy development, understanding of useful generalizations, proof-reading ability, and an appreciation of the history and structure of the English language. Changes in attitudes about spelling and in evaluation procedures would also be required.

BACKGROUND: Initial evidence suggests that depressive symptoms are more frequent in patients with atrial fibrillation. Data from the general population are limited. METHODS AND RESULTS: In 10,000 individuals (mean age 56±11 years, 49.4% women) of the population-based Gutenberg Health Study we assessed depression by the Patient Health Questionnaire (PHQ-9) and a history of depression in relation to manifest atrial fibrillation (n = 309 cases). The median (25th/75th percentile) PHQ-9 score of depressive symptoms was 4 (2/6) in atrial fibrillation individuals versus 3 (2/6) individuals without atrial fibrillation, P(X2-Test) = 0.32. Multivariable regression analyses of the severity of depressive symptoms in relation to atrial fibrillation in cardiovascular risk factor adjusted models revealed a relation of PHQ-9 values and atrial fibrillation (odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01-1.08; P = 0.023). The association was stronger for the somatic symptom dimension of depression (OR 1.08, 95% CI 1.02-1.15; P = 0.0085) than for cognitive symptoms (OR 1.05, 95% CI 0.98-1.11; P = 0.15). Results did not change markedly after additional adjustment for heart failure, partnership status or the inflammatory biomarker C-reactive protein. Both, self-reported physical health status, very good/good versus fair/bad, (OR 0.54, 95% CI 0.41-0.70; P

Our understanding of how children learn to spell and punctuate has undergone a major transformation in the past twenty-five years, as theory and research have illuminated the ways in which such learning is an acquisition of complex linguistic and conceptual systems rather than a compilation of discrete words and rules. Work has focused on general developmental progressions in spelling and punctuation, children’s growing understanding of the nature and components of the systems they are learning, and the processes by which that learning occurs, both consciously and tacitly. This review will first discuss those factors for spelling (including the learning that takes place before spelling as such can begin), and then offer a briefer overview of punctuation.

We are very grateful to Curriculum Inquiry for choosing to review our book at such length and for the opportunity to comment on Barbara Burnaby's review. We thank Burnaby for her careful reading of the book and would like to respond to some of the issues she raised about the focus of the research and our relationship to the Native American community where our study took place. The major purpose of our research was to learn more about children as writers in the classroom context. At the time we began the research, Donald Graves and his exploration of the writing process as seen in a white, middle-class population (Graves 1983) were becoming known and were beginning to transform writing curricula and instruction in elementary schools in North America. We were invited by the principal of the primary school on the Tohono O'odham reservation (with full support of the tribal council) to conduct a similar exploration of the writing process there. The children in Ann Francisco's school regularly scored near the bottom on standardized tests administered to students by the state of Arizona, and she believed that these measures (which have, of course, often been accused of cultural bias) did not reflect the true literacy achievements of her students. She invited us to document who they really were as writers. In so doing, our intentions were also to add to the body of research knowledge about the writing process, in this case with Native American children. We have included in our book information about the children's culture and

This study explored various aspects of the spelling and punctuation development of six Native American children from the United States during their third and fourth grade years, as seen in classroom writing samples. A number of conclusions were drawn up from the analysis. The subjects spelled most words conventionally. The more frequently a word appeared in the subject's writing, the more likely it was to be spelled conventionally. Selected orthographic features varied widely in how conventionally they were spelled, with those which were less frequent, less predictable, or more abstract tending to be more difficult. Almost every spelling feature examined showed growth from third to fourth grade. The invented spellings of particular features tended to reflect understandable, logical processes. Invented spellings which were either real words or permutations of the intended word were common. Punctuation was more difficult than spelling for the subjects. Children used a variety of linguistic informa...