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BACKGROUND: The aim of the study was to demonstrate the efficacy of human muscle stem cells (MuSCs) isolated using innovative technology in restoring internal urinary sphincter function in a preclinical animal model. METHODS: Colonies of pure human MuSCs were obtained from muscle biopsy specimens. Athymic rats were subjected to internal urethral sphincter damage by electrocauterization. Five days after injury, 2 × 10(5) muscle stem cells or medium as control were injected into the area of sphincter damage (n = 5 in each group). Peak bladder pressure and rise in pressure were chosen as outcome measures. To repeatedly obtain the necessary pressure values, telemetry sensors had been implanted into the rat bladders 10 days prior to injury. RESULTS: There was a highly significant improvement in the ability to build up peak pressure as well as a pressure rise in animals that had received muscle stem cells as compared to control (p = 0.007) 3 weeks after the cells had been injected. Only minimal histologic evidence of scarring was observed in treated rats. CONCLUSION: Primary human muscle stem cells obtained using innovative technology functionally restore internal urethral sphincter function after injury. Translation into use in clinical settings is foreseeable.

Purpose To investigate the effect of the ongoing COVID-19 pandemic on interventional radiology (IR) in Germany in 2020 and 2021. Materials und Methods This retrospective study is based on the nationwide interventional radiology procedures documented in the quality register of the German Society for Interventional Radiology and Minimally Invasive Therapy (DeGIR-QS-Register). The nationwide volume of interventions in the pandemic years 2020 and 2021 was compared with the pre-pandemic period (Poisson-test, Mann-Whitney test). The aggregated data were additionally evaluated by intervention type with differentiated consideration of the temporal epidemiological infection occurrence. Results During the two pandemic years 2020 and 2021, the number of interventional procedures increased by appr. 4 % compared to the same period of the previous year (n = 190 454 and 189 447 vs. n = 183 123, respectively, p Conclusion The COVID-19 pandemic in Germany led to a significant short-term decrease in interventional radiology procedures in the initial phase. A compensatory increase in the number of procedures was observed in the subsequent period. This reflects the adaptability and robustness of IR and the high demand for minimally invasive radiological procedures in medical care. Key points: Citation Format

Introduction: The objective of this retrospective study was to compare the predictive performance of the soluble fms-like tyrosine kinase 1 (sFlt-1) / placental growth factor (PlGF)-ratio alone or in a multi-marker regression model for preeclampsia-related maternal and/or fetal adverse outcomes in women >34 weeks of gestation. Methods: We analyzed the data collected from 655 women with suspected preeclampsia. Adverse outcomes were predicted by multivariable and univariable logistic regression models. The outcome of patients was evaluated within 14 days after presentation with signs and symptoms of preeclampsia or diagnosed preeclampsia. Results: The full model integrating available, standard clinical information and the sFlt-1/PlGF-ratio had the best predictive performance for adverse outcomes with an AUC of 72.6%, which corresponds to a sensitivity of 73.3% and specificity of 66.0%. The positive predictive value of the full model was 51.4% and the negative predictive value was 83.5%. 24.5% of patients, who did not experience adverse outcomes but were classified as high risk by sFlt-1/PlGF-ratio (≥38), were correctly classified by the regression model. The sFlt-1/PlGF-ratio alone had a significantly lower AUC of 65.6%. Conclusions: Integrating angiogenic biomarkers in a regression model improved the prediction of preeclampsia-related adverse outcomes in women at risk after 34 weeks of gestation.

The study of eye movements in programming has many implications to software engineering and computing education in industry and academia. The 10th International Workshop on Eye Movements in Programming (EMIP 2022) was co-located with the 44th International Conference on Software Engineering (ICSE), with the goal to further develop the methodology of using eye tracking for programming and software engineering, both theoretically and in practice.

CD36 transports fatty acids (FA) into adipocytes and is increased in white adipose tissue (WAT) in obesity. In rodents, however, it was shown that CD36 knock out is protective for diet induced adiposity. In humans a hypocaloric high fat diet decreased CD36 gene expression in WAT. This study investigated the response of gene expression of FA uptake and metabolism in sub cutaneous WAT after a sudden switch from a healthy isocaloric low fat diet to an isocaloric high fat diet (HF) in healthy human twins. 35 monzyogotic and dizygotic healthy pairs of twins (women and men, age 18 - 70) were investigated for 12 weeks. An isocaloric diet rich in carbohydrates (55% carbohydrates, 30% fat, 15% protein, LF) was applied for 6 weeks, followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein, HF) for another 6 weeks. Body weight (BW) , BMI, serum FA and gene expression of CD36, PDK4, PGC1α and CPT1α by qPCR were analyzed after the LF period, after one week (HF1) and at the end (HF6) of the HF period. BW did not change during the study. Serum FA were unchanged at HF1 but decreased at HF6 by 18% (P Disclosure M.Kruse: None. A.Ost: None. S.Hornemann: None. D.Hoffmann: None. T.Frahnow: None. A.Busjahn: None. A.F.Pfeiffer: None. Funding German Federal Ministry of Education and Research (0315424)

This retrospective real-world study investigated the clinical use of the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio alone or in combination with other clinical tests to predict an adverse maternal (maternal death, kidney failure, hemolysis elevated liver enzymes low platelets-syndrome, pulmonary edema, disseminated intravascular coagulation, cerebral hemorrhage, or eclampsia) or fetal (delivery before 34 weeks because of preeclampsia and/or intrauterine growth restriction, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, placental abruption or intrauterine fetal death or neonatal death within 7 days post natum) pregnancy outcome in patients with signs and symptoms of preeclampsia. We evaluated the sFlt-1/PlGF-ratio cutoff values of 38 and 85 and evaluated its integration into a multimarker model. Of 1117 subjects, 322 (28.8%) developed an adverse fetal or maternal outcome. Patients with an adverse versus no adverse outcome had a median sFlt-1/PlGF-ratio of 177 (interquartile range, 54–362) versus 14 (4–64). Risk-stratification with the sFlt-1/PlGF cutoff values into high- (>85), intermediate- (38–85), and low-risk (

Several studies show an association of maternal diabetes during pregnancy with adverse offspring metabolic health. Other studies, however, suggest that this effect might be biased by obesity, which is independently associated with offspring metabolic disease and often coexistent to maternal diabetes. We performed a prospective study in a rat model to test the hypothesis that the burden of a diabetic pregnancy without obesity deteriorates metabolic health in male offspring. We generated maternal type 2 diabetes before conception that persisted during pregnancy by knockdown of the insulin receptor in small hairpin RNA–expressing transgenic rats. Male WT (wild type) offspring were followed up until adulthood and metabolically challenged by high-fat diet. Blood glucose was measured continuously via a telemetry device. Glucose and insulin tolerance tests were performed, and body composition was analyzed. Weight gain and glucose levels during adolescence and adulthood were similar in male offspring of diabetic and control pregnancies. Body weight and fat mass after high-fat diet, as well as glucose and insulin tolerance tests, were unaltered between male adult offspring of both groups. Glycemic control consisting of up to 49 000 individual glucose measures was comparable between both groups. Intrauterine exposure to maternal hyperglycemia and hyperinsulinemia without obesity had no impact on male offspring metabolic health in our model. We conclude that the intrauterine exposure itself does not represent a mechanism for fetal programming of diabetes and obesity in our model. Other maternal metabolic parameters during pregnancy, such as obesity, might impact long-term offspring metabolic health.

Background: The dysfunction of energy metabolism in white adipose tissue (WAT) induces adiposity. Obesogenic diets that are high in saturated fat disturb nutrient metabolism in adipocytes. This study investigated the effect of an isocaloric high-fat diet without the confounding effects of weight gain on the gene expression of fatty acid and carbohydrate transport and metabolism and its genetic inheritance in subcutaneous (s.c.) WAT of healthy human twins. Methods: Forty-six healthy pairs of twins (34 monozygotic, 12 dizygotic) received an isocaloric carbohydrate-rich diet (55% carbohydrates, 30% fat, 15% protein; LF) for 6 weeks followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein; HF) for another 6 weeks. Results: Gene expression analysis of s.c. WAT revealed that fatty acid transport was reduced after one week of the HF diet, which persisted throughout the study and was not inherited, whereas intracellular metabolism was decreased after six weeks and inherited. An increased inherited gene expression of fructose transport was observed after one and six weeks, potentially leading to increased de novo lipogenesis. Conclusion: An isocaloric dietary increase of fat induced a tightly orchestrated, partially inherited network of genes responsible for fatty acid and carbohydrate transport and metabolism in human s.c. WAT.

The angiogenic factors sFlt-1 (soluble fms-like tyrosine kinase) and PlGF (Placental Growth Factor) play a key role in the pathophysiology, prediction and diagnosis of preeclampsia-associated pregnancy disorders. However, the correlation between maternal serum levels and the placental weight, especially in hypertensive pregnancy disorders is still unclear.Retrospectively, we analyzed data from a real-world cohort of patients with preeclampsia (PE), intrauterine growth restriction (IUGR), PE + IUGR and controls giving birth within 14 days from inclusion. Herein, correlational analyses were calculated between placental weight, maternal serum levels of sFlt-1, PlGF and the respective sFlt-1/PlGF-ratios.This study included n = 328 patients (n = 134 with PE, n = 40 with IUGR and n = 25 showed PE + IUGR) and n = 129 controls. The gestational age-adjusted placental weight was significantly decreased in patients with PE ± IUGR, but not in PE alone, when comparing to controls. Correlation between PlGF and the placental weight was significantly positive and increasing with severity of disease (controls 0.134, p = 0.131, PE 0.419, p 0.01, IUGR 0.517, p 0.01, PE + IUGR r = 0.723, p 0.01). Furthermore, an inverse correlation between the sFlt-1/PlGF-ratio and the placental weight was found. The sFlt-1/PlGF-ratio per gram placental weight was highest in patients with PE + IUGR and lowest in controls (0.6 (IQR 0.4-1.8) vs. 0.05 (IQR 0.02-0.15)).A correlation between the serum levels of sFlt-1 and PlGF and the placental weight is present in PE-associated pregnancy disorders. This mirrors the model of an angiogenic continuum in the placenta where the serum sFlt-1 to PlGF ratio increases with severity of the disease.

There have been a number of studies on gaze tracking in programming, examining how people read program code when tasked with understanding it, but the implications for programming education are not always entirely clear. We tracked the gaze of both novices and experts while they were reading small Java programs, and subsequently interviewed some of the participants about that task. While experts typically said that they start by looking for the program’s entry point, novices appeared not to follow such a purposeful approach. Subsequent analysis of the gaze data confirms this effect. Experts attend to the main method early on when reading a program without looking at much else beforehand. They also read main more comprehensively than the rest of the program. Novices, on the other hand, arrive at main much later and only after having already read much of the code above main, which was located at the end of the code. We conclude that there is potential benefit in explicitly guiding novices in the art of reading code and the importance of attending to main as they do so – teaching them how to read as an aspect of teaching them how to write.

The proportion of areas of interest that are covered with gaze is employed as metric to compare natural-language text and source code reading, as well as novice and expert programmers’ code reading behavior. Two levels of abstraction are considered for AOIs: lines and elements. AOI coverage is significantly higher on natural-language text than on code, so a detailed account is provided on the areas that are skipped. Between novice and expert programmers, the overall AOI coverage is comparable. However, segmenting the stimuli into meaningful components revealed that they distribute their gaze differently and partly look at different AOIs. Thus, while programming expertise does not strongly influence AOI coverage quantitatively, it does so qualitatively.

Obesity is associated with increased levels of soluble Dipeptidyl Peptidase-4 (DPP-4) in serum leading to adipose tissue inflammation and insulin resistance. Animal studies, however, have shown that a high fat diet acutely decreases serum DDP-4 levels. This study investigated the response of serum DDP-4 to a sudden switch from a healthy isocaloric low fat diet to an isocaloric high fat diet (HFD) in healthy human twins. 35 monzyogotic and 11 dizygotic healthy pairs of twins (women and men, age 18 - 70) were investigated for 12 weeks. An isocaloric diet rich in carbohydrates (55% carbohydrates, 30% fat, 15% protein, LF) was applied for 6 weeks, followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein, HF) for another 6 weeks. Body weight (BW) and serum concentrations of DPP-4, tumor necrosis factor α (TNFα) and insulin were analyzed after the LF period, after one week (HF1w) and at the end (HF6w) of the HF period. Total body fat and lean mass were determined by DEXA-Scan at LF and HF6w. BW was constant over the time of intervention. Serum DPP-4 protein was decreased by 15% at HF1w and by 18% at HF6w, respectively, compared to LF (both P Disclosure M. Kruse: None. A. Ost: None. S. Hornemann: None. D. Hoffmann: None. T. Frahnow: None. A. Busjahn: None. A.F. Pfeiffer: None. Funding German Federal Ministry of Education and Research (0315424)

Overactivation of renin-angiotensin system (RAS) is one of the main pathophysiological features in the evolution of chronic heart failure (CHF). The (pro)renin receptor ((P)RR) represents an important player in a tissue renin-angiotensin system (tissue RAS), which mediates tissue injury through fibrosis and hypertrophy of the affected organs in CHF patients. In our study we used plasma samples from 556 elderly subjects with CHF and 198 healthy participants in order to evaluate prognostic and diagnostic potential of s(P)RR in setting of CHF. The patients with CHF showed significantly higher plasma levels of s(P)RR than the healthy volunteers (p=0.0005). We observed association between higher s(P)RR plasma concentrations and lower left ventricular ejection fraction and higher degree of left ventricular dilatation on baseline echocardiography examination of the CHF patients. Elderly CHF patients with higher baseline s(P)RR plasma concentration were at same risk for death, stroke and hospitalization due to heart failure worsening at mean follow-up from forty-eight months in comparison to low s(P)RR counterparts.

An autoimmune reaction directed against the cardiac b1-adrenergic receptor (beta1-ADR) leading to the generation of autoantibodies (AA) against this G-coupled receptor has been described in patients with heart failure (HF). Agonist-like beta1-ADR-AA are associated with morbidity in HF patients and even predict mortality. Standardised and valid diagnostic tools to detect beta 1-ADR-AA in clinical routine are lacking. We used a novel ELISA approach to investigate beta 1-ADR-AA in a cohort of 574 HF patients of the CIBIS-ELD trial with follow up. The CIBIS-ELD trial compared the titration of bisoprolol and carvedilol to recommended target doses in regard to BB tolerability in patients aged 65 years and older. Patient with left ventricular (LV) ejection fraction (EF) less than 50% or LV diameter end diastolic (DED) more than 55 cm showed significantly higher levels of beta1-ADR-AA. Although not yet fully validated, this ELISA allowed for a negative correlation of beta1-ADR-AA with the EF at baseline and at the follow up, beta1-ADR-AA further correlated positively with basal heart rate at follow up 12 weeks later. beta1-ADR-AA levels thus determined significantly increased under titration with beta-blockers (pless than 0.01). Changes in beta1-ADR-AA between F-Up and baseline were significantly higher in patients who used beta blockers (p=0.016) before study inclusion. The type of beta-blocker titrated in this study did not affect log beta1-ADR-AA levels at baseline (p=0.132), follow-up (p=0.058), nor the change (p=0.426). beta1-ADR-AA levels were estimated using a novel, commercially available ELISA. Although not yet fully validated, this ELISA allowed for pathophysiological insights: beta1-ADR-AA levels thus determined significantly increased under titration with beta-blockers (pless than 0.01), irrespective of type of BB. Higher levels of beta1-ADR-AA at baseline are associated with higher heart rates, lower ejection fraction and enlarged left ventricles. The relevance of the beta1-ADR-AA biomarker should be further evaluated.

Elevated C-reactive protein (CRP) is associated with adverse outcomes in heart failure (HF) patients. Beta-blocker therapy may lower CRP levels. To assess if the changes of high-sensitivity (hs) CRP levels in HF patients over 12-week titration with beta-blockers correlate with functional capacity, plasma hs-CRP levels were measured in 488 HF patients [72.1 ± 5.31 years, LVEF 40% (33/50)]. Hs-CRP, NT-proBNP and 6-min-walk-test (6MWT) were assessed at baseline and at week 12. Patients were divided based on hs-CRP changes (cut-off > 0.3 mg/dl) into low–low (N = 225), high–high (N = 132), low–high (N = 54), high–low (N = 77) groups. At baseline, median hs-CRP concentration was 0.25 (0.12/0.53) mg/dl, NT-proBNP 551 (235/1455) pg/ml and average 6MWT distance 334 ± 105 m. NT-proBNP changes were significantly different between the four hs-CRP groups (P = 0.011). NT-proBNP increased in the low–high group by 30 (− 14/88) pg/ml and decreased in the high–low group by − 8 (− 42/32) pg/ml. 6MWT changes significantly differed between groups [P = 0.002; decrease in the low–high group (− 18 ± 90 m) and improvement in the low–low group (24 ± 62 m)]. After beta-blocker treatment, hs-CRP levels are associated with functional capacity in HF patients. Whether this represents a potential target for intervention needs further study.

Endothelial dysfunction plays a major role in cardiovascular diseases and pulse amplitude tonometry (PAT) offers a non-invasive way to assess endothelial dysfunction. However, data about the reliability of PAT in cardiovascular patient populations are scarce. Thus, we evaluated the test-retest reliability of PAT using the natural logarithmic transformed reactive hyperaemia index (LnRHI). Our cohort consisted of 91 patients (mean age: 65±9.7 years, 32% female), who were divided into four groups: those with heart failure with preserved ejection fraction (HFpEF) ( n=25), heart failure with reduced ejection fraction (HFrEF) ( n=22), diabetic nephropathy ( n=21), and arterial hypertension ( n=23). All subjects underwent two separate PAT measurements at a median interval of 7 days (range 4–14 days). LnRHI derived by PAT showed good reliability in subjects with diabetic nephropathy (intra-class correlation (ICC) = 0.863) and satisfactory reliability in patients with both HFpEF (ICC = 0.557) and HFrEF (ICC = 0.576). However, in subjects with arterial hypertension, reliability was poor (ICC = 0.125). We demonstrated that PAT is a reliable technique to assess endothelial dysfunction in adults with diabetic nephropathy, HFpEF or HFrEF. However, in subjects with arterial hypertension, we did not find sufficient reliability, which can possibly be attributed to variations in heart rate and the respective time of the assessments. Clinical Trial Registration Identifier: NCT02299960.

AIMS Previous studies demonstrated poor public awareness of heart failure (HF) compared with myocardial infarction and stroke. With respect to several activities to improve HF awareness in recent years, we present data on the development of HF awareness and information sources in Germany over 8 years. METHODS AND RESULTS In 2007, 2012, and 2015, respectively, 2531, 359, and 171 respondents answered questions about causes, presentation, prognosis, and treatment of HF from a survey developed by the German Competence Network HF. Relationships between respondents' sociodemographic data and their HF knowledge were explored and changes in knowledge and use of information sources analysed. Sixty-eight per cent of respondents knew HF as 'weakness of the heart'. Seventy-nine per cent knew shortness of breath, 74% reduced exercise tolerance, and 52% knew leg edema as symptoms. Only 40% knew all three symptoms. Although up to 34% of the respondents were directly or indirectly affected by HF, they demonstrated poor knowledge about severity and prognosis. Between 2007 and 2015, overall HF awareness has not changed; awareness about treatment has dropped significantly. Younger respondents used all media, especially internet, for information about health; older respondents preferred printed/verbal media and their physician. CONCLUSIONS We found rather insufficient public knowledge on HF etiology and symptoms but especially about management, severity, and prognosis, which is essential for good self-care and adherence of patients. Heart failure awareness has not improved even though awareness campaigns were held over the years. It seems that especially older patients should be much more approached by their family physicians.

Die Verbesserung der Lebensqualitat gehort zu den wichtigsten Behandlungszielen der Herzinsuffizienztherapie. Korperliches Wohlbefinden, wesentlicher Bestandteil der Lebensqualitat, wurde bislang durch krankheitsspezifische Erfassungsinstrumente ungenugend berucksichtigt. Unser Studienziel war die Validierung des zur Erfassung des subjektiven korperlichen Wohlbefindens entwickelten FEW16-Fragebogens im Kollektiv der Studie „Exercise Training in Diastolic Heart Failure“ (Ex-DHF‑P). 64 herzinsuffiziente Patienten mit erhaltener Ejektionsfraktion (HFpEF; 65 Jahre, 56 % weiblich) erhielten eine Standardbehandlung mit (n = 44) oder ohne Trainingsintervention (n = 20). Bei Studienbeginn und nach 3 Monaten wurden sie klinisch untersucht und zu Lebensqualitat (SF36), korperlichem Wohlbefinden (FEW16) und Depression (PHQ-D) befragt. Der FEW16 zeigte gute Cronbachs-Alpha-Werte (0,85–0,93). Bei Studienbeginn korrelierte der FEW16-Gesamtwert mit Alter, 6‑Minuten-Gehtest und den SF36- und PHQ-D-Skalen, jedoch starker mit psychisch als mit korperlich ausgerichteten Skalen. Bei Follow-up waren Gesamtscore und Widerstandsfahigkeit in der Trainingsgruppe verbessert. Der FEW16 stellte keine Unterschiede zwischen den Studiengruppen dar, wie fur den SF36 bei Ex-DHF‑P fruher publiziert. Der FEW16 demonstrierte gute interne Konsistenz und Kreuzkorrelation mit dem SF36 und spiegelte das verbesserte Wohlbefinden der Patienten, reflektierte jedoch Veranderungen durch die Intervention nicht gut genug. Er ist daher eher fur die Erfassung des allgemeinen/psychischen Wohlbefindens geeignet als fur die Erfassung des subjektiven korperlichen Wohlbefindens.

A large dataset that contains the eye movements of N=216 programmers of different experience levels captured during two code comprehension tasks is presented. Data are grouped in terms of programming expertise (from none to high) and other demographic descriptors. Data were collected through an international collaborative effort that involved eleven research teams across eight countries on four continents. The same eye tracking apparatus and software was used for the data collection. The Eye Movements in Programming (EMIP) dataset is freely available for download. The varied metadata in the EMIP dataset provides fertile ground for the analysis of gaze behavior and may be used to make novel insights about code comprehension.

The evidence that physical exercise lowers metabolic and cardiovascular risk is undisputed. Normobaric hypoxia training has been introduced to facilitate the effects of exercise. We tested the hypothesis that hypoxia training augments exercise‐related effects. We randomized 23 men with metabolic‐syndrome to single‐blinded exercise at normoxia (FiO2 21%) or hypoxia (FiO2 15%). Six weeks endurance training on a treadmill, 3 days per week, over 60 min at 60% VO 2max was required. The study included the following: (1) metabolic phenotyping by indirect calorimetry and adipose and muscle tissue microdialysis to gain insight into effects on resting, postprandial, and exercise metabolism, (2) cardiac imaging, and (3) biopsies. Primary endpoint was the change in cardiorespiratory fitness; secondary endpoints were as follows: changes in body weight, waist circumference, blood pressure, cardiac dimensions, and adipose and muscle tissue metabolism and gene expression. Our subjects reduced waist circumference and improved several cardiovascular risk markers including blood pressure. However, these effects were similar in both training groups. Cardiac dimensions were not influenced. We focused on glucose metabolism. After an oral glucose load, adipose tissue metabolism was significantly shifted to a more lipolytic state under hypoxia, whereas muscle metabolism was similar under both conditions. Postprandial energy expenditure was significantly increased under hypoxia, whereas activity energy expenditure was improved under normoxia. Gene expression was not consistently influenced by FiO2. Adipose tissue triglyceride lipase, leptin, and hypoxia‐inducible factor‐alpha expression were increased by normoxia but not hypoxia.

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor(1). Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB)(2). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated(3,4). In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.

Angiogenic and antiangiogenic factors have proven to be an accurate predictive means of preeclampsia. Echocardiographic studies have shown that women with preeclampsia exhibit significant cardiovascular strain, especially early-onset preeclampsia. The aim of this study is to determine preeclampsia risk with soluble fms-like tyrosin kinase 1/placental growth factor ratio, serum NT-proBNP (N-terminal pro B-type natriuretic peptide), and biophysical markers of cardiovascular function in a prospective case–control study. We examined a cohort of 110 pregnant women with uneventful pregnancy outcome (controls) and 129 with hypertensive pregnancy disorders, including 77 with preeclampsia and 52 with pregnancy-induced hypertension. Cardiac indices were obtained with a USCOM-1A monitor, and soluble fms-like tyrosin kinase 1, placental growth factor, and NT-proBNP were measured in serum samples on automated platforms. Logistic regression, as well as Cox proportional hazard analysis, was performed. There were significant contributions from all variables tested, except for heart rate, stroke volume index, and cardiac index to the prediction model. When testing accuracy of respective markers in combination (full model) versus individual markers (soluble fms-like tyrosin kinase 1/placental growth factor ratio and total peripheral resistance) was compared. The soluble fms-like tyrosin kinase 1/placental growth factor ratio and total peripheral resistance performed as good as the full model, except for hypertensive pregnancy disorders and pregnancy-induced hypertension, where the full model performed better. The additional assessment of biophysical and biochemical markers of cardiovascular strain in pregnancy increases the detection of the composite group of hypertensive pregnancy disorders, while not significantly improving detection of preeclampsia alone. This offers a more precise insight into the pathogenesis of the disease, as well as offering a window for intervention, possibly decreasing cardiovascular mortality in these women.

Sample size, mean, standard deviation and range for age by cohort in females from same- and opposite-sex dizygotic twin pairs. Table S2. Sample size, mean, standard deviation, and range for age by cohort in males from same- and opposite-sex dizygotic twin pairs. Table S3. Sample size, mean, and standard deviation for height (cm) and BMI (kg/m2) by cohort in females from same- and opposite-sex dizygotic twin pairs. Table S4. Sample size, mean, and standard deviation for height (cm) and BMI (kg/m2) by cohort in males from same- and opposite-sex dizygotic twin pairs. (DOCX 45 kb)

Heikkila, Kauko/0000-0002-9256-8028; McAdams, Tom/0000-0002-6825-3499; Ordonana, Juan R./0000-0001-7779-6017; Siribaddana, Sisira/0000-0001-5821-2557; Tan, Qihua/0000-0003-3194-0030; Skytthe, Axel E/0000-0002-8629-4913; Hjelmborg, Jacob/0000-0001-9630-9149; Kaprio, Jaakko/0000-0002-3716-2455; Loos, Ruth J F/0000-0002-8532-5087; ONCEL, Sevgi YURT/0000-0002-0990-292X; Fagnani, Corrado/0000-0001-5771-7772; mangino, massimo/0000-0002-2167-7470; Colodro-Conde, Lucia/0000-0002-9004-364X; Kandler, Christian/0000-0002-9175-235X; ROMERA, JUAN FRANCISCO SANCHEZ/0000-0002-5405-6216; Montgomery, Grant W/0000-0002-4140-8139; Medland, Sarah E/0000-0003-1382-380X; Christensen, Kaare/0000-0002-5429-5292; Aliev, Fazil/0000-0001-8357-4699; Huibregtse, Brooke M./0000-0003-0977-7249; Busjahn, Andreas/0000-0001-9650-6919; Tan, Qihua/0000-0003-3194-0030; Sund, Reijo/0000-0002-6268-8117; Kremen, William/0000-0002-8629-5609; Pahlen, Shandell/0000-0003-0753-4155; Rasmussen, Finn/0000-0001-7915-7809; Franz, Carol/0000-0002-8987-1755; Pedersen, Nancy/0000-0001-8057-3543; Aaltonen, Sari/0000-0002-2873-4263; Hotopf, Matthew/0000-0002-3980-4466; Rebato, Esther/0000-0003-1221-8501; Kyvik, Kirsten Ohm/0000-0003-2981-0245; Rijsdijk, Fruhling/0000-0003-4762-2803; Silventoinen, Karri/0000-0003-1759-3079 WOS: 000391277600001 PubMed: 27964777 Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 18861994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve. Suomen Akatemia [266592] Suomen Akatemia 266592 Karri Silventoinenr The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Aims Previous studies demonstrated poor public awareness of heart failure (HF) compared with myocardial infarction and stroke. With respect to several activities to improve HF awareness in recent years, we present data on the development of HF awareness and information sources in Germany over 8 years. Methods and results In 2007, 2012, and 2015, respectively, 2531, 359, and 171 respondents answered questions about causes, presentation, prognosis, and treatment of HF from a survey developed by the German Competence Network HF. Relationships between respondents' sociodemographic data and their HF knowledge were explored and changes in knowledge and use of information sources analysed. Sixty‐eight per cent of respondents knew HF as ‘weakness of the heart’. Seventy‐nine per cent knew shortness of breath, 74% reduced exercise tolerance, and 52% knew leg edema as symptoms. Only 40% knew all three symptoms. Although up to 34% of the respondents were directly or indirectly affected by HF, they demonstrated poor knowledge about severity and prognosis. Between 2007 and 2015, overall HF awareness has not changed; awareness about treatment has dropped significantly. Younger respondents used all media, especially internet, for information about health; older respondents preferred printed/verbal media and their physician. Conclusions We found rather insufficient public knowledge on HF etiology and symptoms but especially about management, severity, and prognosis, which is essential for good self‐care and adherence of patients. Heart failure awareness has not improved even though awareness campaigns were held over the years. It seems that especially older patients should be much more approached by their family physicians.

Einleitung: Angiogene und antiangiogener Faktoren, insbesondere sFlt-1 und PlGF, konnen eine Praeklampsie akkurat vorhersagen. Patientinnen mit Praeklampsie zeigen echokardiographische Zeichen einer diastolischen und systolischen Dysfunktion, die nach Geburt zum Teil bestehen bleiben. Wir prufen die Hypothese, dass biochemische und biophysikalische Parameter der maternalen kardiovaskularen Funktion die Vorhersage der Praeklampsie verbessern. Methoden: In einer Kohorte von 239 Schwangeren, von denen 77 eine Praeklampsie (PE), 52 einen schwangerschaftsinduzierten Hypertonus (SIH) und 110 einen unauffalligen Schwangerschaftsausgang hatten (Kontrollen, Ko) wurden echokardiographisch kardiale Funktionsparameter wie Schlagvolumen (SV), Herzminutenvolumen (HMV), Herzindex (CI) und totaler peripherer Gefaswiderstand (TPRI) untersucht. Im Blut wurde der biochemische kardiale Funktionsparamter NTproBNP sowie sFlt-1 und PlGF untersucht. Resultate: Die logistische Regressionsanalyse zeigte, dass TPRI, NTproBNP und der sFlt-1/PlGF-Quotient, nicht aber SV oder HMV signifikante Pradiktoren fur PE vs. PIH und Ko waren. In der multivariaten Analyse verblieben ebenfalls TPRI, NTproBNP und sFlt-1/PlGF-ratio als fur PE pradiktive Marker. Die Cox proportional hazard Analyse zeigte, dass neben NTproBNP auch der TPRI die pradiktive Genauigkeit des sFlt-1/PlGF-Quotienten verbessern konnten. Diskussion: Zusatzlich zum sFlt-1/PlGF-Quotienten konnen biochemische und biophysikalische Parameter der maternalen kardialen Funktion die Vorhersage fur Praeklampsie verbessern. Prospektive Studien mussen den Stellenwert der Echokardiografie als Verlaufsparameter bei stattgehabter PE untersuchen.

The Berlin Twin Registry has its focus on health research. It is operated as a private company, making twin studies available to academic institutions as well as commercial partners in the area of biotechnology and nutrition. Recruitment is based on invitation in the context of mass media coverage of scientific results. Phenotyping in the unselected twin subjects is directed toward intermediate phenotypes that can bear on common diseases. These phenotypes include proteomic approaches and gene expression. Some results are briefly described to give an impression of the range of research topics and related opportunities for retrospective and prospective collaborative research.

The benefit obtained from antihypertensive treatment is related more to overall cardiovascular risk reduction than to blood pressure levels. Accurate implementation of cardiovascular diagnostics is a key step toward assessment of cardiovascular risk. In the 3A Registry study, data about patient history, concomitant diseases, diagnostic procedures, and medications were prospectively collected. A total of 14,738 patients recruited by 899 physicians in 2008 and 2009 were analyzed. Assessment of cardiovascular risk factors and subclinical end-organ damage (SOD) showed broad differences in the implementation of European Society of Hypertension/European Society of Cardiology recommendations. Electrocardiograms were available in 59% of patients, cholesterol in 71.4%, and glucose in 69.7%. Almost all patients (99.6%) had creatinine measurements performed and microalbuminuria was measured in 8.5%. Metabolic syndrome (MS) had been evaluated in 59.7%. Implementation of diagnostic guidelines was highest in hypertensive patients with diabetes, followed by patients with known cardiovascular disease and established chronic renal insufficiency. For hypertensive patients without known comorbidities, the authors estimated that up to 29% had missed SOD (detection rate

Background and Purpose: Restoration of cerebrovascular reserve capacity (CVRC) depends on the recruitment and positive outward remodeling of preexistent collaterals (arteriogenesis). With this study, we provide functional evidence that granulocyte colony-stimulating factor (G-CSF) augments therapeutic arteriogenesis in two animal models of cerebral hypoperfusion. We identified an effective dosing regimen that improved CVRC and stimulated collateral growth, thereby improving the outcome after experimentally induced stroke. Methods: We used two established animal models of (a) cerebral hypoperfusion (mouse, common carotid artery ligation) and (b) cerebral arteriogenesis (rat, 3-vessel occlusion). Following therapeutic dose determination, both models received either G-CSF, 40 µg/kg every other day, or vehicle for 1 week. Collateral vessel diameters were measured following latex angiography. Cerebrovascular reserve capacities were assessed after acetazolamide stimulation. Mice with left common carotid artery occlusion (CCAO) were additionally subjected to middle cerebral artery occlusion, and stroke volumes were assessed after triphenyltetrazolium chloride staining. Given the vital role of monocytes in arteriogenesis, we assessed (a) the influence of G-CSF on monocyte migration in vitro and (b) monocyte counts in the adventitial tissues of the growing collaterals in vivo. Results: CVRC was impaired in both animal models 1 week after induction of hypoperfusion. While G-CSF, 40 µg/kg every other day, significantly augmented cerebral arteriogenesis in the rat model, 50 or 150 µg/kg every day did not show any noticeable therapeutic impact. G-CSF restored CVRC in mice (5 ± 2 to 12 ± 6%) and rats (3 ± 4 to 19 ± 12%). Vessel diameters changed accordingly: in rats, the diameters of posterior cerebral arteries (ipsilateral: 209 ± 7–271 ± 57 µm; contralateral: 208 ± 11–252 ± 28 µm) and in mice the diameter of anterior cerebral arteries (185 ± 15–222 ± 12 µm) significantly increased in the G-CSF groups compared to controls. Stroke volume in mice (10 ± 2%) was diminished following CCAO (7 ± 4%) and G-CSF treatment (4 ± 2%). G-CSF significantly increased monocyte migration in vitro and perivascular monocyte numbers in vivo. Conclusion: G-CSF augments cerebral collateral artery growth, increases CVRC and protects from experimentally induced ischemic stroke. When comparing three different dosing regimens, a relatively low dosage of G-CSF was most effective, indicating that the common side effects of this cytokine might be significantly reduced or possibly even avoided in this indication.

Introduction The ratio of the antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and the angiogenic placental growth factor (PlGF) has proven to be a accurate marker for the prediction and diagnosis of pre-eclampsia. The established cut-offs of the ratio provide precise prognoses for the occurrence of especially early-onset pre-eclampsia. However its predictive and diagnostic value is significantly lower in the late-onset disease. Objective To evaluate, whether a high sFlt-1/PlGF-ratio correlates with higher rates of adverse maternal and perinatal outcomes and a shorter remaining time to delivery in patients with late-onset pre-eclampsia. Patients and methods We retrospectively assessed 176 women with suspected pre-eclampsia, bearing a singleton pregnancy, whose first measurement of the sFlt-1/PlGF-ratio took place after 336/7 weeks of gestation. The plasma levels of the ratio were examined for an association with time to delivery as well as adverse maternal and perinatal outcomes until discharge from the hospital. Results We were able to show correlations between the level of sFlt-1/PlGF, adverse maternal and perinatal outcomes and time of delivery. The remaining time to delivery became significantly shorter with a rising sFlt-1/PlGF-ratio ( r = 0,477; p p Conclusion The sFlt-1/PlGF ratio was inversely correlated with the remaining time to delivery and positively correlated with the incidence of maternal and perinatal adverse outcomes. Validating existing cut-offs predicting the remaining time to delivery and finding a specific cut-off on the basis of these data will be the aim of further analyses.

This study investigated the effects of acetylsalicylic acid (ASA) and clopidogrel, standardly used in the secondary prevention of vascular occlusions, on cerebral arteriogenesis in vivo and in vitro. Cerebral hypoperfusion was induced by three-vessel occlusion (3-VO) in rats, which subsequently received vehicle, ASA (6.34 mg/kg), or clopidogrel (10 mg/kg). Granulocyte colony-stimulating factor (G-CSF), which enhanced monocyte migration in an additional cell culture model, augmented cerebrovascular arteriogenesis in subgroups (40 μg/kg). Cerebrovascular reactivity and vessel diameters were assessed at 7 and 21 days. Cerebrovascular reserve capacity was completely abolished after 3-VO and remained severely compromised after 7 (−14 ± 14%) and 21 (−5 ± 11%) days in the ASA groups in comparison with controls (4 ± 5% and 10 ± 10%) and clopidogrel (4 ± 13% and 10 ± 8%). It was still significantly decreased when ASA was combined with G-CSF (1 ± 4%) compared with G-CSF alone (20 ±8%). Posterior cerebral artery diameters confirmed these data. Monocyte migration into the vessel wall, improved by G-CSF, was significantly reduced by ASA. Acetylsalicylic acid, but not clopidogrel, inhibits therapeutically augmented cerebral arteriogenesis.

AIMS: Low-dose epoetin-{beta} improved neo-angiogenesis and cardiac regeneration in experimental models of ischaemic cardiomyopathy without raising haemoglobin. No clinical study has tested this approach to date. METHODS AND RESULTS: We performed a randomized, placebo-controlled, double-blind, single-centre study of 35 IU/kg body weight epoetin-{beta} given subcutaneously once weekly for 6 months started within 3 weeks after successful percutaneous coronary intervention (PCI). Patients were included if they presented with a lesion within the proximal segment of the left anterior descending artery, the right coronary artery, or circumflex and had symptomatic heart failure. Patients with ST-segment elevation due to an acute myocardial infarct were excluded. The outcome variables were measured at baseline and at 6 months. Primary outcome measure was individual change in ejection fraction; secondary outcome was safety, change in N-terminal pro-brain natriuretic peptide, and peak VO(2). Twenty-four patients completed the 6-month treatment course. No adverse event related to the treatment occurred. Low-dose epoetin-{beta} following PCI significantly improved global ejection fraction as measured by echocardiography (EPO: {delta}EF 5.2 +/- 2.0%, P= 0.013; placebo: DeltaEF 0.3 +/- 1.6%, P= 0.851; P= 0.019 for the inter-group difference) and cardiac magnetic resonance (EPO: DeltaEF 3.1 +/- 1.6%, P= 0.124; placebo: -1.9 +/- 1.2%, P= 0.167; P= 0.042 for the inter-group difference). N-terminal pro-brain natriuretic peptide levels decreased in both groups without significant inter-group differences. Peak VO(2) levels increased significantly by 3.9 +/- 1.1% (P< 0.05) in the EPO group, whereas in the placebo group the increase did not reach statistical significance ({delta}peak VO(2) 3.0 +/- 1.6, P = ns). No significant difference regarding peak VO(2) was observed between the EPO and placebo groups. CONCLUSIONS: Low-dose epoetin-{beta} treatment following PCI is safe and feasible, and has possible beneficial effects on global ejection fraction and measures of exercise capacity. Extended low-dose epoetin-{beta} treatment warrants further mechanistic studies as well as larger clinical trials. Clinical Trial Registration Information: NCT00568542.

Previous association studies suggested that common polymorphisms of the beta-2 adrenoreceptor gene leading to glycine for arginine substitution at position 16 or glutamic acid for glutamine substitution at position 27 affect blood pressure. We reasoned that measurements of resting sympathetic nerve traffic could increase the sensitivity of defining a gene phenotype relationship. We studied 111 Caucasian subjects (70 men, 41 women) with blood pressure

Background Stimulation of collateral artery growth is a promising therapeutic option for patients with coronary artery disease. External counterpulsation is a non-invasive technique suggested to promote the growth of myocardial collateral arteries via increase of shear stress. The Art.Net.2 Trial tests invasively and functionally for the first time the hypothesis whether a treatment course with external counterpulsation (over 7 weeks) can induce the growth of myocardial collateral arteries. Methods This study is designed as a prospective, controlled, proof-of-concept study. Inclusion criteria are (1) age 40 to 80 years, (2) stable coronary disease, (3) a residual significant stenosis of at least one epicardial artery and (4) a positive ischemic stress-test for the region of interest. As primary endpoint serves the pressure-derived collateral flow index (CFIp), the invasive gold-standard to assess myocardial collateral pathways. CFIp is determined by simultaneous measurement of mean aortic pressure ( P a , mm Hg), distal coronary occlusive (wedge) pressure ( P w , mm Hg) and central venous pressure ( P v , mm Hg). The index is calculated as CFIp=( P w − P v )/( P a − P v ). The pressure derived fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) are assessed as secondary invasive endpoints to investigate the effect of ECP on the myocardial vasculature. The non-invasive secondary endpoints include symptoms (CCS and NYHA classification), treadmill-testing and analysis of shear-stress related soluble proteins. Conclusions The Art.Net.-2 Trial will report within the next months whether direct evidence can be brought that ECP promotes coronary collateral growth in patients with stable angina pectoris.

Purpose Comparing the chromosomal radiosensitivity of prostate cancer patients with that of healthy donors. Materials and methods The study was performed on 81 prostate cancer patients characterised by a clinical stage of predominantly pT2c or pT3a and a median age of 67years. As healthy donors 60 male monozygotic twin pairs were recruited with a median age of 28years. Chromosomal radiosensitivity was measured using both G0- and G2-assay. Results No difference between healthy donors and prostate cancer patients was detected concerning G0-radiosensitivity, since medians were similar (Hodges–Lehmann estimate: −0.05, 95% CI: −0.18–0.08, p =0.4167). However, a pronounced difference was determined for G2-radiosensitivity with prostate cancer patients showing a significantly higher sensitivity compared to healthy donors (Hodges–Lehmann estimate: −0.41, 95% CI: −0.53 to −0.30, p =1.75 −9 ). Using the 90% quantile of G2-radiosensitivity in healthy donors as a threshold for discrimination the fraction of prostate cancer patients with elevated radiosensitivity increased to 49%. Conclusion G2-, but not G0-radiosensitivity is a promising marker for predisposition of prostate cancer.

The aim of this study was to explore the effects of a single lipoprotein apheresis session on myocardial stress/rest (S/R) perfusion in patients with elevated lipoprotein(a) (Lp(a)) and coronary artery disease using cardiac magnetic resonance imaging. Twenty patients with Lp(a) > 60 mg/dL and coronary artery disease were randomized into a control or a treatment group. Both groups underwent cardiac magnetic resonance imaging with assessment of left ventricular function, perfusion and viability, and the treatment group underwent lipoprotein apheresis immediately afterwards. Repeat magnetic resonance imaging was performed at 24 h for both groups and at 96 h for just the treatment group. The transmyocardial perfusion gradient (i.e. endo-epi ratio [EER]) was determined and a comprehensive parameter of resting and adenosine-induced stress perfusion was derived (EER-S/R). While the hematocrit remained unchanged, apheresis reduced lipoproteins and rheological parameters: Lp(a) - 55.1%, total cholesterol - 34.5%, low density lipoprotein (LDL) - 54.6%, Lp(a)-corrected LDL - 54.3%, high density lipoprotein - 17.4%, apolipoprotein B - 39.2%, plasma viscosity - 10.7%, and fibrinogen - 30.6% at 24 h (P < 0.05 for all). At 96 h these parameters, except for plasma viscosity, apolipoprotein B and Lp(a)-corrected LDL, recovered but did not reach baseline values (P < 0.05 for all). The EER-S/R at 24 h was lowered by therapy (DeltaEER-S/R 5%; P < 0.03), whereas this effect disappeared at 96 h. The ejection fraction (EF) was slightly improved at 24 h (67.07 +/- 6.28% vs. 64.89 +/- 6.39%; DeltaEF 2.2%, P < 0.05) and returned to baseline at 96 h. In the control group no corresponding changes were detected. In conclusion, cardiac magnetic resonance imaging detects subtle treatment-related changes in regional myocardial perfusion in patients with elevated Lp(a) and coronary artery disease undergoing lipoprotein apheresis.

Context: Sympathetic activation promotes insulin resistance and arterial hypertension with increasing adiposity. A difference in the relationship between adiposity and sympathetic activity between women and men could contribute to the known gender difference in cardiovascular disease risk. Objective: We tested whether muscle sympathetic nerve activity (MSNA) is correlated differently with waist circumference, waist to hip ratio (WHR), and body mass index (BMI) in women and men. Design and Setting: We pooled data from two microneurography centers (Berlin, Germany; Gdansk, Poland) for a cross-sectional study. Participants: We studied 111 normotensive, healthy Caucasian subjects (70 males and 41 females). Age ranged between 19 and 62 yr and BMI ranged between 18 and 40 kg/m2. Intervention: No intervention was applied during the study. Measurements: Supine heart rate, blood pressure, and MSNA were recorded after at least 30 min rest. Results: MSNA in bursts per minute was age dependent in both sexes [r (male) = 0.56, r (female) = 0.34, P < 0.01]. Controlling for waist and hip circumferences, age dependence remained highly significant in men (r = 0.43) and women (r = 0.43). Adjusting for age, in men, waist circumference (r = 0.29), WHR (r = 0.39), and BMI (r = 0.31) were predictive for MSNA and directly correlated (P < 0.01) but not in women. Adjusting for BMI, in men, only WHR (r = 0.40) remained predictive for MSNA. Conclusion: These data support the hypothesis of a gender difference in the regulation of the sympathetic nervous system, in which MSNA mainly relates to WHR in men but not women. The phenomenon may contribute to the sexual dimorphism in cardiovascular disease risk.

BACKGROUND: Gender is an independent risk factor for heart failure mortality in hypertrophic cardiomyopathy (HCM). AIMS: To explore the interaction between gender, myocardial fibrosis and remodelling in HCM. METHODS: We studied 64 HCM patients (28 females, aged 51+/-16 years) categorized as non-obstructive (HNCM, n=31) or obstructive (HOCM, n=33) and 60 healthy subjects (31 females, aged 43+/-14 years). Cine imaging was performed to assess left ventricular volumes and mass. LV remodelling index (LVRI) was calculated. Extension of late gadolinium enhancement (LGE) was quantified. RESULTS: Females in the control group and in the HNCM group had a lower LVRI than males (control: 0.7+/-0.1 vs. 0.9+/-0.2 g/ml, p

Hypertension is a harmful disease factor that develops unnoticed over time. The treatment of hypertension is aimed at an early diagnosis followed by adequate lifestyle changes rather than pharmacological treatment. The olive leaf extract EFLA943, having antihypertensive actions in rats, was tested as a food supplement in an open study including 40 borderline hypertensive monozygotic twins. Twins of each pair were assigned to different groups receiving 500 or 1000 mg/day EFLA943 for 8 weeks, or advice on a favourable lifestyle. Body weight, heart rate, blood pressure, glucose and lipids were measured fortnightly. Blood pressure changed significantly within pairs, depending on the dose, with mean systolic differences of < or =6 mmHg (500 mg vs control) and < or =13 mmHg (1000 vs 500 mg), and diastolic differences of < or =5 mmHg. After 8 weeks, mean blood pressure remained unchanged from baseline in controls (systolic/diastolic: 133 +/- 5/77 +/- 6 vs 135 +/- 11/80 +/- 7 mmHg) and the low-dose group (136 +/- 7/77 +/- 7 vs 133 +/- 10/76 +/- 7), but had significantly decreased for the high dose group (137 +/- 10/80 +/- 10 vs 126 +/- 9/76 +/- 6). Cholesterol levels decreased for all treatments with significant dose-dependent within-pair differences for LDL-cholesterol. None of the other parameters showed significant changes or consistent trends. Concluding, the study confirmed the antihypertensive and cholesterol-lowering action of EFLA943 in humans.

Background: Both genetic and environmental factors are known to affect body mass index (BMI), but detailed understanding of how their effects differ during childhood and adolescence is lacking.

The armadillo-related protein β-catenin has multiple functions in cardiac tissue homeostasis: stabilization of β-catenin has been implicated in adult cardiac hypertrophy, and downregulation initiates heart formation in embryogenesis. The protein is also part of the cadherin/catenin complex at the cell membrane, where depletion might result in disturbed cell–cell interaction similar to N-cadherin knockout models. Here, we analyzed the in vivo role of β-catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II). The cardiac-specific mifepristone-inducible αMHC-CrePR1 transgene was used to induce β-catenin depletion (loxP-flanked exons 3 to 6, β-cat Δex3–6 mice) or stabilization (loxP-flanked exon 3, β-cat Δex3 mice). Levels of β-catenin were altered both in membrane and nuclear extracts. Analysis of the β-catenin target genes Axin2 and Tcf-4 confirmed increased β-catenin–dependent transcription in β-catenin stabilized mice. In both models, transgenic mice were viable and healthy at age 6 months. β-Catenin appeared dispensable for cell membrane function. Ang II infusion induced cardiac hypertrophy both in wild-type mice and in mice with β-catenin depletion. In contrast, mice with stabilized β-catenin had decreased cross-sectional area at baseline and an abrogated hypertrophic response to Ang II infusion. Stabilizing β-catenin led to impaired fractional shortening compared with control littermates after Ang II stimulation. This functional deterioration was associated with altered expression of the T-box proteins Tbx5 and Tbx20 at baseline and after Ang II stimulation. In addition, atrophy-related protein IGFBP5 was upregulated in β-catenin–stabilized mice. These data suggest that β-catenin downregulation is required for adaptive cardiac hypertrophy.

Background and purpose The radiosensitivity of human lymphocytes measured using a G0- or G2-assay has been linked with an individual's risk of developing normal tissue complications following radiotherapy. This study was performed to increase basic knowledge of the genetics of the human radiation response, and chromosomal aberration induction in particular. Materials and methods The study was carried out with blood samples taken from 15 monozygotic twin pairs. G0-assay was performed for cells irradiated with 6 Gy counting only deletions and G2-assay for cells irradiated with 0.5 Gy scoring only chromatid breaks. Results The mean number of deletions measured at 6 Gy for all 30 samples using the G0-assay amounted to 2.96±0.37 (means±SD), which corresponds to a coefficient of variation (CV) of 13%. There is a highly significant intra-pair correlation for this number among twins ( r 2 =0.911) demonstrating that this parameter is mostly determined by genetic factors. According to the mean number of deletions, a theoretical classification based on the definition =MV+SD as sensitive was made, identifying two pairs as sensitive or resistant, respectively, while nine were normal and two pairs are intermediate. For chromatid breaks measured at 0.5 Gy with the G2-assay the mean number was 1.35±0.42 (means±SD) corresponding to a CV of 31%. There was again a strong intra-pair correlation among twins with r 2 =0.837 showing that this sensitivity is also determined mostly by genetic factors. There was, however, no inter-assay correlation between the G0- and G2-sensitivity ( r 2 =0.006) demonstrating that these two sensitivities depend on different genetic factors. Conclusion The chromosomal radiosensitivity of lymphocytes as defined by G0- or G2-assay is largely determined by different genetic factors, which may allow the use of genetic profiling as an indicator of the respective individual radiosensitivity.

CONTEXT: The circadian clock coordinates numerous metabolic processes with light-dark and feeding regimens. However, in humans it is unknown whether dietary patterns influence circadian rhythms. OBJECTIVE: We examined the effects of switching from a high-carbohydrate, low-fat diet to a low-carbohydrate, high fat (LC/HFD) isocaloric diet on the central and peripheral circadian clocks in humans. DESIGN: Diurnal patterns of salivary cortisol and gene expression were analyzed in blood monocytes of 29 nonobese healthy subjects before and 1 and 6 weeks after the dietary switch. For this, we established a method of rhythm prediction by 3-time point data. RESULTS: The centrally driven cortisol rhythm showed a phase delay 1 and 6 weeks after the dietary switch to a LC/HFD as well as an amplitude increase. The dietary switch altered diurnal oscillations of core clock genes (PER1, PER2, PER3, and TEF) and inflammatory genes (CD14, CD180, NFKBIA, and IL1B). The LC/HFD also affected the expression of nonoscillating genes contributing to energy metabolism (SIRT1) and fat metabolism (ACOX3 and IDH3A). Expression of clock genes but not of salivary cortisol in monocytes tightly correlated with levels of blood lipids and with expression of metabolic and inflammatory genes. CONCLUSIONS: Our results suggest that the modulation of the dietary fat and carbohydrate content alters the function of the central and peripheral circadian clocks in humans.