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1.  Associations of Novel and Traditional Vascular Biomarkers of Arterial Stiffness: Results of the SAPALDIA 3 Cohort Study 
PLoS ONE  2016;11(9):e0163844.
Background and Objectives
There is a lack of evidence concerning associations between novel parameters of arterial stiffness as cardiovascular risk markers and traditional structural and functional vascular biomarkers in a population-based Caucasian cohort. We examined these associations in the second follow-up of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA 3).
Arterial stiffness was measured oscillometrically by pulse wave analysis to derive the cardio-ankle vascular index (CAVI), brachial-ankle (baPWV) and aortic pulse wave velocity (aPWV), and amplitude of the forward and backward wave. Carotid ultrasonography was used to measure carotid intima-media thickness (cIMT) and carotid lumen diameter (LD), and to derive a distensibility coefficient (DC). We used multivariable linear regression models adjusted for several potential confounders for 2,733 people aged 50–81 years.
CAVI, aPWV and the amplitude of the forward and backward wave were significant predictors of cIMT (p < 0.001). All parameters were significantly associated with LD (p < 0.001), with aPWV and the amplitude of the forward wave explaining the highest proportion of variance (2%). Only CAVI and baPWV were significant predictors of DC (p < 0.001), explaining more than 0.3% of the DC variance.
We demonstrated that novel non-invasive oscillometric arterial stiffness parameters are differentially associated with specific established structural and functional local stiffness parameters. Longitudinal studies are needed to follow-up on these cross-sectional findings and to evaluate their relevance for clinical phenotypes.
PMCID: PMC5042378  PMID: 27685325
2.  Retinal Vessel Analysis (RVA) in the Context of Subarachnoid Hemorrhage - A Proof of Concept Study 
PLoS ONE  2016;11(7):e0158781.
Timely detection of impending delayed cerebral ischemia after subarachnoid hemorrhage (SAH) is essential to improve outcome, but poses a diagnostic challenge. Retinal vessels as an embryological part of the intracranial vasculature are easily accessible for analysis and may hold the key to a new and non-invasive monitoring technique. This investigation aims to determine the feasibility of standardized retinal vessel analysis (RVA) in the context of SAH.
In a prospective pilot study, we performed RVA in six patients awake and cooperative with SAH in the acute phase (day 2–14) and eight patients at the time of follow-up (mean 4.6±1.7months after SAH), and included 33 age-matched healthy controls. Data was acquired using a manoeuvrable Dynamic Vessel Analyzer (Imedos Systems UG, Jena) for examination of retinal vessel dimension and neurovascular coupling.
Image quality was satisfactory in the majority of cases (93.3%). In the acute phase after SAH, retinal arteries were significantly dilated when compared to the control group (124.2±4.3MU vs 110.9±11.4MU, p<0.01), a difference that persisted to a lesser extent in the later stage of the disease (122.7±17.2MU, p<0.05). Testing for neurovascular coupling showed a trend towards impaired primary vasodilation and secondary vasoconstriction (p = 0.08, p = 0.09 resp.) initially and partial recovery at the time of follow-up, indicating a relative improvement in a time-dependent fashion.
RVA is technically feasible in patients with SAH and can detect fluctuations in vessel diameter and autoregulation even in less severely affected patients. Preliminary data suggests potential for RVA as a new and non-invasive tool for advanced SAH monitoring, but clinical relevance and prognostic value will have to be determined in a larger cohort.
PMCID: PMC4936715  PMID: 27388619
3.  Muscle-Derived IL-6 Is Not Regulated by IL-1 during Exercise. A Double Blind, Placebo-Controlled, Randomized Crossover Study 
PLoS ONE  2015;10(10):e0139662.
Exercise increases muscle derived Interleukin–6 (IL–6) leading to insulin secretion via glucagon-like peptide–1. IL–1 antagonism improves glycemia and decreases systemic inflammation including IL–6 in patients with type 2 diabetes. However, it is not known whether physiological, exercise-induced muscle-derived IL–6 is also regulated by the IL–1 system. Therefore we conducted a double blind, crossover study in 17 healthy male subjects randomized to receive either the IL–1 receptor antagonist IL-1Ra (anakinra) or placebo prior to an acute treadmill exercise. Muscle activity led to a 2–3 fold increase in serum IL–6 concentrations but anakinra had no effect on this exercise-induced IL–6. Furthermore, the IL–1 responsive inflammatory markers CRP, cortisol and MCP–1 remained largely unaffected by exercise and anakinra. We conclude that the beneficial effect of muscle-induced IL–6 is not meaningfully affected by IL–1 antagonism.
Trial Registration NCT01771445
PMCID: PMC4597979  PMID: 26448147
4.  The effect of workplace smoking bans on heart rate variability and pulse wave velocity of non-smoking hospitality workers 
To investigate the effect of a change in second hand smoke (SHS) exposure on heart rate variability (HRV) and pulse wave velocity (PWV), this study utilized a quasi-experimental setting when a smoking ban was introduced.
HRV, a quantitative marker of autonomic activity of the nervous system, and PWV, a marker of arterial stiffness, were measured in 55 non-smoking hospitality workers before and 3 to 12 months after a smoking ban and compared to a control group that did not experience an exposure change. SHS exposure was determined with a nicotine specific badge and expressed as inhaled cigarette equivalents per day (CE/d).
PWV and HRV parameters significantly changed in a dose dependent manner in the intervention group compared to the control group. A one CE/d decrease was associated with a 2.3% (95% CI: 0.2, 4.4; p=0.031) higher root mean square of successive differences (RMSSD), a 5.7 % (95% CI: 0.9, 10.2; p=0.02) higher high frequency component and a 0.72% (95 % CI: 0.40–1.05; p<0.001) lower PWV.
PWV and HRV significantly improved after introducing smoke-free workplaces indicating a decreased cardiovascular risk.
PMCID: PMC4179883  PMID: 24504155
5.  Carotid Stiffness and Physical Activity in Elderly—A Short Report of the SAPALDIA 3 Cohort Study 
PLoS ONE  2015;10(6):e0128991.
Regular physical activity has been shown to reduce cardiovascular disease risk in the general population. While smaller studies in specified groups (highly trained versus untrained individuals) indicate a certain dose-dependent effect of physical activity on the reduction of carotid stiffness (an indicator of subclinical vascular disease), it is unclear whether this association is present in a representative sample. Thus, we investigated this question cross-sectionally in participants from the population-based Swiss Cohort Study on Air Pollution And Lung and Heart Diseases In Adults (SAPALDIA).
Self-reported total, moderate and vigorous physical activity and distensibility as a measure of local arterial stiffness among 1636 participants aged 50 to 81 years without clinically manifest diseases were evaluated. Mixed regression models were used to examine associations of physical activity intensity with distensibility.
Vigorous physical activity, but not total nor moderate physical activity, was significantly associated with increased distensibility (= reduced carotid stiffness) in univariate analyses (percent change in the geometric mean and 95% confidence interval per 1 standard deviation increment in vigorous physical activity = 2.54 (0.69; 4.43), p<0.01; in total physical activity = 1.62 (-0.22; 3.50), p = 0.08; in moderate physical activity = 0.70 (-1.12; 2.56), p = 0.45). These associations disappeared when we additionally adjusted for age.
After adjustment for the most important confounders and risk factors, we found no evidence for an association of physical activity with carotid stiffness in the general middle aged to elderly population.
PMCID: PMC4452761  PMID: 26035590
6.  The Transeurope Footrace Project: longitudinal data acquisition in a cluster randomized mobile MRI observational cohort study on 44 endurance runners at a 64-stage 4,486km transcontinental ultramarathon 
BMC Medicine  2012;10:78.
The TransEurope FootRace 2009 (TEFR09) was one of the longest transcontinental ultramarathons with an extreme endurance physical load of running nearly 4,500 km in 64 days. The aim of this study was to assess the wide spectrum of adaptive responses in humans regarding the different tissues, organs and functional systems being exposed to such chronic physical endurance load with limited time for regeneration and resulting negative energy balance. A detailed description of the TEFR project and its implemented measuring methods in relation to the hypotheses are presented.
The most important research tool was a 1.5 Tesla magnetic resonance imaging (MRI) scanner mounted on a mobile unit following the ultra runners from stage to stage each day. Forty-four study volunteers (67% of the participants) were cluster randomized into two groups for MRI measurements (22 subjects each) according to the project protocol with its different research modules: musculoskeletal system, brain and pain perception, cardiovascular system, body composition, and oxidative stress and inflammation. Complementary to the diverse daily mobile MR-measurements on different topics (muscle and joint MRI, T2*-mapping of cartilage, MR-spectroscopy of muscles, functional MRI of the brain, cardiac and vascular cine MRI, whole body MRI) other methods were also used: ice-water pain test, psychometric questionnaires, bioelectrical impedance analysis (BIA), skinfold thickness and limb circumference measurements, daily urine samples, periodic blood samples and electrocardiograms (ECG).
Thirty volunteers (68%) reached the finish line at North Cape. The mean total race speed was 8.35 km/hour. Finishers invested 552 hours in total. The completion rate for planned MRI investigations was more than 95%: 741 MR-examinations with 2,637 MRI sequences (more than 200,000 picture data), 5,720 urine samples, 244 blood samples, 205 ECG, 1,018 BIA, 539 anthropological measurements and 150 psychological questionnaires.
This study demonstrates the feasibility of conducting a trial based centrally on mobile MR-measurements which were performed during ten weeks while crossing an entire continent. This article is the reference for contemporary result reports on the different scientific topics of the TEFR project, which may reveal additional new knowledge on the physiological and pathological processes of the functional systems on the organ, cellular and sub-cellular level at the limits of stress and strain of the human body.
Please see related articles: and
PMCID: PMC3409063  PMID: 22812450
7.  The Stimulating Effect of Bright Light on Physical Performance Depends on Internal Time 
PLoS ONE  2012;7(7):e40655.
The human circadian clock regulates the daily timing of sleep, alertness and performance and is synchronized to the 24-h day by the environmental light-dark cycle. Bright light exposure has been shown to positively affect sleepiness and alertness, yet little is known about its effects on physical performance, especially in relation to chronotype. We, therefore, exposed 43 male participants (mean age 24.5 yrs ± SD 2.3 yrs) in a randomized crossover study to 160 minutes of bright (BL: ≈ 4.420 lx) and dim light (DL: ≈ 230 lx). During the last 40 minutes of these exposures, participants performed a bicycle ergometer test. Time-of-day of the exercise sessions did not differ between the BL and DL condition. Chronotype (MSFsc, mid-sleep time on free days corrected for oversleep due to sleep debt on workdays) was assessed by the Munich ChronoType Questionnaire (MCTQ). Total work was significantly higher in BL (median 548.4 kJ, min 411.82 kJ, max 875.20 kJ) than in DL (median 521.5 kJ, min 384.33 kJ, max 861.23 kJ) (p = 0.004) going along with increased exhaustion levels in BL (blood lactate (+12.7%, p = 0.009), heart rate (+1.8%, p = 0.031), and Borg scale ratings (+2.6%, p = 0.005)) in all participants. The differences between total work levels in BL and DL were significantly higher (p = 0.004) if participants were tested at a respectively later time point after their individual mid-sleep (chronotype). These novel results demonstrate, that timed BL exposure enhances physical performance with concomitant increase in individual strain, and is related not only to local (external) time, but also to an individual’s internal time.
PMCID: PMC3394763  PMID: 22808224
8.  How to improve walking, balance and social participation following stroke: a comparison of the long term effects of two walking aids--canes and an orthosis TheraTogs--on the recovery of gait following acute stroke. A study protocol for a multi-centre, single blind, randomised control trial 
BMC Neurology  2012;12:18.
Annually, some 9000 people in Switzerland suffer a first time stroke. Of these 60% are left with moderate to severe walking disability. Evidence shows that rehabilitation techniques which emphasise activity of the hemiplegic side increase ipsilesional cortical plasticity and improve functional outcomes. Canes are commonly used in gait rehabilitation although they significantly reduce hemiplegic muscle activity. We have shown that an orthosis "TheraTogs" (a corset with elasticated strapping) significantly increases hemiplegic muscle activity during gait. The aim of the present study is to investigate the long term effects on the recovery of gait, balance and social participation of gait rehabilitation with TheraTogs compared to gait rehabilitation with a cane following first time acute stroke.
Multi-centre, single blind, randomised trial with 120 patients after first stroke. When subjects have reached Functional Ambulation Category 3 they will be randomly allocated into TheraTogs or cane group. TheraTogs will be applied to support hip extensor and abductor musculature according to a standardised procedure. Cane walking held at the level of the radial styloid of the sound wrist. Subjects will walk throughout the day with only the assigned walking aid. Standard therapy treatments and usual care will remain unchanged and documented. The intervention will continue for five weeks or until patients have reached Functional Ambulation category 5. Outcome measures will be assessed the day before begin of intervention, the day after completion, 3 months, 6 months and 2 years. Primary outcome: Timed "up and go" test, secondary outcomes: peak surface EMG of gluteus maximus and gluteus medius, activation patterns of hemiplegic leg musculature, temporo-spatial gait parameters, hemiplegic hip kinematics in the frontal and sagittal planes, dynamic balance, daily activity measured by accelerometry, Stroke Impact Scale. Significance levels will be 5% with 95% CI's. IntentionToTreat analyses will be performed. Descriptive statistics will be presented.
This study could have significant implications for the clinical practice of gait rehabilitation after stroke, particularly the effect and appropriate use of walking aids.
The results could be important for the development of clinical guidelines and for the socio-economic costs of post-stroke care
Trial registration number NCT01366729.
PMCID: PMC3342107  PMID: 22462692
9.  Automatic detection of the carotid artery boundary on cross-sectional MR image sequences using a circle model guided dynamic programming 
Systematic aerobe training has positive effects on the compliance of dedicated arterial walls. The adaptations of the arterial structure and function are associated with the blood flow-induced changes of the wall shear stress which induced vascular remodelling via nitric oxide delivered from the endothelial cell. In order to assess functional changes of the common carotid artery over time in these processes, a precise measurement technique is necessary. Before this study, a reliable, precise, and quick method to perform this work is not present.
We propose a fully automated algorithm to analyze the cross-sectional area of the carotid artery in MR image sequences. It contains two phases: (1) position detection of the carotid artery, (2) accurate boundary identification of the carotid artery. In the first phase, we use intensity, area size and shape as features to discriminate the carotid artery from other tissues and vessels. In the second phase, the directional gradient, Hough transform, and circle model guided dynamic programming are used to identify the boundary accurately.
We test the system stability using contrast degraded images (contrast resolutions range from 50% to 90%). The unsigned error ranges from 2.86% ± 2.24% to 3.03% ± 2.40%. The test of noise degraded images (SNRs range from 16 to 20 dB) shows the unsigned error ranging from 2.63% ± 2.06% to 3.12% ± 2.11%. The test of raw images has an unsigned error 2.56% ± 2.10% compared to the manual tracings.
We have proposed an automated system which is able to detect carotid artery cross sectional boundary in MRI sequences during heart cycles. The accuracy reaches 2.56% ± 2.10% compared to the manual tracings. The system is stable, reliable and results are reproducible.
PMCID: PMC3083378  PMID: 21477378
10.  Immunomodulatory Effects of Aerobic Training in Obesity 
Mediators of Inflammation  2011;2011:308965.
Introduction. Physical inactivity and obesity are independent risk factors for atherosclerosis. We analyzed the immunomodulatory capacity of 10-week intensified exercise training (ET) in obese and lean athletes. Markers of the innate immune response were investigated in obese (ONE: ET≤40 km/week) and lean athletes (LNE: ET≤40 km/week and LE: ET≥55 km/week). Methods. Circulating dendritic cells (DC) were analyzed by flow-cytometry for BDCA-1/-2-expression. TLR-2/-4/-7 and MyD88 were analyzed by RT-PCR and Western blot. Circulating oxLDL levels were analyzed by ELISA. Results. BDCA-1 expression at baseline was lower in ONE compared to both other groups (ONE 0.15%; LNE 0.27%; LE 0.33%; P < .05), but significantly increased in ONE after training (+50%; P < .05). In contrast, BDCA-2 expression at baseline was higher in ONE (ONE 0.25%; LNE 0.11%; LE 0.09%; P < .05) and decreased in ONE after the 10-week training period (−27%; P < .05). Gene activations of TLR-4 and TLR-7 with corresponding protein increase were found for all three groups (P < .01/P < .05) compared to pre training. A reduction of oxLDL levels was seen in ONE (−61%; P < .05). Conclusions. Intensified exercise induces an increase of BDCA-1+ DCs and TLR-4/-7 in obese athletes. We hereby describe new immune modulatory effects, which—through regular aerobic exercise—modulate innate immunity and pro-inflammatory cytokines in obesity.
PMCID: PMC3065046  PMID: 21461352
11.  Automated Detection of the Arterial Inner Walls of the Common Carotid Artery Based on Dynamic B-Mode Signals 
Sensors (Basel, Switzerland)  2010;10(12):10601-10619.
In this paper we propose a novel scheme able to automatically detect the intima and adventitia of both near and far walls of the common carotid artery in dynamic B-mode RF (radiofrequency) image sequences, with and without plaques. Via this automated system the lumen diameter changes along the heart cycle can be detected. Three image sequences have been tested and all results are compared to manual tracings made by two professional experts. The average errors for near and far wall detection are 0.058 mm and 0.067 mm, respectively. This system is able to analyze arterial plaques dynamically which is impossible to do manually due to the tremendous human workload involved.
PMCID: PMC3231092  PMID: 22163488
intima; media; adventitia; CCA; plaque

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