Jari Hyttinen

Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture

SUMMARY Long QT syndrome (LQTS) is caused by functional alterations in cardiac ion channels and is associated with prolonged cardiac repolarization time and increased risk of ventricular arrhythmias. Inherited type 2 LQTS (LQT2) and drug-induced LQTS both result from altered function of the hERG channel. We investigated whether the electrophysiological characteristics of LQT2 can be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology. Spontaneously beating cardiomyocytes were differentiated from two iPSC lines derived from an individual with LQT2 carrying the R176W mutation in the KCNH2 (HERG) gene. The individual had been asymptomatic except for occasional palpitations, but his sister and father had died suddenly at an early age. Electrophysiological properties of LQT2-specific cardiomyocytes were studied using microelectrode array and patch-clamp, and were compared with those of cardiomyocytes derived from control cells. The action potential duration of LQT2-specific cardiomyocytes was significantly longer than that of control cardiomyocytes, and the rapid delayed potassium channel (IKr) density of the LQT2 cardiomyocytes was significantly reduced. Additionally, LQT2-derived cardiac cells were more sensitive than controls to potentially arrhythmogenic drugs, including sotalol, and demonstrated arrhythmogenic electrical activity. Consistent with clinical observations, the LQT2 cardiomyocytes demonstrated a more pronounced inverse correlation between the beating rate and repolarization time compared with control cells. Prolonged action potential is present in LQT2-specific cardiomyocytes derived from a mutation carrier and arrhythmias can be triggered by a commonly used drug. Thus, the iPSC-derived, disease-specific cardiomyocytes could serve as an important platform to study pathophysiological mechanisms and drug sensitivity in LQT2.

Targeted exercises against hip fragility

SummaryCompared to high-impact exercises, moderate-magnitude impacts from odd-loading directions have similar ability to thicken vulnerable cortical regions of the femoral neck. Since odd-impact exercises are mechanically less demanding to the body, this type of exercise can provide a reasonable basis for devising feasible, targeted bone training against hip fragility.IntroductionRegional cortical thinning at the femoral neck is associated with hip fragility. Here, we investigated whether exercises involving high-magnitude impacts, moderate-magnitude impacts from odd directions, high-magnitude muscle forces, low-magnitude impacts at high repetition rate, or non-impact muscle forces at high repetition rate were associated with thicker femoral neck cortex.MethodsUsing three-dimensional magnetic resonance imaging, we scanned the proximal femur of 91 female athletes, representing the above-mentioned five exercise-loadings, and 20 referents. Cortical thickness at the inferior, anterior, superior, and posterior regions of the femoral neck was evaluated. Between-group differences were analyzed with ANCOVA.ResultsFor the inferior cortical thickness, only the high-impact group differed significantly (~60%, p = 0.012) from the reference group, while for the anterior cortex, both the high-impact and odd-impact groups differed (~20%, p = 0.042 and p = 0.044, respectively). Also, the posterior cortex was ~20% thicker (p = 0.014 and p = 0.006, respectively) in these two groups.ConclusionsOdd-impact exercise-loading was associated, similar to high-impact exercise-loading, with ~20% thicker cortex around the femoral neck. Since odd-impact exercises are mechanically less demanding to the body than high-impact exercises, it is argued that this type of bone training would offer a feasible basis for targeted exercise-based prevention of hip fragility.

Wireless, Multipurpose In-Home Health Monitoring Platform: Two Case Trials

We propose a general purpose home area sensor network and monitoring platform that is intended for e-Health applications, ranging from elderly monitoring to early homecoming after a hospitalization period. Our monitoring platform is multipurpose, meaning that the system is easily configurable for various user needs and is easy to set up. The system could be temporarily rented from a service company by, for example, hospitals, elderly service providers, specialized physiological rehabilitation centers, or individuals. Our system consists of a chosen set of sensors, a wireless sensor network, a home client, and a distant server. We evaluated our concept in two initial trials: one with an elderly woman living in sheltered housing, and the other with a hip surgery patient during his rehabilitation phase. The results prove the functionality of the platform. However, efficient utilization of such platforms requires further work on the actual e-Health service concepts.

Arterial pulse wave velocity in relation to carotid intima-media thickness, brachial flow-mediated dilation and carotid artery distensibility: The Cardiovascular Risk in Young Finns Study and the Health 2000 Survey

OBJECTIVE Increased arterial pulse wave velocity (PWV) is a strong predictor of cardiovascular events and mortality. The data regarding the relationships between PWV and other indices of vascular damage is limited and partly controversial. We conducted the present study to examine PWV in relation to non-invasive measures of early atherosclerosis (brachial flow-mediated dilation [FMD], carotid intima-media thickness [IMT]) and local arterial stiffness (carotid artery distensibility [Cdist]). METHODS The study population consisted of 1754 young adults (aged 30-45 years, 45.5% males) participating in the Cardiovascular Risk in Young Finns Study (YFS), and of 336 older adults (aged 46-76 years, 43.2% males) participating in the Health 2000 Survey. FMD was measured only in the YFS cohort. FMD, IMT and Cdist were assessed by ultrasound, and PWV was measured using the whole-body impedance cardiography device. RESULTS In young adults, FMD and IMT were not associated with PWV independently of cardiovascular risk factors. Moreover, FMD status was not found to modulate the association between cardiovascular risk factors and PWV. In older adults, PWV and IMT were directly and independently associated (β=1.233, p=0.019). In both cohorts, PWV was inversely related with Cdist, and this relation remained significant (p<0.04) in models adjusted for cardiovascular risk factors. CONCLUSIONS The current findings suggest that PWV reflects a different aspect of vascular damage than FMD or IMT in young adults, whereas in older adults the information provided by PWV and IMT may be, to some extent, similar as regards subclinical vascular damage. The present observations also suggest that PWV and Cdist represent, at least in part, a similar adverse vascular wall process.

Human embryonic stem cell-derived neuronal cells form spontaneously active neuronal networks in vitro

The production of functional human embryonic stem cell (hESC)-derived neuronal cells is critical for the application of hESCs in treating neurodegenerative disorders. To study the potential functionality of hESC-derived neurons, we cultured and monitored the development of hESC-derived neuronal networks on microelectrode arrays. Immunocytochemical studies revealed that these networks were positive for the neuronal marker proteins beta-tubulin(III) and microtubule-associated protein 2 (MAP-2). The hESC-derived neuronal networks were spontaneously active and exhibited a multitude of electrical impulse firing patterns. Synchronous bursts of electrical activity similar to those reported for hippocampal neurons and rodent embryonic stem cell-derived neuronal networks were recorded from the differentiated cultures until up to 4 months. The dependence of the observed neuronal network activity on sodium ion channels was examined using tetrodotoxin (TTX). Antagonists for the glutamate receptors NMDA [D(-)-2-amino-5-phosphonopentanoic acid] and AMPA/kainate [6-cyano-7-nitroquinoxaline-2,3-dione], and for GABAA receptors [(-)-bicuculline methiodide] modulated the spontaneous electrical activity, indicating that pharmacologically susceptible neuronal networks with functional synapses had been generated. The findings indicate that hESC-derived neuronal cells can generate spontaneously active networks with synchronous communication in vitro, and are therefore suitable for use in developmental and drug screening studies, as well as for regenerative medicine.

The effects of vibration loading on adipose stem cell number, viability and differentiation towards bone-forming cells

Mechanical stimulation is an essential factor affecting the metabolism of bone cells and their precursors. We hypothesized that vibration loading would stimulate differentiation of human adipose stem cells (hASCs) towards bone-forming cells and simultaneously inhibit differentiation towards fat tissue. We developed a vibration-loading device that produces 3g peak acceleration at frequencies of 50 and 100 Hz to cells cultured on well plates. hASCs were cultured using either basal medium (BM), osteogenic medium (OM) or adipogenic medium (AM), and subjected to vibration loading for 3 h d–1 for 1, 7 and 14 day. Osteogenesis, i.e. differentiation of hASCs towards bone-forming cells, was analysed using markers such as alkaline phosphatase (ALP) activity, collagen production and mineralization. Both 50 and 100 Hz vibration frequencies induced significantly increased ALP activity and collagen production of hASCs compared with the static control at 14 day in OM. A similar trend was detected for mineralization, but the increase was not statistically significant. Furthermore, vibration loading inhibited adipocyte differentiation of hASCs. Vibration did not affect cell number or viability. These findings suggest that osteogenic culture conditions amplify the stimulatory effect of vibration loading on differentiation of hASCs towards bone-forming cells.

DexterNet: An Open Platform for Heterogeneous Body Sensor Networks and its Applications

We present an open-source platform for wireless body sensor networks called DexterNet. The system supports real-time, persistent human monitoring in both indoor and outdoor environments. The platform utilizes a three-layer architecture to control heterogeneous body sensors. The first layer called the body sensor layer (BSL) deals with design of heterogeneous body sensors and their instrumentation on the body. At the second layer called the personal network layer (PNL), the body sensors on a single subject communicate with a mobile base station, which supports Linux OS and the IEEE 802.15.4 protocol. The BSL and PNL functions are abstracted and implemented as an open-source software library, called Signal Processing In Node Environment (SPINE). A DexterNet network is scalable, and can be reconfigured on-the-fly via SPINE. At the third layer called the global network layer (GNL), multiple PNLs communicate with a remote Internet server to permanently log the sensor data and support higher-level applications. We demonstrate the versatility of the DexterNet platform via several real-world applications.

Substantial variation in the cardiac differentiation of human embryonic stem cell lines derived and propagated under the same conditions—a comparison of multiple cell lines

Aim. The differentiation efficiencies of human embryonic stem cell (hESC) lines differ from each other. To assess this in more detail we studied the cardiac differentiation of eight hESC lines derived in the same laboratory. Results. Substantial variation in growth and in the ability to form beating areas was seen between the different hESC lines; line HS346 gave the best efficiency (9.4%), while HS293 did not differentiate into beating colonies at all. Nine germ layer and differentiation markers were quantified during early differentiation in four hESC lines. The expression levels of Brachyury T, MESP1 and NKX2.5 were highest in the most efficient cardiac line (HS346). A systematic characterization of the beating cells revealed proper cardiac marker expression, electrophysiological activity, and pharmacological response. Conclusions. The hESC lines derived in the same laboratory varied considerably in their potential to differentiate into beating cardiomyocytes. None of the expression markers could clearly predict cardiac differentiation potential, although the expression of early cardiomyogenic genes was upregulated in the best cardiac line. The proper cardiomyocyte characteristics and pharmacological response indicate that these cells could be used as a model for human cardiomyocytes in pharmacological and toxicological analyses when investigating new heart medications or cardiac side-effects.

Measurement of noise and impedance of dry and wet textile electrodes, and textile electrodes with hydrogel

Textile sensors, when embedded into clothing, can provide new ways of monitoring physiological signals, and improve the usability and comfort of such monitoring systems in the areas of medical, occupational health and sports. However, good electrical and mechanical contact between the electrode and the skin is very important, as it often determines the quality of the signal. This paper introduces a study where the properties of dry textile electrodes, textile electrodes moistened with water, and textile electrodes covered with hydrogel were studied with five different electrode sizes. The aim was to study how the electrode size and preparation of the electrode (dry electrode/wet electrode/electrode covered with hydrogel membrane) affect the measurement noise, and the skin-electrode impedance. The measurement noise and skin-electrode impedance were determined from surface biopotential measurements. These preliminary results indicate that noise level increases as the electrode size decreases. The noise level is high in dry textile electrodes, as expected. Yet, the noise level of wet textile electrodes is quite low and similar to that of textile electrodes covered with hydrogel. Hydrogel does not seem to improve noise properties, however it may have effects on movement artifacts. Thus, it is feasible to use textile embedded sensors in physiological monitoring applications when moistening or hydrogel is applied

Sensitivity Distributions of Impedance Cardiography Using Band and Spot Electrodes Analyzed by a Three-Dimensional Computer Model

AbstractImpedance cardiography (ICG) offers a safe, noninvasive, and inexpensive method to track stroke volume estimates over long periods of time. Several modified ICG measurement configurations have been suggested where for convenience or improved performance the standard band electrodes are replaced with electrocardiogram electrodes. This report assesses the sensitivity of the conventional and three modified ICG methods in detecting regional conductivity changes in the simulated human thorax. The theoretical analyses of the measurement sensitivity employ the reciprocity theorem and the lead field theory with a highly detailed, anatomically accurate, three-dimensional computer thorax model. This model is based on the finite-difference element method and the U.S. National Library of Medicines Visible Human Man anatomy data. The results obtained indicate that the conventional four-band ICG is not specifically sensitive to detect conductivity changes in the region of the heart, aortas, and lungs. Analyzed modified electrode configurations do not reproduce exactly the measurement sensitivity distribution of the conventional four-band ICG. Thus, although the signals measured with modified spot arrangements may appear similar to the four-band configuration, the distribution of the signal origin may not be the same. Changing from band to spot electrodes does not overcome the methodological problems associated with ICG.