Physical fitness training in Subacute Stroke (PHYS-STROKE) - study protocol for a randomised controlled trial

BACKGROUND: Given the rising number of strokes worldwide, and the large number of individuals left with disabilities after stroke, novel strategies to reduce disability, increase functions in the motor and the cognitive domains, and improve quality of life are of major importance. Physical activity is a promising intervention to address these challenges but, as yet, there is no study demonstrating definite outcomes. Our objective is to assess whether additional treatment in the form of physical fitness-based training for patients early after stroke will provide benefits in terms of functional outcomes, in particular gait speed and the Barthel Index (co-primary outcome measures) reflecting activities of daily living (ADL). We will gather secondary functional outcomes as well as mechanistic parameters in an exploratory approach. METHODS/DESIGN: Our phase III randomised controlled trial will recruit 215 adults with moderate to severe limitations of walking and ADL 5 to 45 days after stroke onset. Participants will be stratified for the prognostic variables of “centre”, “age”, and “stroke severity”, and randomly assigned to one of two groups. The interventional group receives physical fitness training delivered as supported or unsupported treadmill training (cardiovascular active aerobic training; five times per week, over 4 weeks; each session 50 minutes; total of 20 additional physical fitness training sessions) in addition to standard rehabilitation treatment. The control intervention consists of relaxation sessions (non-cardiovascular active; five times per week week, over 4 weeks; each session 50 minutes) in addition to standard rehabilitation treatment. Co-primary efficacy endpoints will be gait speed (in m/s, 10 m walk) and the Barthel Index (100 points total) at 3 months post-stroke, compared to baseline measurements. Secondary outcomes include standard measures of quality of life, sleep and mood, cognition, arm function, maximal oxygen uptake, and cardiovascular risk factors including blood pressure, pulse, waist-to-hip ratio, markers of inflammation, immunity and the insulin-glucose pathway, lipid profile, and others. DISCUSSION: The goal of this endpoint-blinded, phase III randomised controlled trial is to provide evidence to guide post-stroke physical fitness-based rehabilitation programmes, and to elucidate the mechanisms underlying this intervention. TRIAL REGISTRATION: Registered in ClinicalTrials.gov with the Identifier NCT01953549

Mining geriatric assessment data for in-patient fall prediction models and high-risk subgroups

<p>Abstract</p> <p>Background</p> <p>Hospital in-patient falls constitute a prominent problem in terms of costs and consequences. Geriatric institutions are most often affected, and common screening tools cannot predict in-patient falls consistently. Our objectives are to derive comprehensible fall risk classification models from a large data set of geriatric in-patients' assessment data and to evaluate their predictive performance (aim#1), and to identify high-risk subgroups from the data (aim#2).</p> <p>Methods</p> <p>A data set of n = 5,176 single in-patient episodes covering 1.5 years of admissions to a geriatric hospital were extracted from the hospital's data base and matched with fall incident reports (n = 493). A classification tree model was induced using the C4.5 algorithm as well as a logistic regression model, and their predictive performance was evaluated. Furthermore, high-risk subgroups were identified from extracted classification rules with a support of more than 100 instances.</p> <p>Results</p> <p>The classification tree model showed an overall classification accuracy of 66%, with a sensitivity of 55.4%, a specificity of 67.1%, positive and negative predictive values of 15% resp. 93.5%. Five high-risk groups were identified, defined by high age, low Barthel index, cognitive impairment, multi-medication and co-morbidity.</p> <p>Conclusions</p> <p>Our results show that a little more than half of the fallers may be identified correctly by our model, but the positive predictive value is too low to be applicable. Non-fallers, on the other hand, may be sorted out with the model quite well. The high-risk subgroups and the risk factors identified (age, low ADL score, cognitive impairment, institutionalization, polypharmacy and co-morbidity) reflect domain knowledge and may be used to screen certain subgroups of patients with a high risk of falling. Classification models derived from a large data set using data mining methods can compete with current dedicated fall risk screening tools, yet lack diagnostic precision. High-risk subgroups may be identified automatically from existing geriatric assessment data, especially when combined with domain knowledge in a hybrid classification model. Further work is necessary to validate our approach in a controlled prospective setting.</p

The role of the protein kinase inhibitor α in the modulation of the phospholamban-dependent Ca2+ - uptake into the sarcoplasmic reticulum

Die Herzinsuffizienz ist die zweithäufigste Aufnahmediagnose im Krankenhaus und die häufigste Todesursache in Deutschland 1,2. Die mangelnde Fähigkeit des Herzens, das vom Körper benötigte Blutvolumen innerhalb der erforderlichen Zeit aufzubringen, wird auf eine reduzierte Kontraktionskraft und eine verzögerte Relaxation des Herzens zurückgeführt 3–5. Sowohl im Tierversuch als auch bei humanen insuffizienten Herzen konnte gezeigt werden, dass eine verzögerte diastolische Relaxation des Herzens Folge einer verminderten Aufnahme des zytosolischen Ca2+ in das sarkoplasmatische Retikulum (SR) durch die sarkoplasmatische Ca2+-ATPase (SERCA2a) ist 3–5. Phospholamban (PLB) ist ein potenter Inhibitor der SERCA2a 6,7 und kann durch Phosphorylierung z.B. infolge einer β-adrenergen Stimulation oder durch erhöhte intrazelluläre Ca2+-Konzentrationen seine inhibitorische Wirkung auf die SERCA2a verlieren. Die Folge ist eine erhöhte Ca2+-Aufnahme in das SR, was zu einer beschleunigten Relaxation und letztlich auch zu einer erhöhten Myokardkontraktilität führt 8,9. Olsen und Uhler konnten 1991 zeigen, dass es prinzipiell möglich ist, mit Hilfe eines Plasmid-Vektors (CMV-Neo) PKIα in COS Zellen zu exprimieren 10. Weiterhin zeigte die Arbeitsgruppe, dass durch Überexpression von PKIα die Kinaseaktivität der katalytischen Untereinheiten der PKA, Cα und Cβ, mit gleicher Effizienz inhibiert werden kann. Ziel dieser Arbeit war es, durch Inhibierung der PKIα-Expression in neonatalen Rattenkardiomyozyten (nRCM) die Hemmwirkung auf die PKA zu reduzieren und somit die Phosphorylierung von PLB zu steigern. Infolge sollte der Anstieg der sarkoplasmatischen Ca2+-Konzentration als Maß für die diastolische Relaxation und Kontraktilität des Myokards gesteigert werden. Es wurden zwei adenovirale Vektoren, AdVPKIsense und AdVPKIantisense, aus dem E1-deletierten Adenovirus 5 Genom mit einem Insert aus PKIα-cDNA in sense und antisense Orientierung konstruiert. nRCM wurden mit AdVPKIsense und AdVPKIantisense je 50000 Partikel/Zelle transfiziert. Zum Nachweis der vektorspezifischen PKI-mRNA Expression wurde ein Northern Blot mit einer PKI spezifischen ssDNA-Sonde durchgeführt. Der Proteinnachweis erfolgte im Anschluss an die Konzentrationsbestimmung nach Lowry mittels Western Blot. Durch Verwendung des Anti-PS16 Antikörpers konnte die PLB Konzentration bestimmt werden. Der Anti- PKI-AK diente der Detektion von PKIα. Zur Bestimmung der sarkoplasmatischen Ca2+-Konzentration wurde der SERCA2a-katalysierte ATP-abhängige Transport von Ca2+ in die Membranvesikel des SR der nRCM durch Oxalat-stimulierte 45Ca2+-Aufnahme gemessen 11. Die korrekte Insertion der PKIα-cDNA in Sense- und Antisense-Orientierung konnte mittels DNA Sequenzanalyse nachgewiesen werden. Dabei war PKIα im konstruierten Vektor 100% homolog zu humanem PKIα aus der Neuroblastoma Zelllinie. Der open reading frame betrug 230 bp 12. PKI- mRNA konnte mit einer Signalanreicherung bei 0,6-0,8 kb im Northern Blot detektiert werden. Außerdem gelang der Nachweis von endogen synthetisierter PKI-mRNA bei 4,4 kb. Im Western Blot konnte gezeigt werden, dass die Transfektion von nRCM mit AdVPKIsense zu einer signifikanten Abnahme an phosphoryliertem PLB (pPLB) im Vergleich zur Kontrolle führte. AdVPKIantisense transfizierte nRCM zeigten eine erhöhte Konzentration von pPLB im Vergleich zum Kontrollvektor. Von besonderer Bedeutung war auch die Tatsache, dass sich der Effekt des AdVPKIsense konzentrationsabhängig durch AdVPKIantisense antagonisieren ließ. Ferner konnte gezeigt werden, dass Isoproterenol die Phosphorylierung von PLB unabhängig von den Vektoren AdVPKIsense und AdVPKIantisense stimuliert, wodurch der Effekt der Vektoren minimiert wurde. Schließlich konnte erstmalig demonstriert werden, dass eine AdV-vermittelte Suppression von PKIα bei AdVPKIantisense transfizierten nRCM eine erhöhte 45Ca2+-Aufnahme in das SR zur Folge hat. Die erhöhte Ca2+-Aufnahme bei PKIα- Suppression ließ sich durch Überexpression von PKIα antagonisieren. Die Ergebnisse verdeutlichen, dass es möglich ist, die PLB-abhängige Ca2+-Aufnahme in das SR über den PKI-PKA Signalweg zu regulieren und durch die adenoviralen Vektoren AdVPKIsense und AdVPKIantisense konzentrationsabhängig moduliert werden kann. Die AdV-vermittelte Suppression von PKI stellt ein weiteres vielversprechendes molekulares Ziel in der ß-adrenergen Signalkaskade dar. Weiterführende Untersuchungen zu den Auswirkungen einer PKI-Downregulation auf subzelluläre Prozesse, sowie in vivo-Untersuchungen sind notwendig, um diesen neuen Ansatz als potentiell therapeutische Option bei der Behandlung der Herzinsuffizienz zu verifizieren.The role of the protein kinase inhibitor α in the modulation of the phospholamban-dependent Ca2+-uptake into the sarcoplasmic reticulum Heart failure is the second most common admission diagnosis in the hospital and the most common cause of death in Germany. In animals and in human failing hearts it has been shown that a delayed diastolic relaxation of the heart is caused by a reduced uptake of cytosolic Ca2+ into the sarcoplasmic reticulum (SR) through the sarcoplasmic Ca2+-ATPase (SERCA2a). Phospholamban (PLB) is a potent inhibitor of SERCA2a and can lose its inhibitory effect on the SERCA2a by phosphorylation. As a result the Ca2+-uptake into the SR is increased, resulting in an accelerated relaxation and an increased myocardial contractility. Olsen and Uhler showed the feasibility of the expression of PKIα through a plasmid vector (CMV-neo) in COS cells and the inhibition of protein kinase A (PKA) by overexpression of PKIα. The aim of this work was to show an increased uptake of Ca2+ into the sarcoplasmic reticulum through an AdVPKIα antisense mediated increase in PLB-Phosphorylation. Two adenoviral vectors AdVPKIsense and AdVPKIantisense were constructed from the E1-deleted adenovirus-5 genome with an insert of PKIα-cDNA in sense and antisense orientation. Neonatal rat cardiomyocytes (NRCM) were transfected with 50 000 particles per cell with AdVPKIsense and AdVPKIantisense. To show the vector- specific mRNA expression of PKIα, a northern blot analysis with a PKI-specific ssDNA probe was conducted. Total PKIα and phosphorylated PLB was determined by a standard Lowry protein assay and western blot analysis using an anti-PS16 and PKI antibody. To determine the sarcoplasmic Ca2+-concentration, the SERCA2a-catalyzed transport of Ca2+ into the SR was measured by oxalate- stimulated 45Ca2+-uptake. The correct insertion of the PKIα cDNA in sense and antisense orientation could be detected by DNA sequence analysis. PKIα showed a 100% homology to human PKIα from the neuroblastoma cell line in the blast search (medline). The open reading frame was 230 bp. PKI mRNA was detected in northern blot analysis with a signal at 0.6-0.8 kb. In addition, the successful detection of endogenously synthesized PKIα mRNA was detected at 4.4kb. The western blot analysis showed that the transfection of NRCM with AdVPKIsense lead to a significant decrease of phosphorylated PLB (PPLB) in comparison to the control. AdVPKIantisense transfected NRCM showed an increased concentration of PPLB compared to the control vector. This effect could be antagonized concentration-dependently by AdVPKIsense. Finally, it could be demonstrated for the first time that an AdV-mediated suppression of PKIα in AdVPKIantisense transfected NRCM lead to an increased Ca2+-uptake into the SR. The increased Ca2+-uptake could be antagonized by overexpression of PKIα. These results illustrate that it is possible to regulate the PLB- dependent Ca2+-uptake into the SR via the PKI-PKA pathway through an AdV mediated down regulation of PKIα. AdV-mediated suppression of PKIα could be a new promising molecular target in the field of cardiovascular gene therapy. Further studies on the effects of PKIα-down regulation especially on the modulation of the physiologic functions of PKIα as well as in vivo studies are necessary to prove this approach as a potential therapeutic option in the treatment of heart failure

Design and Verification of a Health-Monitoring Driver Assistance System

Health-monitoring driver assistance systems support an independent and self-determined lifestyle enhancing the driver's safety. These systems are health-critical and need to guarantee correct behavior in emergency situations such as heart attacks. Furthermore, they have to be adjustable and extendable with respect to integrated functionalities to fit individual and changing needs. We present a concept for a mobile, service-oriented driver assistance system with dynamic network behavior. Additionally, we introduce a verification approach to ensure correct behavior

Smart senior's interactive trainer - Development of an interactive system for a home-based fall-prevention training for elderly people

In this article we picture the process of development for an interactive training system for the prevention of falls for older people in the project SmartSenior. Initially, we will depict the medical background of falls, which is the basis of the user-centered design of our device. Following a thoroughly evaluation of evidenced-based therapeutic strategies and a detailed requirement analysis, an interdisciplinary team consisting of physical therapists, medical practitioners and system engineers developed a technical architecture to enable older people to train their individual functional deficits via a home based telemedical infrastructure. Furthermore, we describe the sensor technology, feedback system used for motivation and correction of the trainee and the security model for the transmission of movement data to an assisting physical therapist

The Lower Saxony research network design of environments for ageing : towards interdisciplinary research on information and communication technologies in ageing societies

Worldwide, ageing societies are bringing challenges for independent living and healthcare. Health-enabling technologies for pervasive healthcare and sensor-enhanced health information systems offer new opportunities for care. In order to identify, implement and assess such new information and communication technologies (ICT) the 'Lower Saxony Research Network Design of Environments for Ageing' (GAL) has been launched in 2008 as interdisciplinary research project. In this publication, we inform about the goals and structure of GAL, including first outcomes, as well as to discuss the potentials and possible barriers of such highly interdisciplinary research projects in the field of health-enabling technologies for pervasive healthcare. Although GAL's high interdisciplinarity at the beginning slowed down the speed of research progress, we can now work on problems, which can hardly be solved by one or few disciplines alone. Interdisciplinary research projects on ICT in ageing societies are needed and recommended