43 research outputs found
Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects
Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics
Graphical visualization of the pattern of muscular weakness in neuromuscular diseases.
A graphical method for the description of the spatial extension and temporal development of muscular weakness in neurological disorders implemented on a personal computer is described. Different degrees of paresis of individual muscle groups are represented by distinct grey tone values or colors in a semi-anatomic scheme. This representation provides a rapid recognition of essential features of the clinical syndrome, such as the pattern of muscular weakness and its temporal development. In parallel to the results of force testing, the results of other investigations in the same muscle groups can also be presented by the graphical method.A graphical method for the description of the spatial extension and temporal development of muscular weakness in neurological disorders implemented on a personal computer is described. Different degrees of paresis of individual muscle groups are represented by distinct grey tone values or colors in a semi-anatomic scheme. This representation provides a rapid recognition of essential features of the clinical syndrome, such as the pattern of muscular weakness and its temporal development. In parallel to the results of force testing, the results of other investigations in the same muscle groups can also be presented by the graphical method
Immunohistochemical demonstration of choline acetyltransferase (ChAT) containing neurons in the human central nervous system
Fitzpatrick\u27s color atlas & synopsis of clinical dermatology
In the present paper, the observation and characterization of isolated response curves (IRCs) are experimentally reported in the case of a nonlinear system consisting of two masses sliding on an horizontal guide. Transverse springs are attached to one mass to provide the nonlinear restoring force, and a harmonic motion of the complete system is imposed by prescribing the displacement of their supports. The existence of an IRC is related to a 3:1 internal resonance between the two modes of the system. The observed IRC is studied in detached and merged conditions using swept-sine excitations and system perturbations
Prediction of isolated resonance curves using nonlinear normal modes
Isolated resonance curves are separate from the main nonlinear forced-response branch, so they can easily be missed by a continuation algorithm and the resonant response might be underpredicted. The present work explores the connection between these isolated resonances and the nonlinear normal modes of the system and adapts an energy balance criterion to connect the two. This approach provides new insights into the occurrence of isolated resonances as well as a method to find an initial guess to compute the isolated resonance curve using numerical continuation.
The concepts are illustrated on a finite element model of a cantilever beam with a nonlinear spring at its tip. This system presents jumps in both frequency and amplitude in its response to a swept sinusoidal excitation. The jumps are found to be the result of a modal interaction that creates an isolated resonance curve that eventually merges with the main resonance branch as the excitation force increases. Excellent insight into the observed dynamics is provided with the NNM theory, which supports that NNMs can also be a useful tool for predicting isolated resonance curves and other behaviors in the damped, forced response.</jats:p
Vergleichende Untersuchungen über die Wirkung von Sulfonylharnstoff (D 860) und von Insulin auf die Aktivität der Glucose-6-Phosphatase in der Leber von normalen und alloxandiabetischen Ratten
A Novel Computational Method to Calculate Nonlinear Normal Modes of Complex Structures
In this study, a simple and efficient computational approach to obtain nonlinear normal modes (NNMs) of nonlinear structures is presented. Describing function method (DFM) is used to capture the nonlinear internal forces under periodic motion. DFM has the advantage of expressing the nonlinear internal force as a nonlinear stiffness matrix multiplied by a displacement vector, where the off-diagonal terms of the nonlinear stiffness matrix can provide a comprehensive knowledge about the coupling between the modes. Nonlinear differential equations of motion are converted into a set of nonlinear algebraic equations using DFM under harmonic motion assumption. A matrix manipulation based on dynamic stiffness concept was used to localize nonlinearities and reduce the number of nonlinear equations improving the efficiency of the approach, which becomes important in solving large complex structures. The nonlinear algebraic equations are solved numerically by using Newton’s method with Arc-Length continuation. The efficiency of proposed computational approach is demonstrated using a two-degree-of-freedom nonlinear system. The proposed approach has the potential to be applied to large-scale engineering structures with multiple nonlinear elements and strong nonlinearities