Development of a Minimally Invasive Device Based Therapy Incorporating Simultaneous Adjustable Passive Support and Synchronous Active Assist Designed to Treat Congestive Heart Failure

The technology described herein is a device based therapy targeting recovery of cardiac function in patients with congestive heart failure. This represents a shift in the present paradigm wherein available treatment options conservatively target inhibiting disease progression, e.g. non-adjustable cardiac support devices and/or alleviating symptoms, e.g. blood pumps for circulatory assist. Specifically, the innovation is a minimally invasive device incorporating adjustable passive cardiac support and synchronous active cardiac assist - device based technology designed to provide rehabilitative physical therapy for the heart muscle, mediating restorative remodeling processes to facilitate recovery of cardiac function. CHF affects more than 5.3 million people in the U.S. with 550,000 new cases diagnosed each year. For 300,000 Americans in end-stage failure, transplant is the preferred treatment; however, with less than 3,000 hearts available this treatment plan is epidemiologically trivial. The development of a therapeutic option targeting recovery of cardiac function would be a substantial advancement in the treatment of heart failure, and consequently a great benefit to the healthcare economy, biomedical science, and society as whole. Device performance was assessed in an acute implantation in an ovine model of acute heart failure (esmolol overdose). In the study it was confirmed that the device which was designed to be collapsible into a 1 1/2" diameter deployment tube and could be deployed using minimally invasive procedures. In examining pressure-volume loops, it was confirmed that the passive component of the device enabled a leftward shift in the enddiastolic pressure-volume relationship; important as disease typically shifts this relationship to the right. Further, it was verified that the active component of the device was capable of restoring stroke work lost in the esmolol induced failure model. Finally, the device did not invert the curvature of the heart, did not interfere with normal cardiac function, and remained in place through an intrinsic pneumatic attachment and thus did not require tethering to the myocardium. The versatile combination of support and assist provide the cardiologist with powerful therapeutic options to treat a wide variety of patient specific anomalies - with the primary target, rehabilitation of the heart and recovery of cardiac function and performance

Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery

Background The relationship between monogenic and polygenic forms of epilepsy is poorly understood, and the extent to which the genetic and acquired epilepsies share common pathways is unclear. Here, we use an integrated systems-level analysis of brain gene expression data to identify molecular networks disrupted in epilepsy. Results We identify a co-expression network of 320 genes (M30), which is significantly enriched for non-synonymous de novo mutations ascertained from patients with monogenic epilepsy, and for common variants associated with polygenic epilepsy. The genes in M30 network are expressed widely in the human brain under tight developmental control, and encode physically interacting proteins involved in synaptic processes. The most highly connected proteins within M30 network are preferentially disrupted by deleterious de novo mutations for monogenic epilepsy, in line with the centrality-lethality hypothesis. Analysis of M30 expression revealed consistent down-regulation in the epileptic brain in heterogeneous forms of epilepsy including human temporal lobe epilepsy, a mouse model of acquired temporal lobe epilepsy, and a mouse model of monogenic Dravet (SCN1A) disease. These results suggest functional disruption of M30 via gene mutation or altered expression as a convergent mechanism regulating susceptibility to epilepsy broadly. Using the large collection of drug-induced gene expression data from Connectivity Map, several drugs were predicted to preferentially restore the down-regulation of M30 in epilepsy toward health, most notably valproic acid, whose effect on M30 expression was replicated in neurons. Conclusions Taken together, our results suggest targeting the expression of M30 as a potential new therapeutic strategy in epilepsy

Magnetic field generation in fully convective rotating spheres

Magnetohydrodynamic simulations of fully convective, rotating spheres with volume heating near the center and cooling at the surface are presented. The dynamo-generated magnetic field saturates at equipartition field strength near the surface. In the interior, the field is dominated by small-scale structures, but outside the sphere by the global scale. Azimuthal averages of the field reveal a large-scale field of smaller amplitude also inside the star. The internal angular velocity shows some tendency to be constant along cylinders and is ``anti-solar'' (fastest at the poles and slowest at the equator).Comment: 12 pages, 11 figures, 2 tables, to appear in the 10 Feb issue of Ap