Is bridging with intravenous thrombolysis of any benefit in endovascular therapy for acute ischemic stroke?

OBJECTIVE: Large vessel occlusions with heavy clot burden are less likely to improve with intravenous (IV) thrombolysis alone. The purpose of this study was to show whether a combination of IV thrombolysis and endovascular therapy was superior to endovascular treatment alone. METHODS: Data for 104 patients with acute large artery occlusion treated between 2005 and 2010 were reviewed. Forty-two received endovascular therapy in combination with IV thrombolysis (bridging group), and 62 received endovascular therapy only. Clinical outcome, mortality rate, and symptomatic intracranial hemorrhage (sICH) rate were compared between the two groups. RESULTS: The two groups had similar demographic and vascular risk factor distribution, as well as National Institutes of Health Stroke Scale score on admission (mean±SD: 14.8±4.7 and 16.0±5.3; P=0.23). No difference was found in Thrombolysis in Myocardial Infarction recanalization rates (score of 2 or 3) after combined or endovascular therapy alone (83.33% and 79.03%; P=0.585). Favorable outcome, defined as a modified Rankin Scale score of <2 at 90 days, also did not differ between the bridging group and the endovascular-only group (37.5% and 32.76%; P=0.643). There was no difference in mortality rate (19.04% and 29.03%; P=0.5618) and sICH rate (11.9% and 9.68%; P=0.734). A significant difference was found in mean time from symptom onset to treatment in the bridging group and the endovascular-only group (227±88 min vs. 125±40 min; P<0.0001). CONCLUSION: Combining IV thrombolysis with endovascular therapy resulted in similar outcome, revascularization, sICH, and mortality rates compared with endovascular therapy alone. Prospective clinical studies comparing both treatment strategies in acute ischemic stroke are warranted.

A translatable, closed recirculation system for AAV6 vector-mediated myocardial gene delivery in the large animal.

Current strategies for managing congestive heart failure are limited, validating the search for an alternative treatment modality. Gene therapy holds tremendous promise as both a practical and translatable technology platform. Its effectiveness is evidenced by the improvements in cardiac function observed in vector-mediated therapeutic transgene delivery to the murine myocardium. A large animal model validating these results is the likely segue into clinical application. However, controversy still exists regarding a suitable method of vector-mediated cardiac gene delivery that provides for efficient, global gene transfer to the large animal myocardium that is also clinically translatable and practical. Intramyocardial injection and catheter-based coronary delivery techniques are attractive alternatives with respect to their clinical applicability; yet, they are fraught with numerous challenges, including concerns regarding collateral gene expression in other organs, low efficiency of vector delivery to the myocardium, inhomogeneous expression, and untoward immune response secondary to gene delivery. Cardiopulmonary bypass (CPB) delivery with dual systemic and isolated cardiac circuitry precludes these drawbacks and has the added advantage of allowing for control of the pharmacological milieu, multiple pass recirculation through the coronary circulation, the selective addition of endothelial permeabilizing agents, and an increase in vector residence time. Collectively, these mechanics significantly improve the efficiency of global, vector-mediated cardiac gene delivery to the large animal myocardium, highlighting a potential therapeutic strategy to be extended to some heart failure patients.

Efficient myocyte gene delivery with complete cardiac surgical isolation in situ.

BACKGROUND: Previously, we used cardiopulmonary bypass with incomplete cardiac isolation and antegrade administration of vector for global cardiac gene delivery. Here we present a translatable cardiac surgical procedure that allows for complete surgical isolation of the heart in situ with retrograde (through the coronary venous circulation) administration of both vector and endothelial permeabilizing agents to increase myocyte transduction efficiency. METHODS: In 6 adult dogs the heart was completely isolated with tourniquets placed around both vena cavae and cannulas and all pulmonary veins. On cardiopulmonary bypass, the aorta and pulmonary artery were crossclamped, and the heart was isolated. Crystalloid cardioplegia at 4 degrees C containing 10(13) particles of adenovirus encoding LacZ and 15 microg of vascular endothelial growth factor was infused retrograde into the coronary sinus and recirculated for a total of 30 minutes. The dogs were then weaned from cardiopulmonary bypass and allowed to recover. With a catheter, 3 control dogs underwent retrograde infusion of the same cocktail without cardiac isolation or cardiopulmonary bypass. RESULTS: Beta-galactosidase activities in the cardiopulmonary bypass group were several orders of magnitude higher in both the right and left ventricles when compared with those in the control group (P < .05). X-gal staining from the cardiopulmonary bypass group showed unequivocal evidence of myocyte gene expression globally in a significant proportion of cardiac myocytes. No myocyte gene expression was observed in the control group. CONCLUSION: A novel cardiac surgical technique has been developed. This approach with cardiac isolation and retrograde delivery of vector through the coronary sinus results in efficient myocyte transduction in an adult large animal in vivo.

Myosin gene mutation correlates with anatomical changes in the human lineage.

Powerful masticatory muscles are found in most primates, including chimpanzees and gorillas, and were part of a prominent adaptation of Australopithecus and Paranthropus, extinct genera of the family Hominidae. In contrast, masticatory muscles are considerably smaller in both modern and fossil members of Homo. The evolving hominid masticatory apparatus--traceable to a Late Miocene, chimpanzee-like morphology--shifted towards a pattern of gracilization nearly simultaneously with accelerated encephalization in early Homo. Here, we show that the gene encoding the predominant myosin heavy chain (MYH) expressed in these muscles was inactivated by a frameshifting mutation after the lineages leading to humans and chimpanzees diverged. Loss of this protein isoform is associated with marked size reductions in individual muscle fibres and entire masticatory muscles. Using the coding sequence for the myosin rod domains as a molecular clock, we estimate that this mutation appeared approximately 2.4 million years ago, predating the appearance of modern human body size and emigration of Homo from Africa. This represents the first proteomic distinction between humans and chimpanzees that can be correlated with a traceable anatomic imprint in the fossil record.