Direct in vivo gene transfer to canine myocardium using a replication-deficient adenovirus vector

Inter-alpha-inhibitor (I alpha I) is a serine protease inhibitor present in human plasma. It has a molecular weight of about 220 kDa which encompasses 3 chains including two heavy chains and one light chain. The light chain, known as bikunin, is responsible for the antitryptic activity of I alpha I in the inhibition of various enzymes, such as trypsin and chymotrypsin. Under physiologic or certain pathologic circumstances, several macromolecules related to I alpha I appear in plasma and urine. However, the physiologic role of I alpha I remains unclear. As far as urolithiasis is concerned, two urinary macromolecules related to I alpha I have been isolated and shown to be potent inhibitors of calcium oxalate formation. One of these inhibitors, uronic-acid-rich protein (UAP), has been identified and well characterized. The sequence of the first 18 amino acid residues of UAP is identical with that of bikunin. Furthermore, the immunoreaction between UAP and I alpha I antibody using immunoblot analysis was positive. UAP isolated from the urine of stone formers exhibited less inhibitory activity towards calcium oxalate crystallization than that derived from the urine of healthy subjects. This suggests a structural abnormality of the inhibitor obtained from stone patients. The organic matrix extracted from kidney stones contained a protein antigenically related to I alpha I. We conclude that UAP is a member of I alpha I family taking part in inhibiting calcium oxalate crystallization, and modulating the formation of stones in the urinary tract.     

Outcome analysis of 245 CarboMedics and St. Jude valves implanted at the same institution

BACKGROUND: Thromboembolism and valve-related death are major complications associated with prosthetic valve implants, but it is difficult to evaluate the relative incidence of these complications based on studies in which the implantation of only one valve is reported from any given institution. We therefore report the outcome of patients implanted at our institution during the same time period with either the recently released CarboMedics (CM) or the St. Jude Medical (SJ) valve prostheses. METHODS: Between October 1994 and January 1996, 245 consecutive patients received either SJ (116 patients) or CM (129 patients) valves at our institution. Follow up of these patients was 99.6% complete, for a total of 318.5 cumulative patient-years (median follow-up, 1.4 years). RESULTS: The 30-day mortality rates for SJ and CM implants were 3.4% and 3.1%, respectively. Actuarial survival and freedom from valve related mortality rates at 1.5 years for SJ and CM valves were 94%+/-2% versus 86%+/-3% (p = 0.03) and 100% versus 94%+/-2% (p = 0.005), respectively. There was no structural valve failure for either implant, but there were five thrombosed valves in the CM group and none in the SJ group (p = 0.04). All thrombosed valves were mitral (four mitral valve replacement, one aortic and mitral valve replacement). Two of the thrombosed valves were successfully explanted, whereas the three remaining patients died. Freedom from a thromboembolic event in the mitral position at 1.5 years, including thrombosed valves was 97%+/-3% and 83%+/-5% for SJ and CM valves, respectively (p = 0.04). CONCLUSIONS: The results of this study suggest that further evaluation of thromboembolic outcomes after CM compared with SJ valve implantation is warranted.     

Targeted brain hypothermia induced by an interstitial cooling device in the rat neck: Experimental study and model validation

Targeted brain hypothermia has the potential to prevent cerebral ischemia injury during open heart and neck surgeries or after traumatic head injury. In this study, in vivo experiments were performed to test the performance of a newly developed cooling device in an inexpensive animal model. Rat brain hypothermia was induced by inserting an interstitial cooling device in the rat neck muscle and placing the device on the common carotid artery to cool the arterial blood supplied to the brain. Coolant was circulating inside the cooling device to achieve either mild or moderate temperature reductions at the surface of the device. Temperatures were measured inside the rat brain tissue, as well as on the head skin surface. For the mild cooling (cooling device surface temperature was 18.7 ± 4.5 °C), the temperature reductions were 2.2 ± 0.6 °C, 2.1 ± 0.6 °C, 1.9 ± 0.6 °C and 1.6 ± 0.9 °C at sites of brain-5 mm, brain-2 mm, skull, and scalp, respectively. After the surface temperature was further decreased to 12.8 ± 2.8 °C (moderate cooling), the temperature reduction in the head increased more than 85% to 3.7 ± 3.2 °C, 3.7 ± 3.0 °C, 3.3 ± 2.5 °C and 2.5 ± 1.0 °C, respectively. The experimental data were also used to validate a previously developed theoretical model for humans. Experimentally measured geometrical and physiological parameters of the rat neck and brain were substituted into the scaled-down theoretical model to simulate the temperature distribution in the rat neck and brain. The theoretically predicted brain temperatures showed a good agreement with the experiment data. We believe that this study is the first step in developing a reliable cooling device to achieve fast cooling and to control rewarming in future clinical studies and to benefit a large patient population.     

Experience and Materials Affect Combinatorial Construction in Tufted Capuchin Monkeys (Cebus apella).

Three movement procedures can combine nesting cups into seriated structures. Reliance on these procedures changes with age in human children, and the putatively most advanced emerges as a predominant procedure at 3 or more years. Six monkeys' (Cebus apella) combinatorial procedures and successes at nesting seriated cups were evaluated. The current study examined whether the procedures used (a) shift toward more efficient procedures after unguided experience, (b) are dependent on the type of object being combined, and (c) can be altered by specific training history. All factors produced a change in procedure for some individuals, suggesting that combinatorial procedure is a product of the dynamic influences of preexisting tendencies to act in certain ways, of environmental circumstances, and of prior experiences. Some monkeys preferred the putatively most cognitively complex procedure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Salvage angiogenesis induced by adenovirus-mediated gene transfer of vascular endothelial growth factor protects against ischemic vascular occlusion

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, and transgene expression from adenovirus vectors can provide in vivo delivery of proteins. On the basis of this knowledge, we hypothesized that local administration of a replication-deficient adenovirus vector expressing complementary DNA for VEGF (AdVEGF) would induce collateral vessel formation in the setting of ischemia that could protect against subsequent acute vascular occlusion. METHODS: Hindlimb ischemia was induced in Sprague-Dawley rats by means of unilateral ligation of the common iliac artery immediately followed by administration of 4 x 10(9)-plaque-forming units VEGF, the control vector AdNull, or phosphate-buffered saline solution into the iliofemoral adipose tissue and thigh muscles. Untreated rats with common iliac ligation were used as an additional control group. RESULTS: Local VEGF expression was observed for 5 days in AdVEGF-treated rats but not in controls. Three weeks after ligation and vector administration, the ipsilateral femoral artery was ligated for a model of an acute vascular occlusion in the setting of preexisting ischemia. Blood flow to the ischemic hindlimb relative to the contralateral hindlimb evaluated with color microspheres demonstrated significantly increased blood flow in the AdVEGF-treated rats compared with each control group (p < 0.0001). Relative blood flow assessed by means of 99mTc-sestamibi radionuclide scans also demonstrated increased blood flow to the ligated hindlimb of AdVEGF-treated rats compared with each control group (p < 0.002). AdVEGF-treated rats also demonstrated increased vascularity in the ligated limb compared with each control group as assessed by means of angiography (p < 0.0001) and histologic quantification of blood vessels less than 80 microm diameter in local adipose tissue and capillaries per muscle fiber (p < 0.0002). AdVEGF treatment prevented a rise in femoral venous lactate femoral venous concentrations 1 hour after femoral artery ligation in control rats (p < 0.04). CONCLUSIONS: An adenovirus vector expressing VEGF complementary DNA is capable of stimulating an angiogenic response that protects against acute vascular occlusion in the setting of preexisting ischemia, suggesting that in vivo gene transfer of VEGF complementary DNA might be useful in prophylaxis of advancing arterial occlusive disease.     

Cooling Penetration into Normal and Injured Brain via Intraparenchymal Brain Cooling Probe: Theoretical Analyses

The selective cooling of severely injured brain tissue while maintaining normal temperature throughout the remaining body, to avoid cooling-related systemic side effects, has been proposed as a desirable method to improve the outcome of patients with acute brain catastrophes. One approach for targeted brain cooling may utilize miniature cooling probes directly inserted into injured brain tissue. Based on experimental data obtained in primates with normal and injured brains, this study simulates the expected temperature distributions surrounding a prototype brain cooling probe. Our model employs the Pennes bioheat equation to define the effects of local brain perfusion rate on the temperature field within brain tissue. Cooling penetration achieved by this probe under normal and globally ischemic conditions extended from 10 mm to 25 mm, respectively, from the device surface into the surrounding brain parenchyma, and was strongly dependent on the local brain perfusion, with a larger cooling penetration being obtained in injured (less perfused) brain regions. Further, the simulated results indicate that transient brain temperature behavior is affected by both the initial perfusion rate and the blood perfusion response to tissue cooling. Assuming a constant local blood perfusion rate during cooling, our model predicts an established steady state temperature field within 16 min, though additional time may be needed if the blood perfusion rate keeps changing during the cooling. It is also concluded that the brain cooling rate monitored by a temperature sensor close to the device may not be the most accurate measure of cooling penetration, as this estimate neglects to consider key variables such as local blood perfusion rate, monitoring location, and time duration over which the cooling rate is calculated.     

Transmyocardial laser revascularization--a technique in evolution

Transmyocardial laser revascularization (TMLR) is a rapidly evolving technique that represents the recent rediscovery of an old therapy. A growing clinical experience is being assimilated into clear indications and contraindications for and the appropriate performance of this procedure. This technique can be judged to improve patient quality of life and survival in appropriately selected patients. The therapy should still be applied cautiously, in that a full understanding of its indications and mechanism of action remains in a state of evolution.     

Heparin-induced thrombocytopenia and thrombosis: presentation after cardiopulmonary bypass

Heparin-induced thrombocytopenia and thrombosis syndrome was diagnosed in a 63-year-old woman 11 days after coronary artery bypass grafting. Her only presenting complaints were incisional leg pain and vague chest discomfort. The syndrome was suspected when her platelet count was found to be 37,000/microL. A subsequent ventilation-perfusion lung scan showed findings highly probable for pulmonary embolism. An inferior venacavogram obtained before a pulmonary angiogram revealed a large retrohepatic thrombus at the right atrial junction. The patient was successfully treated with the defibrinogenating agent ancrod (Arvin). A diagnosis of heparin-induced thrombocytopenia and thrombosis syndrome should be considered and heparin therapy should be avoided in patients with low platelet counts who have been previously treated with heparin.