Inhibition of vascular smooth muscle cell proliferation by ribozymes that cleave c-myb mRNA

Proliferation of injured smooth muscle cells contributes to the reocclusion or restenosis of coronary arteries that often occurs following angioplasty procedures. We have identified and optimized nuclease-resistant ribozymes that efficiently cleave c-myb RNA. Three ribozymes targeting different sites in the c-myb mRNA were synthesized chemically and delivered to rat aortic smooth muscle cells with cationic lipids; all three inhibited serum-stimulated cell proliferation significantly. RNA molecules with two base substitutions in the catalytic core that render the ribozyme catalytically inactive had little effect on smooth muscle cell proliferation. Ribozymes with scrambled binding arm sequences also failed to affect cell cycle progression of vascular smooth muscle cells. Furthermore, inhibition of rat smooth muscle cell proliferation correlated with a reduction in intact c-myb mRNA. Efficacy of the chemically-modified ribozyme was compared directly to phosphorothioate antisense oligodeoxynucleotides targeting the same site in the c-myb RNA; the ribozyme had superior efficacy and showed greater specificity than the antisense molecules. Exogenously delivered ribozymes also inhibited porcine and human smooth muscle cell proliferation effectively. Ribozymes targeting c-myb or other regulators of smooth muscle cell proliferation may represent novel therapeutics for the treatment of restenosis after coronary angioplasty.     

Using drug chronotherapy to wean patients from mechanical ventilation

Discontinuation of positive pressure mechanical ventilation results in decreased intrathoracic pressure. Although there has been extensive research into factors associated with weaning adults from mechanical ventilatory support, little attention has been paid to the role of left ventricular performance. Research also has not focused on interventions that might optimize ventricular performance. The purpose of this article is to explore the potential effect of cardiac dysfunction in weaning and the role of drug chronotherapy as a strategy to modify patients' responses to weaning from mechanical ventilatory support. Biophysical principles involved are reviewed, and the development of a chronotherapeutic intervention is described. Two case examples illustrate the use of drug chronotherapy during the weaning process.     

Early mortality after surgical repair of postinfarction ventricular septal rupture: importance of rupture location

BACKGROUND: The aim of this study was to identify factors influencing early outcome after surgical treatment of postinfarction ventricular septal rupture. We investigated the influence of proximal or distal rupture location. METHODS: Between 1980 and 1992 109 patients were treated surgically for ventricular septal rupture using a standardized technique. A division in time periods was made. The rupture was categorized according to its anterior or posterior site and proximal or distal location. RESULTS: The 30-day mortality rate was 27.5%. Multivariate logistic regression analysis identified preoperative shock (p = 0.0007) and right atrial oxygen saturation less than 60% (p = 0.021) as predictors for early death; the risk for early death declined over the time periods from 50% to 12.8% (p = 0.0007). Proximal ventricular septal rupture location (p = 0.0092) and interval between infarction and ventricular septal rupture less then 1 day (p = 0.034) were risk factors for the occurrence of preoperative shock. CONCLUSIONS: Proximal ventricular septal rupture location was the main determinant of preoperative cardiogenic shock, which in turn was the strongest predictor of early mortality. Over the time periods a decrease in early mortality was reached.     

Laboratory evaluation of tissue heart valves. A comparative assessment

Tissue of commercially prepared tissue heart valves were evaluated and compared with aluminium treated, fixed porcine valve tissue in vitro (tensile strength, scanning and transmission electron microscopy) and in vivo (calcification potential after subcutaneous implantation in the rat model). Valve leaflets (n = 40) were divided into four groups according to the method of treatment: Group I (fixed in 0.652% glutaraldehyde, control), Group II (fixed and treated with aluminium), Group III (fixed and treated with Toluidine blue) and Group IV (fixed and treated with watersoluble alkyl sulphate). Tensile strength was not influenced in Group II and III (p > 0.05). Group IV indicated a significant (p < 0.05) reduction in tensile strength. Scanning electron microscopy revealed damage and loss of surface endothelium in Group III and IV respectively. Transmission electron microscopy indicated damage to underlying matricial cells in Group III and IV. Calcification potential was significantly (p < 0.001) reduced in Group II to IV. We conclude that damage ultrastructure could contribute to the reduced tensile strength in Group IV and that reduced tensile strength might have an influence on the long-term durability of tissue heart valves. Antimineralization treatment of tissue heart valves does retard calcification but is yet unable to inhibit the process completely.     

The topographical organization of descending projections from the central nucleus of the inferior colliculus in guinea pig

We describe the descending projections from the central nucleus of the inferior colliculus (CNIC) in guinea pig. Focal injections of the tracer biocytin, made in physiologically defined frequency regions of the CNIC, labelled laminated axonal terminal fields in the ipsilateral dorsal nucleus of the lateral lemniscus, and bilaterally in the ventral nucleus of the trapezoid body and the dorsal cochlear nucleus. Labelling was also present in the rostral periolivary nucleus, but we could not distinguish a clear border between the terminal fields in this nucleus and those in the ventral nucleus of the trapezoid body. Labelling observed in the ventral nucleus of the lateral lemniscus, and to a lesser extent in the dorsal nucleus of the lateral lemniscus, was accompanied by retrogradely labelled somata and therefore we cannot conclude unequivocally that the CNIC projects to these lemniscal nuclei. Where the labelling was ordered topographically, its position varied as a function of the best frequency at the injection site. High-frequency regions in the CNIC project to the medial parts of the ventral nucleus of the trapezoid body and dorsal cochlear nucleus, while low-frequency regions in the CNIC project to the lateral parts of the ventral nucleus of the trapezoid body and dorsal cochlear nucleus. Additional axonal labelling with terminal boutons, but with no apparent topographical arrangement, was present in the ipsilateral horizontal cell group, sagulum, and also bilaterally in the superficial granule cell layer of the ventral cochlear nucleus and layer 2 of the dorsal cochlear nucleus. Our findings are consistent with the existence of tonotopically organised feedback projections from the CNIC to the brainstem nuclei that project to it.     

The evaluation of argon laser photocoagulation in a series of animal models of upper gastrointestinal bleeding

During the past five years we have evaluated argon laser photocoagulation in various canine models of upper gastrointestinal hemorrhage. In gastric erosions, the eight-watt argon laser was uniformly effective in stopping bleeding. In our standard acute ulcer model the seven-watt argon laser was effective in stopping bleeding from most ulcers and only occasionally produced deep injury. With the addition of a jet of CO2 exiting the laser catheter coaxial to the laser beam, the argon laser was 100% effective and no deep injury resulted. The application of the argon laser in a more physiologic canine bleeding model using a single bleeding vessel in an ulcer base is currently under study. The development of improved animal models of gastrointestinal bleeding should contribute to the identification of effective and safe endoscopic hemostatic methods.