Effect of heart rate and preload on index of myocardial performance in the normal and abnormal left ventricle.

BACKGROUND: The index of myocardial performance (IMP) has been used as a prognostic systolic-diastolic index for patients with dilated cardiomyopathy and postmyocardial infarction. To date, systematic evaluation of the effect of heart rate and preload alteration on IMP has not been performed with normal or reduced left ventricular (LV) function. METHODS: We studied 14 mongrel dogs at baseline, after the induction of acute ischemic LV dysfunction, and with chronic LV dysfunction. Heart rate was altered by atrial pacing 10 and 20 beats above baseline, and volume loading was accomplished with 10 mL/kg of saline at a paced rate. Hemodynamics, and transmitral and transaortic pulsed Doppler, were obtained. RESULTS: With normal LV function, there were no changes in IMP with pacing. With acute LV dysfunction, IMP was also unchanged with pacing, although both LV ejection time (ET) (192 +/- 23 vs 208 +/- 25 milliseconds, P < .05) and isovolumic contraction time (58 +/- 25 vs 72 +/- 31 milliseconds, P < .05) declined. With chronic LV dysfunction, IMP was unchanged although LV ET declined (188 +/- 15 vs 204 +/- 18 milliseconds, P < .01). Volume loading did not alter the IMP with normal LV function although LV ET increased (208 +/- 25 vs 220 +/- 20 milliseconds, P < .001). With acute LV dysfunction, IMP decreased (0.66 +/- 0.11 vs 0.82 +/- 0.20, P < .05) because of a decrease in isovolumic relaxation time (63 +/- 33 vs 76 +/- 38 milliseconds, P < .05). With chronic LV dysfunction, IMP also declined with volume loading (0.59 +/- 0.29 vs 0.73 +/- 0.28, P < .01) because of an increase in LV ET (224 +/- 30 vs 198 +/- 22 milliseconds, P < .0001). CONCLUSION: Heart rate incrementation does not change IMP. However, volume loading reduces IMP primarily as a result of LV ET lengthening with chronic LV dysfunction. Further systematic evaluation of IMP is needed if this index is to be useful as a prognostic indicator.     

Preferential liver gene expression with polypropylenimine dendrimers.

Previously, the lower generation (DAB 8-generation 2 and DAB 16-generation 3) polypropylenimine dendrimers have been shown to be effective gene delivery systems in vitro. In the current work, we sought to: (a) test the effect of the strength of the carrier, DNA electrostatic interaction on gene transfer and (b) to study the in vivo gene transfer activity of these low molecular weight (<1687 Da) non-amphiphilic plain and quaternary ammonium gene carriers. Towards this aim, methyl quaternary ammonium derivatives of DAB 4 (generation 1), DAB 8, DAB 16 and DAB 32 (generation 4) were synthesised to give Q4, Q8, Q16 and Q32, respectively. Quaternisation of DAB 8 proved to be critical in improving DNA binding, as evidenced by data from the ethidium bromide exclusion assay and dendrimer-DNA colloidal stability data. This improved colloidal stability had a major effect on vector tolerability, as Q8-DNA formulations were well tolerated on intravenous injection while a similar DAB 8-DNA dose was lethally toxic by the same route. Quaternisation also improved the in vitro cell biocompatibility of DAB 16-DNA and DAB 32-DNA dendrimer complexes by about 4-fold but not that of the lower generation DAB 4-DNA and DAB 8-DNA formulations. In contrast to previous reports with non-viral gene delivery systems, the intravenous administration of DAB 16-DNA and Q8-DNA formulations resulted in liver targeted gene expression as opposed to the lung targeted gene expression obtained with the control polymer-Exgen 500 [linear poly(ethylenimine)] and a lung avoidance hypothesis is postulated. We conclude that the polypropylenimine dendrimers are promising gene delivery systems which may be used to target the liver and avoid the lung and also that molecular modifications conferring colloidal stability on gene delivery formulations have a profound effect on their tolerability on intravenous administration.     

The influence of protein solubilisation, conformation and size on the burst release from poly(lactide-co-glycolide) microspheres.

Encapsulation of proteins in poly(lactide-co-glycolide) microspheres via emulsion is known to cause insoluble protein aggregates. Following protein emulsification and encapsulation in PLGA microspheres, we used circular dichroism to show that the recoverable soluble protein fraction also suffers subtle conformational changes. For a panel of proteins selected on the basis of molecular size and structural class, conformational stability measured by chemical denaturation was not indicative of stability during emulsion-encapsulation. Partial loss of structure was observed for alpha-helical proteins released from freeze-dried microspheres in aqueous buffer, with dramatic loss of structure for a beta-sandwich protein. The addition of sucrose (a lyoprotectant) did not prevent the loss of protein conformation upon encapsulation. Therefore, the conformational changes seen for the released soluble protein fraction originates during emulsification rather than microsphere freeze-drying. Analysis of the burst release for all proteins in buffer containing denaturant or surfactant showed that the degree of protein solubilisation was the dominant factor in determining the initial rate and extent of release. Our data for protein release into increasing concentrations of denaturing buffer suggest that the emulsion-denatured protein fraction remains insoluble; this fraction may represent the protein loss encountered upon comparison of protein encapsulated versus protein released.     

Histological changes over time around the site of sustained release naltrexone-poly(DL-lactide) implants in humans.

In order to assess the histological tissue changes over time around the site of implant, tissue biopsies were taken at 1 to 38 months post-implant from 54 (34 male) consenting human subjects who had received the Australian subcutaneous naltrexone-poly(DL-lactide) implant for heroin dependence. The implant consists of multiple tablets containing compressed naltrexone-poly[trans-3,6-dimethyl-1,4-dioxane-2,5-dione] (DL-lactide) loaded microspheres. Assessment of tissue samples by pathologists showed an early phase (up to 12 months post-implant) of inflammation, foreign body reaction, and fibrosis. This subsided gradually over the next 12 months until tissue returned to normal by 25+ months. Sufficient evidence was not available to conclude that the poly(DL-lactide) implant matrix was totally biodegradable within the study period. While implant material was not identified in most of the latter biopsies, its presence was noted in one biopsy at 26 months post-implant. Nevertheless the study results did demonstrate the implant's biocompatibility by the lack of inflammation, foreign body reaction, and fibrosis detected by 25+ months. It seems highly probable that surgical technique rather than the implant itself was associated with the additional finding of fat necrosis. Moderate fat necrosis was observed as a common feature of biopsies carried out during the first 6 months following implant. It subsided to mild levels over the next 18 months, and was notably absent by 25+ months. The results of the study indicated that the Australian naltrexone-poly(DL-lactide) implant is well tolerated and may have a role for use in the management of medical conditions such as heroin dependence.