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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.  相似文献   
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OBJECTIVE: The aim of the study was to describe the occurrence of spontaneous version in twins in the third trimester, as well as the correlation between antepartum and birth presentation. METHODS: Twin pregnancies were divided into four gestational age intervals: 20-23; 24-27; 28-31; and 32-36 weeks. Fetal presentation was categorized as cephalic (C) or non-cephalic (NC). Hospital records were reviewed to determine demographic factors, including mode of conception. Chi-square was used to compare distributions of presentations, and Cramer's V measure of association was used to correlate presentations in individual pregnancies between antepartum intervals and birth. RESULTS: A total of 207 pregnancies were included. The distribution of fetal presentations changed significantly through gestational age intervals (p < 0.001), although they were similar between 32-36 weeks and birth (p = 0.75). Correlation between antepartum and birth presentation in individual pregnancies strengthened throughout the four intervals. No correlation was seen between parity, gender, birthweight, or in vitro fertilization and fetal presentation or rate of spontaneous version.CONCLUSION: Many twins undergo spontaneous version in the third trimester, though there is excellent correlation between presentation at 32-36 weeks and birth. A cephalic presenting twin at > or = 28 weeks is highly likely to be in cephalic presentation at delivery.  相似文献   
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Pesticide regulation is examined in the context of Health Canada’s Pest Management Regulatory Agency’s assessment of the chlorophenoxy herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) for turf. 2,4-D is the most common herbicide used to kill weeds in grass.The medical literature does not uniformly indicate harms from herbicides. However, the balance of epidemiological research suggests that 2,4-D can be persuasively linked to cancers, neurological impairment and reproductive problems. These may arise from 2,4-D itself, from breakdown products or dioxin contamination, or from a combination of chemicals.Regulators rely largely on toxicology, but experiments may not replicate exposures from 2,4-D application to lawns because environmental breakdown products (eg, 2,4-dichlorophenol) may not accumulate and selected herbicides are possibly less contaminated. Dioxins are bioaccumulative chemicals that may cause cancer, harm neurological development, impair reproduction, disrupt the endocrine system and alter immune function. No dioxin analyses were submitted to the Pest Management Regulatory Agency, and the principal contaminants of 2,4-D are not among the 17 congeners covered in pesticide regulation. Independent assessment of all dioxins is needed, in tissues and in the environment.The 2,4-D assessment does not approach standards for ethics, rigour or transparency in medical research. Canada needs a stronger regulator for pesticides. Potentially toxic chemicals should not be registered when more benign solutions exist, risks are not clearly quantifiable or potential risks outweigh benefits. Until landscaping pesticides are curtailed nationally, local bylaws and Quebec’s Pesticide Code are prudent measures to protect public health. Physicians have a role in public education regarding pesticides.  相似文献   
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We thank Coceani and L'Abbate for their comments on our paper.We concur that ‘pathophysiology cannot be inferred fromcoronary lumenography alone’, and this was one of thekey motivations in conducting the present study.  相似文献   
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