Intravenous fate of poly(2-(dimethylamino)ethyl methacrylate)-based polyplexes

The objective of this study was to assess the in vivo fate of poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA)-based polyplexes after intravenous administration into mice. Circulation kinetics and tissue distribution in terms of plasmid localization and transfection efficiency were assessed. To gain more insight into the observed biodistribution and gene expression profile, the interaction of pDMAEMA-based polyplexes with blood components (erythrocytes and albumin) was investigated in vitro. In the case of i.v. injection of positively charged polyplexes at a dose of 30 microg DNA most of the radioactivity was found in the lungs and the liver 60 min after injection. In the case of pDMAEMA/DNA polyplexes with a negative charge, uptake occurred mainly by the liver. Administration of positively charged complexes at a 30 microg DNA dose resulted in reporter gene expression primarily in the lungs. Injection of negatively charged complexes and naked plasmid did not result in luciferase expression in any of the organs examined. In vitro turbidity experiments showed the induction of a charge dependent aggregation process upon addition of albumin to the polyplexes pointing out to the involvement of aggregate formation in the dominant lung uptake of the positively charged polyplexes. Also, incubations of polyplexes after pre-incubation with a physiological concentration of albumin with washed erythrocytes confirmed that polyplexes induce the formation of extremely large structures. This paper underlines the need for the design of systems with reduced interaction with blood components to promote the delivery of DNA to target tissues outside the lungs.     

The relevance of therapeutic drug monitoring in plasma and erythrocytes in anti-cancer drug treatment.

Therapeutic drug monitoring generally focuses on the plasma compartment only. Differentiation between the total plasma concentration and the free fraction (plasma water) has been described for a number of limited drugs. Besides the plasma compartment, blood has also a cellular fraction which has by far the largest theoretical surface and volume for drug transport. It is with anti-cancer drugs that major progress has been made in the study of partition between the largest cellular blood compartment, i.e., erythrocytes, and the plasma compartment. The aim of the present review is to detail the progress made in predicting what a drug does in the body, i.e., pharmacodynamics including toxicity and plasma and/or red blood cell concentration monitoring. Furthermore, techniques generally used in anti-cancer drug monitoring are highlighted. Data for complex Bayesian statistical approaches and population kinetics studies are beyond the scope of this review, since this is generally limited to the plasma compartment only.     

Holographic interferometry forIn Vitro investigation of bioprosthetic valves

Dysfunction of heart valve prostheses—mechanical as well as biological—is a common problem in cardiac surgery. The reasons for the valve failures are still not well understood. Biological valves especially have an unsatisfactory durability; degeneration and calcification very often lead to the failure of the valves. In our opinion, hidden defects present in the valve material prior to implantation of the valves is a plausible explanation for the dysfunction. Hitherto there has been no technique to detect these defects without destructing the specimen. Holographic interferometry proved to be applicable forin vitro evaluation of mechanical heart valve prostheses. In the present paper we describe application of this method to biological valves. Nine porcine bioprostheses and four fresh porcine aortic valves were investigated by means of holographic interferometry. In eight of nine bioprostheses, the results showed irregularities of the leaflet structure which depend on anomalies of the connective tissue of the leaflets of the valves. To make sure that these findings are not due to normal variations of the morphology, the investigations were carried out with fresh and unfixated porcine aortic valves. In the latter, no such anomalies of the structure were detected. The results obtained confirm the above hypothesis on the origin of the later valve dysfunction. Thus, holographic interferometry tests of bioprostheses prior to their implantation prevent the use of potentially dysfunctional valves.Presented at the 35th World Congress, International College of Angiology, Copenhagen, Denmark, July 1993     

Coronary heart disease -- significance of coronary intervention]

Coronary revascularization using percutaneous coronary intervention (PCI) has rapidly developed in the past 2 decades and its technical and pharmaceutical improvements may avoid bypass surgery in many situations. The use of drug-eluting stents (DES) challenges the classic indications for bypass surgery and shifts them toward PCI, with the need for a critical appreciation of procedure- and patient-related risks. Furthermore, invasive measures such as intravascular ultrasound or pressure wire allow lesion-specific and immediate therapeutic decisions. This overview summarizes the actual potential of coronary intervention. To be aware of potentials and limitations may help the non-interventionalist to advise his patient and to choose the appropriate treatment.     

Multicultural Health Care in Practice

This study presents a first assessment of the challenges faced by Dutch health care providers dealing with the increasing cultural diversity in Dutch society. Qualitative interviews with 24 Dutch caregivers and policy-makers point to a number of important difficulties encountered when confronted with the growing diversity of patient populations. The study focuses explicitly on the challenges health care providers perceive in their direct interactions with patients. On the basis of the observations of the 24 respondents five strategies were formulated to improve the delivery of care in a multicultural environment. Their findings were further evaluated by confronting the empirical data with care-ethical notions (attentiveness, responsibility, competence, and responsiveness) and intercultural communication-theory.     

Korrektureingriffe am Fuß nach posttraumatischen ischämischen Kontrakturen

Operationsprinzip Korrektur eines Pes equinus adductus durch keilf?rmige Resektion des Chopart-Gelenkes mit Keilbasis dorsolateral. Bei gleichzeitigem Pes varus keilf?rmige Resektion des subtalaren Gelenkes mit Keilbasis lateral (Lange 1962 [7], Myerson et al. 1986 [8], Witt et al. 1985 [13]) (Abbildungen 1a bis 1f). Bei gleichzeitigem Tarsaltunnelsyndrom Dekompression des Nervus tibialis durch Spaltung des Retinaculum musculi flexorum. Zur Korrektur von Krallenzehen Resektion der jeweiligen distalen Grundphalangen nach Hohmann; bei flektierten Endgelenken Resektion der distalen Mittelphalangen. (Auf diese Techniken wird hier nicht eingegangen).      

Quantitative thallium-201 scintigraphy after dipyridamole infusion combined with low level exercise in healthy volunteers

To establish test specific normal limits for quantitative analysis of uptake and washout of ²⁰¹Tl after dipyridamole infusion combined with low level exercise, 20 healthy volunteers were studied with low likelihood of coronary artery disease (CAD) assessed by a stepwise probability analysis based on age, sex, symptoms, resting electrocardiogram, and exercise electrocardiography. Likelihood of CAD in these volunteers was calculated as 1%. After dipyridamole infusion combined with low level exercise, one volunteer complained of headache; no other side effects were observed. There were no chest pain complaints. Maximal hemodynamic changes were achieved during the 6th and 7th min of the test. No ST segment depression was recorded. Visual analysis of the ²⁰¹Tl scintigrams was normal in all volunteers. Mean regional washout at 4 h was 44.37%±2.11%. The regional washout in the 70° LAO view (46.65%±1.10%) was significantly higher than in the anterior and 30° LAO views (43.44%±1.50% and 43.02%±1.45%, respectively). Profiles of uptake and washout of ²⁰¹Tl were different after dipyridamole infusion combined with low level exercise as compared to maximal exercise. Thus, in quantitative analysis of ²⁰¹Tl scintigraphy after dipyridamole infusion in conjunction with low level exercise as applied in the present study, it is mandatory to use normal limits of uptake and washout of ²⁰¹Tl derived from healthy volunteers who underwent the same combined protocol.