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.     

Framework for interactive million-neuron simulation.

SUMMARY: Large simulations have become increasingly complex in many fields, tending to incorporate scale-dependent modeling and algorithms and wide-ranging physical influences. This scale of simulation sophistication has not yet been matched in neuroscience. The authors describe a framework aimed at enabling natural interaction with complex simulations: their configuration, initial conditions, monitoring, and analysis. The architecture is built on three cornerstone components: active probes, adaptive data capture, and visual interface. The resulting synthesis will enable interactive exploration of live simulations running on supercomputing platforms.     

EEG source imaging: correlating source locations and extents with electrocorticography and surgical resections in epilepsy patients.

SUMMARY: It is desirable to estimate epileptogenic zones with both location and extent information from noninvasive EEG. In the present study, the authors use a subspace source localization method (FINE), combined with a local thresholding technique, to achieve such tasks. The performance of this method was evaluated in interictal spikes from three pediatric patients with medically intractable partial epilepsy. The thresholded subspace correlation, which is obtained from FINE scanning, is a favorable marker, which implies the extents of current sources associated with epileptic activities. The findings were validated by comparing the results with invasive electrocorticographic (ECoG) recordings of interictal spike activity. The surgical resections in these three patients correlated well with the epileptogenic zones identified from both EEG sources and ECoG potential distributions. The value of the proposed noninvasive technique for estimating epileptiform activity was supported by satisfactory surgery outcomes.     

The role of mast cells and histamine in leukocyte-endothelium interactions in four rat strains

 The objective of the present study was to determine the role of mast cells and histamine in leukocyte-endothelium interactions in mesenteric venules of four rat strains: Brown Norway, Lewis, Sprague-Dawley and Wistar. Intravital microscopy showed that the mast cell stabilizer cromoglycate (5 mg/kg i.v. just before exteriorization of the mesentery) did not affect the baseline level and velocity of leukocyte rolling in any of the four strains. This finding is in agreement with the observation that cromoglycate pretreatment only slightly influenced mast cell degranulation in all strains except the Brown Norway. After mast cell stabilization, only in Sprague-Dawley did topical administration of histamine (10^–4 M) result in a significant increase in the level of leukocyte rolling and a decrease in the rolling velocity compared with the time control. Histamine induced leukocyte adhesion only in the Brown Norway strain. In conclusion, the hypothesis presented in other studies, that degranulation of mast cells, and more specifically the release of histamine, is of major importance for the induction of leukocyte-endothelium interactions in rat mesenteric venules is not generally applicable; the present study shows a clear strain dependency. Received: 18 July 1997 / Received after revision: 17 November 1997 / Accepted: 13 March 1998     

The value of ventilation scintigraphy after single lung transplantation.

BACKGROUND: A decrease in forced expiratory volume in 1 second (FEV(1)) as a diagnostic criterion for bronchiolitis obliterans syndrome (BOS) after single lung transplantation may be influenced significantly by the presence of the native lung. To quantify and to discriminate between the relative contribution of graft and native lung to the FEV(1), we retrospectively investigated the diagnostic value of combined FEV(1) measurements and ventilation scintigraphy in pulmonary dysfunction after single lung transplantation in 11 recipients with pulmonary vascular disease, 3 with obstructive lung disease, and 3 with restrictive lung disease. METHODS: We assessed function of the native lung and the graft, and subsequently calculated an adjusted grading of BOS by correcting routine FEV(1) measurements using linear interpolation of bi-annual lung ventilation scans. RESULTS: The contribution of the native lung to the total FEV(1) was slight (median, 9%) in recipients with obstructive disease compared with recipients with vascular (38%) or restrictive lung diseases (27%). Adjusted BOS grading was not useful in patients with obstructive disease. In the other patient groups, the onset of adjusted BOS Grade 1 and standard BOS Grade 1 was at a median of 220 days (range, 127-1146 days) and 836 days (184-3065 days), respectively. CONCLUSION: Ventilation scintigraphy is a useful adjunct in the (early) diagnosis of BOS in recipients of single lung transplants who have vascular and restrictive lung diseases.     

The reversal of cisplatin-protein interactions by the modulating agent WR2721 and its metabolites WR1065 and WR33278

Summary The reversibility of cisplatin-protein interactions by the modulating agent WR2721, its active thiol-metabolite WR1065, and the symmetrical disulfide WR33278 was studied using the model compounds (Pt(diethylenetriammine) monofunctionally bound to the sulfur in glutathione (Pt(dien)SG) and Pt(diethylenetriammine) monofunctionally bound to the sulfur in S-methylglutathione (Pt(dien)SMeG). Both model compounds could be quantified by high-performance liquid chromatography (HPLC) with UV detection. The Pt-cysteine-like bond in Pt(dien)SG could not be reversed by any of the WR compounds or by the strong nucleophiles thiosulfate (TS) and diethyldithiocarbamate (DDTC). However, the Ptmethionine-like bond in Pt(dien)SMeG could be reversed by WR1065, although the reversal was slow (k₂=0.142m ^–1 s^–1) as compared with that obtained using the modulating agents TS (k₂=10.1m ^–1 s^–1) and DDTC (k₂=3.66m ^–1 s^–1). WR2721 was hardly able to reverse the Pt-S bond in Pt(dien)SMeG (k₂=0.00529m ^–1 s^–1), and WR33278 showed no capacity to do so. The activity ofcis-diamminedichloroplatinum(II) (CDDP)-inactivated fumarase was not appreciably restored by any of the WR compounds (16%, 7.7%, and 0 for 20mm WR1065, WR2721, and WR33278, respectively) in contrast to the strong nucleophile DDTC (61% for 2mm DDTC). These in vitro studies provide information at the molecular level that may explain why WR2721, in contrast to DDTC, does not provide protection against cisplatin-induced nephrotoxicity when it is given after platinum-containing chemotherapy. The results support the present clinical use of WR2721 prior to the administration of platinum compounds.This study was financially supported by the Netherlands Cancer Fund (grant IKA 87-12) and by US Bioscience