Multicenter study of the safety and effectiveness of intracranial aneurysm treatment with the p64MW-HPC flow modulation device.

BACKGROUND AND PURPOSE: The new p64 flow diverter with hydrophilic polymer coating (HPC) was designed to reduce thrombogenicity. To date, it is unclear how antithrombogenic surface modifications affect neoendothelialization and thrombus formation in patients with unruptured intracranial aneurysms. The purpose of this study was to evaluate the safety and effectiveness of the p64MW-HPC in the treatment of unruptured aneurysms of small to giant size and of both the anterior and posterior circulation. MATERIALS AND METHODS: Between March 2020 and October 2022 all patients with unruptured intracranial aneurysms treated with the p64MW-HPC were included at five neurovascular centers. Demographic data, aneurysm characteristics, antiplatelet therapy, procedural complications, and clinical and angiographic outcomes were recorded. RESULTS: A total of 100 patients with 100 unruptured intracranial aneurysms met the inclusion criteria. Eighty-three aneurysms were classified as saccular, 12 aneurysms were fusiform, 4 aneurysms dissecting, and 1 aneurysm was blister-like. Dual antiplatelet therapy with Clopidogrel and Aspirin was given in 68 cases, and with Ticagrelor and Aspirin in 24 cases. Technical issues with deployment were encountered in 14 cases (torsion (n = 3), foreshortening (n = 8), and incomplete opening (n = 3)). Ischemic stroke occurred in a total of seven cases. In one patient a wire perforation and subsequent severe ICH occurred. Complete aneurysm occlusion at angiographic follow-up (mean time = 7 months) was seen in 73% and adequate occlusion in 93%. CONCLUSION: This study is the largest multicenter study to date documenting the safety and effectiveness of the new antithrombogenic p64MW-HPC in the treatment of unruptured intracranial aneurysms of the anterior and posterior circulation.

Ultrafast energy transfer and structural dynamics in DNA.

Ultrafast structural dynamics concomitant to excitation energy transfer in DNA has been studied using a pair of pyrene-labeled DNA bases. The temporal evolution of the femtosecond pump-probe spectra reveals the existence of two electronic coupling pathways, through-base stack and through-space, which lead to excitation energy transfer and excimer formation even when the labeled DNA bases are separated by one AT base pair. The electronic coupling which mediates through-base stack energy transfer is so strong that a new absorption band arises in the excited-state absorption spectrum within 300 fs. From the analysis of time-dependent spectral shifts due to through-space excimer formation, the local structural dynamics and flexibility of DNA are characterized on the picosecond and nanosecond time scale.

Thalidomide impairment of trinitrobenzene sulphonic acid-induced colitis in the rat - role of endothelial cell-leukocyte interaction.

1. Immune response-modulating drugs such as thalidomide may be of therapeutic value in the treatment of chronic inflammatory bowel diseases including Crohn's disease (CD). In the present study, we have investigated whether thalidomide exerts this effect by impairing endothelial cell-leukocyte interaction through down-regulation of the expression of pro-inflammatory gene products in these cells. 2. Transient CD-like colitis was induced in male Wistar rats by single enema with trinitrobenzene sulphonic acid (TNBS) in ethanol followed by macroscopic scoring, histology, intravital microscopy, RT - PCR and immunohistochemistry (IHC) analyses. Thalidomide or its analogue supidimide were administered in olive oil by intragastric instillation 6 h prior to the induction of colitis and then daily for one week. 3. Both thalidomide and supidimide (200 mg kg(-1) d(-1)) significantly attenuated TNBS-induced colitis as compared to vehicle-treated control animals (44 and 37% inhibition, respectively), and this effect persisted for 7 days post cessation of thalidomide treatment (46% inhibition). 4. Moreover, thalidomide significantly reduced leukocyte sticking to postcapillary venular endothelial cells in the submucosa (by 45%), improved functional capillary density and perfusion, and attenuated endothelial interleukin-8 expression, as judged by IHC analysis. According to RT - PCR analysis, both thalidomide and supidimide also significantly reduced vascular cell adhesion molecule-1 mRNA expression in the affected part of the descending colon. 5. These findings suggest that thalidomide and one of its derivatives impairs CD-like TNBS-induced colitis in the rat by down-regulating endothelial adhesion molecule and chemokine expression and, as a consequence, the interaction of these cells with circulating leukocytes.

Femtosecond direct observation of charge transfer between bases in DNA.

Charge transfer in supramolecular assemblies of DNA is unique because of the notion that the pi-stacked bases within the duplex may mediate the transport, possibly leading to damage and/or repair. The phenomenon of transport through pi-stacked arrays over a long distance has an analogy to conduction in molecular electronics, but the mechanism still needs to be determined. To decipher the elementary steps and the mechanism, one has to directly measure the dynamics in real time and in suitably designed, structurally well characterized DNA assemblies. Here, we report our first observation of the femtosecond dynamics of charge transport processes occurring between bases within duplex DNA. By monitoring the population of an initially excited 2-aminopurine, an isomer of adenine, we can follow the charge transfer process and measure its rate. We then study the effect of different bases next to the donor (acceptor), the base sequence, and the distance dependence between the donor and acceptor. We find that the charge injection to a nearest neighbor base is crucial and the time scale is vastly different: 10 ps for guanine and up to 512 ps for inosine. Depending on the base sequence the transfer can be slowed down or inhibited, and the distance dependence is dramatic over the range of 14 A. These observations provide the time scale, and the range and efficiency of the transfer. The results suggest the invalidity of an efficient wire-type behavior and indicate that long-range transport is a slow process of a different mechanism.

Femtosecond dynamics of DNA-mediated electron transfer.

Diverse biophysical and biochemical studies have sought to understand electron transfer (ET) in DNA in part because of its importance to DNA damage and its repair. However, the dynamics and mechanisms of the elementary processes of ET in this medium are not fully understood and have been heavily debated. Two fundamental issues are the distance over which charge is transported and the time-scale on which the transport through the pi-stack of the DNA base pairs may occur. With femtosecond resolution, we report direct observation in DNA of ultrafast ET, initiated by excitation of tethered ethidium (E), the intercalated electron acceptor (A); the electron donor (D) is 7-deazaguanine (Z), a modified base, placed at different, fixed distances from A. The ultrafast ET between these reactants in DNA has been observed with time constants of 5 ps and 75 ps and was found to be essentially independent of the D-A separation (10-17 A). However, the ET efficiency does depend on the D-A distance. The 5-ps decay corresponds to direct ET observed from 7-deazaguanine but not guanine to E. From measurements of orientation anisotropies, we conclude that the slower 75-ps process requires the reorientation of E before ET, similar to E/nucleotide complexes in water. These results reveal the nature of ultrafast ET and its mechanism: in DNA, ET cannot be described as in proteins simply by a phenomenological parameter, beta. Instead, the involvement of the base pairs controls the time scale and the degree of coherent transport.

Femtosecond dynamics of the DNA intercalator ethidium and electron transfer with mononucleotides in water.

Ethidium (E) is a powerful probe of DNA dynamics and DNA-mediated electron transfer (ET). Molecular dynamical processes, such as solvation and orientation, are important on the time scale of ET. Here, we report studies of the femtosecond and picosecond time-resolved dynamics of E, E with 2'deoxyguanosine triphosphate (GTP) in water, and E with 7-deaza-2'-deoxyguanosine triphosphate (ZTP) in water; E undergoes ET with ZTP but not GTP. These studies elucidate the critical role of relative orientational motions of the donor-acceptor complex on ET processes in solution. For ET from ZTP to E, such motions are in fact the rate-determining step. Our results indicate that these complexes reorient before ET. The time scale for the solvation of E in water is 1 ps, and the orientational relaxation time of E is 70 ps. The impact of orientational and solvation effects on ET between E and mononucleotides must be considered in the application of E as a probe of DNA ET.