Quantized ionic conductance in nanopores

Ionic transport in nanopores is a fundamentally and technologically important problem in view of its occurrence in biological processes and its impact on novel DNA sequencing applications. Using microscopic calculations, here we show that ion transport may exhibit strong nonlinearities as a function of the pore radius reminiscent of the conductance quantization steps as a function of the transverse cross section of quantum point contacts. In the present case, however, conductance steps originate from the break up of the hydration layers that form around ions in aqueous solution. Once in the pore, the water molecules form wavelike structures due to multiple scattering at the surface of the pore walls and interference with the radial waves around the ion. We discuss these effects as well as the conditions under which the step-like features in the ionic conductance should be experimentally observable.Comment: 6 pages, 3 figures, updated to fix font

Risk of coronary stenosis after adjuvant radiotherapy for breast cancer

Purpose Adjuvant radiotherapy (RT) for breast cancer is associated with an increased risk of ischemic heart disease. We examined the risk of coronary artery stenosis in a large cohort of women with breast cancer receiving adjuvant RT. Methods A cohort of women diagnosed with breast cancer between 1992 and 2012 in three Swedish health care regions (n = 57,066) were linked to the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) to identify women receiving RT who subsequently underwent a percutaneous coronary intervention (PCI) due to coronary stenosis. Cox regression analyses were performed to examine risk of a coronary intervention and competing risk analyses were performed to calculate cumulative incidence. Results A total of 649 women with left-sided breast cancer and 494 women with right-sided breast cancer underwent a PCI. Women who received left-sided RT had a significantly higher risk of a PCI in the left anterior descending artery (LAD) compared to women who received right-sided RT, hazard ratio (HR) 1.44 (95% confidence interval [CI] 1.21-1.77, p < 0.001). For the proximal, mid, and distal LAD, the HRs were 1.60 (95% CI 1.22-2.10), 1.38 (95% CI 1.07-1.78), and 2.43 (95% CI 1.33-4.41), respectively. The cumulative incidence of coronary events at 25 years from breast cancer diagnosis were 7.0% in women receiving left-sided RT and 4.4% in women receiving right-sided RT. Conclusion Implementing and further developing techniques that lower cardiac doses is important in order to reduce the risk of long-term side effects of adjuvant RT for breast cancer.Peer reviewe

Transverse Electronic Transport through DNA Nucleotides with Functionalized Graphene Electrodes

Graphene nanogaps and nanopores show potential for the purpose of electrical DNA sequencing, in particular because single-base resolution appears to be readily achievable. Here, we evaluated from first principles the advantages of a nanogap setup with functionalized graphene edges. To this end, we employed density functional theory and the non-equilibrium Green's function method to investigate the transverse conductance properties of the four nucleotides occurring in DNA when located between the opposing functionalized graphene electrodes. In particular, we determined the electrical tunneling current variation as a function of the applied bias and the associated differential conductance at a voltage which appears suitable to distinguish between the four nucleotides. Intriguingly, we observe for one of the nucleotides a negative differential resistance effect.Comment: 19 pages, 7 figure

DNA nucleotide-specific modulation of \mu A transverse edge currents through a metallic graphene nanoribbon with a nanopore

We propose two-terminal devices for DNA sequencing which consist of a metallic graphene nanoribbon with zigzag edges (ZGNR) and a nanopore in its interior through which the DNA molecule is translocated. Using the nonequilibrium Green functions combined with density functional theory, we demonstrate that each of the four DNA nucleotides inserted into the nanopore, whose edge carbon atoms are passivated by either hydrogen or nitrogen, will lead to a unique change in the device conductance. Unlike other recent biosensors based on transverse electronic transport through DNA nucleotides, which utilize small (of the order of pA) tunneling current across a nanogap or a nanopore yielding a poor signal-to-noise ratio, our device concept relies on the fact that in ZGNRs local current density is peaked around the edges so that drilling a nanopore away from the edges will not diminish the conductance. Inserting a DNA nucleotide into the nanopore affects the charge density in the surrounding area, thereby modulating edge conduction currents whose magnitude is of the order of \mu A at bias voltage ~ 0.1 V. The proposed biosensor is not limited to ZGNRs and it could be realized with other nanowires supporting transverse edge currents, such as chiral GNRs or wires made of two-dimensional topological insulators.Comment: 6 pages, 6 figures, PDFLaTe

Vaccination with DNA plasmids expressing Gn coupled to C3d or alphavirus replicons expressing Gn protects mice against rift valley fever virus

Background: Rift Valley fever (RVF) is an arthropod-borne viral zoonosis. Rift Valley fever virus (RVFV) is an important biological threat with the potential to spread to new susceptible areas. In addition, it is a potential biowarfare agent. Methodology/Principal Findings: We developed two potential vaccines, DNA plasmids and alphavirus replicons, expressing the Gn glycoprotein of RVFV alone or fused to three copies of complement protein, C3d. Each vaccine was administered to mice in an all DNA, all replicon, or a DNA prime/replicon boost strategy and both the humoral and cellular responses were assessed. DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited high titer neutralizing antibodies that were similar to titers elicited by the live-attenuated MP12 virus. Mice vaccinated with an inactivated form of MP12 did elicit high titer antibodies, but these antibodies were unable to neutralize RVFV infection. However, only vaccine strategies incorporating alphavirus replicons elicited cellular responses to Gn. Both vaccines strategies completely prevented weight loss and morbidity and protected against lethal RVFV challenge. Passive transfer of antisera from vaccinated mice into naïve mice showed that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn elicited antibodies that protected mice as well as sera from mice immunized with MP12. Conclusion/Significance: These results show that both DNA plasmids expressing Gn-C3d and alphavirus replicons expressing Gn administered alone or in a DNA prime/replicon boost strategy are effective RVFV vaccines. These vaccine strategies provide safer alternatives to using live-attenuated RVFV vaccines for human use. © 2010 Bhardwaj et al

The effect of tobacco smoking and treatment strategy on the one-year mortality of patients with acute non-ST-segment elevation myocardial infarction

<p>Abstract</p> <p>Background</p> <p>The aim of the present study was to investigate whether a previously shown survival benefit resulting from routine early invasive management of unselected patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) may differ according to smoking status and age.</p> <p>Methods</p> <p>Post-hoc analysis of a prospective observational cohort study of consecutive patients admitted for NSTEMI in 2003 (conservative strategy cohort [CS]; n = 185) and 2006 (invasive strategy cohort [IS]; n = 200). A strategy for transfer to a high-volume invasive center and routine early invasive management was implemented in 2005. Patients were subdivided into current smokers and non-smokers (including ex-smokers) on admission.</p> <p>Results</p> <p>The one-year mortality rate of smokers was reduced from 37% in the CS to 6% in the IS (p < 0.001), and from 30% to 23% for non-smokers (p = 0.18). Non-smokers were considerably older than smokers (median age 80 vs. 63 years, p < 0.001). The percentage of smokers who underwent revascularization (angioplasty or coronary artery bypass grafting) within 7 days increased from 9% in the CS to 53% in the IS (p < 0.001). The corresponding numbers for non-smokers were 5% and 27% (p < 0.001). There was no interaction between strategy and age (p = 0.25), as opposed to a significant interaction between strategy and smoking status (p = 0.024). Current smoking was an independent predictor of one-year mortality (hazard ratio 2.61, 95% confidence interval 1.43-4.79, p = 0.002).</p> <p>Conclusions</p> <p>The treatment effect of an early invasive strategy in unselected patients with NSTEMI was more pronounced among smokers than non-smokers. The benefit for smokers was not entirely explained by differences in baseline confounders, such as their younger age.</p

In-stent thrombosis after 68 months of implantation inspite of continuous dual antiplatelet therapy: a case report

Lately, there has been an increased incidence of late stent thrombosis; especially following Drug eluting stent (DES) implantation. Several factors are associated with an increased risk of stent thrombosis, including the procedure itself, patient and lesion characteristics, stent design, and premature cessation of anti-platelet drugs. We present a case of late stent thrombosis (LST) following DES implantation after a period of 68 months, making it the longest reported case of LST reported in the literature, despite the use of dual anti-platelet therapy

Non Thermal Irreversible Electroporation: Novel Technology for Vascular Smooth Muscle Cells Ablation

Non thermal Irreversible electroporation (NTIRE) is a new tissue ablation method that induces selective damage only to the cell membrane while sparing all other tissue components. Our group has recently showed that NTIRE attenuated neointimal formation in rodent model. The goal of this study was to determine optimal values of NTIRE for vascular smooth muscle cell (VSMC) ablation.33 Sprague-Dawley rats were used to compare NTIRE protocols. Each animal had NTIRE applied to its left common carotid artery using a custom-made electrodes. The right carotid artery was used as control. Electric pulses of 100 microseconds were used. Eight IRE protocols were compared: 1-4) 10 pulses at a frequency of 10 Hz with electric fields of 3500, 1750, 875 and 437.5 V/cm and 5-8) 45 and 90 pulses at a frequency of 1 Hz with electric fields of 1750 and 875 V/cm. Animals were euthanized after one week. Histological analysis included VSMC counting and morphometry of 152 sections. Selective slides were stained with elastic Van Gieson and Masson trichrome to evaluate extra-cellular structures. The most efficient protocols were 10 pulses of 3500 V/cm at a frequency of 10 Hz and 90 pulses of 1750 V/cm at a frequency of 1 Hz, with ablation efficiency of 89+/-16% and 94+/-9% respectively. Extra-cellular structures were not damaged and the endothelial layer recovered completely.NTIRE is a promising, efficient and simple novel technology for VMSC ablation. It enables ablation within seconds without causing damage to extra-cellular structures, thus preserving the arterial scaffold and enabling endothelial regeneration. This study provides scientific information for future anti-restenosis experiments utilizing NTIRE

Estrogen-Eluting Stents

Coronary stenting is routinely utilized to treat symptomatic obstructive coronary artery disease. However, the efficacy of bare metal coronary stents has been historically limited by restenosis, which is primarily due to excessive neointima formation. Drug-eluting stents (DES) are composed of a stainless steel backbone encompassed by a polymer in which a variety of drugs that inhibit smooth muscle cell proliferation and excessive neointima formation are incorporated. DES have significantly reduced the incidence of restenosis but are also associated with a small (~0.5% per year) but significant risk of late stent thrombosis. In that regard, estrogen-eluting stents have also undergone clinical evaluation in reducing restenosis with the additional potential benefit of enhancing reendothelialization of the stent surface to reduce stent thrombosis. Estrogen directly promotes vasodilatation, enhances endothelial healing, and prevents smooth muscle cell migration and proliferation. Due to these mechanisms, estrogen has been postulated to reduce neointimal hyperplasia without delaying endothelial healing. In animal studies, estrogen treatment was effective in decreasing neointimal hyperplasia after both balloon angioplasty and stenting regardless of the method of drug delivery. The first uncontrolled human study using estrogen-coated stents demonstrated acceptable efficacy in reducing late lumen loss. However, subsequent randomized clinical trials did not show superiority of estrogen-eluting stents over bare metal stents or DES. Further studies are required to determine optimal dose and method of estrogen delivery with coronary stenting and whether this approach will be a viable alternative to the current DES armamentarium