Short- and long-term experience in pulmonary vein segmental ostial ablation for paroxysmal atrial fibrillation*

Introduction: Segmental ostial pulmonary vein isolation (PVI) is considered a potentially curative therapeutic approach in the treatment of paroxysmal atrial fibrillation (PAF). There is only limited data available on the long-term effect of this procedure. Methods: Patients (Pts) underwent a regular clinical follow up visit at 3, 6 and 24 months after PVI. Clinical success was classified as complete (i.e. no arrhythmia recurrences, no antiarrhythmic drug), partial (i.e. no/only few recurrences, on drug) or as a failure (no benefit). The clinical responder rate (CRR) was determined by combining complete and partial success. Results: 117 patients (96 male, 21 female), aged 51±11 years (range 25 to 73) underwent a total of 166 procedures (1.4/patient) in 2-4 pulmonary veins (PV). 115 patients (98%) had AF, 2 patients presented with regular PV atrial tachycardia. ,109/115 patients. exhibited PAF as the primary arrhythmia (versus persistent AF). A total of 113 patients with PVI in the years 2001 to 2003 were evaluated for their CRR after 6 (3) months. A single intervention was carried out in 63 patients (55.8%), two interventions were performed in 45 patients (39.8%) and three interventions in 5 patients (4.4%). The clinical response demonstrated a complete success of 52% (59 patients), a partial success of 26% (29 patients) and a failure rate of 22% (25 patients), leading to a CRR of 78% (88 patients). Ostial PVI in all 4 PVs exhibited a tendency towards higher curative success rates (54% versus 44% in patients with 3 PVs ablated for the 6 month follow up). Long-term clinical outcome was evaluated in 39 patients with an ablation attempt at 3 PVs only (excluding the right inferior PV in our early experience) and a mean clinical follow up of 21±6 months. At this point in time the success rate was 41% (complete, 16 patients) and 21% (partial, 8 patients), respectively, adding up to a CRR of 62% (24 patients). In total, 20 patients (17.1%) had either a single or 2 (3 patients, 2.6%) complications independent of the number of procedures performed with PV stenosis as the leading cause (7.7%). Conclusion: The CRR of patients with medical refractory PAF in our patient cohort is 78% at the 6 month follow up. PV stenosis is the main cause for procedure-related complications. Ablation of all 4 PV exhibits a tendency towards higher complete success rates despite equal CRR. Calculation of the clinical response after a mid- to long-term follow of 21±6 months in those patients with an ostial PVI in only 3 pulmonary veins (sparing the right inferior PV) shows a further reduction to 62%, exclusively caused by a drop in patients with a former partial success. To evaluate the long-term clinical benefit of segmental ostial PVI in comparison with other ablation techniques, more extended follow up periods are mandatory, including a larger study cohort and a detailed description of procedural parameters

Critical Areas Planning In Minnesota

The Critical Areas Planning Program was established by Minnesota legislation in 1973. Its primary work is with local units of government, regional or state agencies located within areas possessing significant natural, scientific, cultural or historical resources to develop consistent plans and regulations for area use and management. Local units of government prepare the plans and regulations according to guidelines approved by the governor for each critical area\u27. with technical and financial assistance from the Environmental Quality Board (EQB). The enabling act directed the EQB to develop an inventory of potential critical areas in the state. Inventory methods were evaluated. The EQB established a large committee representing a balanced group from each region with equal composition of resource professionals, elected officials, interested citizens and others. The inventory resulted in identification of 41 potential critical areas throughout Minnesota. The 41 areas were further ranked into three general groups indicating importance or urgency for management. The EQB critical areas staff will be completing evaluation reports on each potential critical area to examine its characteristics and the potential use of the critical area program in planning and management

Stability of the shell structure in 2D quantum dots

We study the effects of external impurities on the shell structure in semiconductor quantum dots by using a fast response-function method for solving the Kohn-Sham equations. We perform statistics of the addition energies up to 20 interacting electrons. The results show that the shell structure is generally preserved even if effects of high disorder are clear. The Coulomb interaction and the variation in ground-state spins have a strong effect on the addition-energy distributions, which in the noninteracting single-electron picture correspond to level statistics showing mixtures of Poisson and Wigner forms.Comment: 7 pages, 8 figures, submitted to Phys. Rev.

Electrically detected magnetic resonance of carbon dangling bonds at the Si-face 4H-SiC/SiO2_2 interface

SiC based metal-oxide-semiconductor field-effect transistors (MOSFETs) have gained a significant importance in power electronics applications. However, electrically active defects at the SiC/SiO$_2$ interface degrade the ideal behavior of the devices. The relevant microscopic defects can be identified by electron paramagnetic resonance (EPR) or electrically detected magnetic resonance (EDMR). This helps to decide which changes to the fabrication process will likely lead to further increases of device performance and reliability. EDMR measurements have shown very similar dominant hyperfine (HF) spectra in differently processed MOSFETs although some discrepancies were observed in the measured $g$-factors. Here, the HF spectra measured of different SiC MOSFETs are compared and it is argued that the same dominant defect is present in all devices. A comparison of the data with simulated spectra of the C dangling bond (P$_\textrm{bC}$) center and the silicon vacancy (V$_\textrm{Si}$) demonstrates that the P$_\textrm{bC}$ center is a more suitable candidate to explain the observed HF spectra.Comment: Accepted for publication in the Journal of Applied Physic

Geometric and impurity effects on quantum rings in magnetic fields

We investigate the effects of impurities and changing ring geometry on the energetics of quantum rings under different magnetic field strengths. We show that as the magnetic field and/or the electron number are/is increased, both the quasiperiodic Aharonov-Bohm oscillations and various magnetic phases become insensitive to whether the ring is circular or square in shape. This is in qualitative agreement with experiments. However, we also find that the Aharonov-Bohm oscillation can be greatly phase-shifted by only a few impurities and can be completely obliterated by a high level of impurity density. In the many-electron calculations we use a recently developed fourth-order imaginary time projection algorithm that can exactly compute the density matrix of a free-electron in a uniform magnetic field.Comment: 8 pages, 7 figures, to appear in PR

In vitro interactions of Alternaria mycotoxins, an emerging class of food contaminants, with the gut microbiota: a bidirectional relationship

The human gut microbiota plays an important role in the maintenance of human health. Factors able to modify its composition might predispose the host to the development of pathologies. Among the various xenobiotics introduced through the diet, Alternaria mycotoxins are speculated to represent a threat for human health. However, limited data are currently available about the bidirectional relation between gut microbiota and Alternaria mycotoxins. In the present work, we investigated the in vitro effects of different concentrations of a complex extract of Alternaria mycotoxins (CE; containing eleven mycotoxins; e.g. 0.153 µM alternariol and 2.3 µM altersetin, at the maximum CE concentration tested) on human gut bacterial strains, as well as the ability of the latter to metabolize or adsorb these compounds. Results from the minimum inhibitory concentration assay showed the scarce ability of CE to inhibit the growth of the tested strains. However, the growth kinetics of most of the strains were negatively affected by exposure to the various CE concentrations, mainly at the highest dose (50 µg/mL). The CE was also found to antagonize the formation of biofilms, already at concentrations of 0.5 µg/mL. LC–MS/MS data analysis of the mycotoxin concentrations found in bacterial pellets and supernatants after 24 h incubation showed the ability of bacterial strains to adsorb some Alternaria mycotoxins, especially the key toxins alternariol, alternariol monomethyl ether, and altersetin. The tendency of these mycotoxins to accumulate within bacterial pellets, especially in those of Gram-negative strains, was found to be directly related to their lipophilicity

Baricitinib and tofacitinib off-target profile, with a focus on Alzheimer's disease

INTRODUCTION: Janus kinase (JAK) inhibitors were recently identified as promising drug candidates for repurposing in Alzheimer's disease (AD) due to their capacity to suppress inflammation via modulation of JAK/STAT signaling pathways. Besides interaction with primary therapeutic targets, JAK inhibitor drugs frequently interact with unintended, often unknown, biological off-targets, leading to associated effects. Nevertheless, the relevance of JAK inhibitors’ off-target interactions in the context of AD remains unclear. METHODS: Putative off-targets of baricitinib and tofacitinib were predicted using a machine learning (ML) approach. After screening scientific literature, off-targets were filtered based on their relevance to AD. Targets that had not been previously identified as off-targets of baricitinib or tofacitinib were subsequently tested using biochemical or cell-based assays. From those, active concentrations were compared to bioavailable concentrations in the brain predicted by physiologically based pharmacokinetic (PBPK) modeling. RESULTS: With the aid of ML and in vitro activity assays, we identified two enzymes previously unknown to be inhibited by baricitinib, namely casein kinase 2 subunit alpha 2 (CK2-α2) and dual leucine zipper kinase (MAP3K12), both with binding constant (Kd) values of 5.8 μM. Predicted maximum concentrations of baricitinib in brain tissue using PBPK modeling range from 1.3 to 23 nM, which is two to three orders of magnitude below the corresponding binding constant. CONCLUSION: In this study, we extended the list of baricitinib off-targets that are potentially relevant for AD progression and predicted drug distribution in the brain. The results suggest a low likelihood of successful repurposing in AD due to low brain permeability, even at the maximum recommended daily dose. While additional research is needed to evaluate the potential impact of the off-target interaction on AD, the combined approach of ML-based target prediction, in vitro confirmation, and PBPK modeling may help prioritize drugs with a high likelihood of being effectively repurposed for AD. Highlights: This study explored JAK inhibitors' off-targets in AD using a multidisciplinary approach. We combined machine learning, in vitro tests, and PBPK modelling to predict and validate new off-target interactions of tofacitinib and baricitinib in AD. Previously unknown inhibition of two enzymes (CK2-a2 and MAP3K12) by baricitinib were confirmed using in vitro experiments. Our PBPK model indicates that baricitinib low brain permeability limits AD repurposing. The proposed multidisciplinary approach optimizes drug repurposing efforts in AD research.</p

Effects of nitridation on SiC/SiO2 structures studied by hard X-ray photoelectron spectroscopy

SiC is set to enable a new era in power electronics impacting a wide range of energy technologies, from electric vehicles to renewable energy. Its physical characteristics outperform silicon in many aspects, including band gap, breakdown field, and thermal conductivity. The main challenge for further development of SiC-based power semiconductor devices is the quality of the interface between SiC and its native dielectric SiO$_2$. High temperature nitridation processes can improve the interface quality and ultimately the device performance immensely, but the underlying chemical processes are still poorly understood. Here, we present an energy-dependent hard X-ray photoelectron spectroscopy (HAXPES) study probing non-destructively SiC and SiO$_2$ and their interface in device stacks treated in varying atmospheres. We successfully combine laboratory- and synchrotron-based HAXPES to provide unique insights into the chemistry of interface defects and their passivation through nitridation processes

Mutations in FKBP10 can cause a severe form of isolated Osteogenesis imperfecta

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>FKBP10 </it>gene were first described in patients with Osteogenesis imperfecta type III. Two follow up reports found <it>FKBP10 </it>mutations to be associated with Bruck syndrome type 1, a rare disorder characterized by congenital contractures and bone fragility. This raised the question if the patients in the first report indeed had isolated Osteogenesis imperfecta or if Bruck syndrome would have been the better diagnosis.</p> <p>Methods</p> <p>The patients described here are affected by severe autosomal recessive Osteogenesis imperfecta without contractures.</p> <p>Results</p> <p>Homozygosity mapping identified <it>FKBP10 </it>as a candidate gene, and sequencing revealed a base pair exchange that causes a C-terminal premature stop codon in this gene.</p> <p>Conclusions</p> <p>Our study demonstrates that <it>FKBP10 </it>mutations not only cause Bruck syndrome or Osteogenesis imperfecta type III but can result in a severe type of isolated Osteogenesis imperfecta type IV with prenatal onset. Furthermore, it adds dentinogenesis imperfecta to the spectrum of clinical symptoms associated with <it>FKBP10 </it>mutations.</p