D-branes in overcritical electric fields

We collect some arguments for treating a D-brane with overcritical electric field as a well-posed initial condition for a D-brane decay. Within the field theoretical toy model of Minahan and Zwiebach we give an estimate for the condensates of the related infinite tower of tachyonic excitations.Comment: 11 pages, 2 figures; references and comments added, version to appear in PR

Methodologic European External Quality Assurance for DNA Sequencing: The EQUALseq Program

Abstract Background: DNA sequencing is a key technique in molecular diagnostics, but to date no comprehensive methodologic external quality assessment (EQA) programs have been instituted. Between 2003 and 2005, the European Union funded, as specific support actions, the EQUAL initiative to develop methodologic EQA schemes for genotyping (EQUALqual), quantitative PCR (EQUALquant), and sequencing (EQUALseq). Here we report on the results of the EQUALseq program. Methods: The participating laboratories received a 4-sample set comprising 2 DNA plasmids, a PCR product, and a finished sequencing reaction to be analyzed. Data and information from detailed questionnaires were uploaded online and evaluated by use of a scoring system for technical skills and proficiency of data interpretation. Results: Sixty laboratories from 21 European countries registered, and 43 participants (72%) returned data and samples. Capillary electrophoresis was the predominant platform (n = 39; 91%). The median contiguous correct sequence stretch was 527 nucleotides with considerable variation in quality of both primary data and data evaluation. The association between laboratory performance and the number of sequencing assays/year was statistically significant (P <0.05). Interestingly, more than 30% of participants neither added comments to their data nor made efforts to identify the gene sequences or mutational positions. Conclusions: Considerable variations exist even in a highly standardized methodology such as DNA sequencing. Methodologic EQAs are appropriate tools to uncover strengths and weaknesses in both technique and proficiency, and our results emphasize the need for mandatory EQAs. The results of EQUALseq should help improve the overall quality of molecular genetics findings obtained by DNA sequencing

VARDA (VARved sediments DAtabase) – providing and connecting proxy data from annually laminated lake sediments

Varved lake sediments provide long climatic records with high temporal resolution and low associated age uncertainty. Robust and detailed comparison of well-dated and annually laminated sediment records is crucial for reconstructing abrupt and regionally time-transgressive changes as well as validation of spatial and temporal trajectories of past climatic changes. The VARved sediments DAtabase (VARDA) presented here is the first data compilation for varve chronologies and associated palaeoclimatic proxy records. The current version 1.0 allows detailed comparison of published varve records from 95 lakes. VARDA is freely accessible and was created to assess outputs from climate models with high-resolution terrestrial palaeoclimatic proxies. VARDA additionally provides a technical environment that enables to explore the database of varved lake sediments using a connected data-model and can generate a state-of-the-art graphic representation of multi-site comparison. This allows to reassess existing chronologies and tephra events to synchronize and compare even distant varved lake records. Furthermore, the present version of VARDA permits to explore varve thickness data. In this paper, we report in detail on the data mining and compilation strategies for the identification of varved lakes and assimilation of high-resolution chronologies as well as the technical infrastructure of the database. Additional paleoclimate proxy data will be provided in forthcoming updates. The VARDA graph-database and user interface can be accessed online at https://varve.gfz-potsdam.de, all datasets of version 1.0 are available at http://doi.org/10.5880/GFZ.4.3.2019.003 (Ramisch et al., 2019)

Brain Exposure to Piperacillin in Acute Hemorrhagic Stroke Patients Assessed by Cerebral Microdialysis and Population Pharmacokinetics

Background The broad antibacterial spectrum of piperacillin/tazobactam makes the combination suitable for the treatment of nosocomial bacterial central nervous system (CNS) infections. As limited data are available regarding piperacillin CNS exposure in patients without or with low-grade inflammation, a clinical study was conducted (1) to quantify CNS exposure of piperacillin by cerebral microdialysis and (2) to evaluate different dosing regimens in order to improve probability of target attainment (PTA) in brain. Methods Ten acute hemorrhagic stroke patients (subarachnoid hemorrhage, n = 6; intracerebral hemorrhage, n = 4) undergoing multimodality neuromonitoring received 4 g piperacillin/0.5 g tazobactam every 8 h by 30-min infusions for the management of healthcare-associated pneumonia. Cerebral microdialysis was performed as part of the clinical neuromonitoring routine, and brain interstitial fluid samples were retrospectively analyzed for piperacillin concentrations after the first and after multiple doses for at least 5 days and quantified by high-performance liquid chromatography. Population pharmacokinetic modeling and Monte Carlo simulations with various doses and types of infusions were performed to predict exposure. A T->MIC of 50% was selected as pharmacokinetic/pharmacodynamic target parameter. Results Median peak concentrations of unbound piperacillin in brain interstitial space fluid were 1.16 (range 0.08-3.59) and 2.78 (range 0.47-7.53) mg/L after the first dose and multiple doses, respectively. A one-compartment model with a transit compartment and a lag time (for the first dose) between systemic and brain exposure was appropriate to describe the brain concentrations. Bootstrap median estimates of the parameters were: transfer rate from plasma to brain (0.32 h(-1)), transfer rate from brain to plasma (7.31 h(-1)), and lag time [2.70 h (coefficient of variation 19.7%)]. The simulations suggested that PTA would exceed 90% for minimum inhibitory concentrations (MICs) up to 0.5 mg/L and 1 mg/L at a dose of 12-16 and 24 g/day, respectively, regardless of type of infusion. For higher MICs, PTA dropped significantly. Conclusion Limited CNS exposure of piperacillin might be an obstacle in treating patients without general meningeal inflammation except for infections with highly susceptible pathogens. Brain exposure of piperacillin did not improve significantly with a prolongation of infusions

Mythical numbers and the proceeds of organised crime: estimating mafia proceeds in Italy

Organised crime is a field vulnerable to mythical numbers, i.e. exaggerated estimates lacking empirical support, but acquiring acceptance through repetition. The figures on mafia proceeds in Italy are a striking example of this problem. This study proposes an estimation of mafia proceeds in Italy from nine criminal activities (sexual exploitation of women, illicit firearms trafficking, drug trafficking, counterfeiting, the illicit cigarette trade, illicit gambling, illicit waste disposal, loan sharking, and extortion racketeering) by region and type of mafia (Cosa Nostra, Camorra,\u2018Ndrangheta, Apulian mafias, and other mafias). The results estimate yearly mafia proceeds at approximately \u20ac10.7 bn (0.7% of the Italian GDP), discussing the impact on the regional and national economies and the differences among the types of mafias as to their geographical sources of revenue

Phylogeographic pattern and extensive mitochondrial DNA divergence disclose a species complex within the Chagas disease vector Triatoma dimidiata.

ABSTARCT: Previous studies have shown that "bioequivalent" generic products of vancomycin are less effective in vivo against Staphylococcus aureus than the innovator compound. Considering that suboptimal bactericidal effect has been associated with emergence of resistance, we aimed to assess in vivo the impact of exposure to innovator and generic products of vancomycin on S. aureus susceptibility. A clinical methicillin-resistant S. aureus (MRSA) strain from a liver transplant patient with persistent bacteremia was used for which MIC, minimum bactericidal concentration (MBC), and autolytic properties were determined. Susceptibility was also assessed by determining a population analysis profile (PAP) with vancomycin concentrations from 0 to 5 mg/liter. ICR neutropenic mice were inoculated in each thigh with ∼7.0 log(10) CFU. Treatment with the different vancomycin products (innovator and three generics; 1,200 mg/kg of body weight/day every 3 h) started 2 h later while the control group received sterile saline. After 24 h, mice were euthanized, and the thigh homogenates were plated. Recovered colonies were reinoculated to new groups of animals, and the exposure-recovery process was repeated until 12 cycles were completed. The evolution of resistance was assessed by PAP after cycles 5, 10, 11, and 12. The initial isolate displayed reduced autolysis and higher resistance frequencies than S. aureus ATCC 29213 but without vancomycin-intermediate S. aureus (VISA) subpopulations. After 12 cycles, innovator vancomycin had significantly reduced resistant subpopulations at 1, 2, and 3 mg/liter, while the generic products had enriched them progressively by orders of magnitude. The great capacity of generic vancomycin to select for less susceptible organisms raises concerns about the role of therapeutic inequivalence of any antimicrobial on the epidemiology of resistance worldwide

Tumor marker utility and prognostic relevance of cathepsin B, cathepsin L, urokinase-type plasminogen activator, plasminogen activator inhibitor type-1, CEA and CA 19-9 in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Cathepsin B and L (CATB, CATL), urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 play an important role in colorectal cancer invasion. The tumor marker utility and prognostic relevance of these proteases have not been evaluated in the same experimental setting and compared with that of CEA and CA-19-9.</p> <p>Methods</p> <p>Protease, CEA and CA 19-9 serum or plasma levels were determined in 56 patients with colorectal cancer, 25 patients with ulcerative colitis, 26 patients with colorectal adenomas and 35 tumor-free control patients. Protease, CEA, CA 19-9 levels have been determined by ELISA and electrochemiluminescence immunoassay, respectively; their sensitivity, specificity, diagnostic accuracy have been calculated and correlated with clinicopathological staging.</p> <p>Results</p> <p>The protease antigen levels were significantly higher in colorectal cancer compared with other groups. Sensitivity of PAI-1 (94%), CATB (82%), uPA (69%), CATL (41%) were higher than those of CEA or CA 19-9 (30% and 18%, respectively). PAI-1, CATB and uPA demonstrated a better accuracy than CEA or CA 19-9. A combination of PAI-1 with CATB or uPA exhibited the highest sensitivity value (98%). High CATB, PAI-1, CEA and CA 19-9 levels correlated with advanced Dukes stages. CATB (<it>P </it>= 0.0004), CATL (<it>P </it>= 0.02), PAI-1 (<it>P </it>= 0.01) and CA 19-9 (<it>P </it>= 0.004) had a significant prognostic impact. PAI-1 (<it>P </it>= 0.001), CATB (<it>P </it>= 0.04) and CA 19-9 (<it>P </it>= 0.02) proved as independent prognostic variables.</p> <p>Conclusion</p> <p>At the time of clinical detection proteases are more sensitive indicators for colorectal cancer than the commonly used tumor markers. Determinations of CATB, CATL and PAI-1 have a major prognostic impact in patients with colorectal cancer.</p

Antimalarial Activity and Mechanisms of Action of Two Novel 4-Aminoquinolines against Chloroquine-Resistant Parasites

Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation