Extreme value statistics of jump processes.

We investigate extreme value statistics (EVS) of general discrete time and continuous space symmetric jump processes. We first show that for unbounded jump processes, the semi-infinite propagator G_{0}(x,n), defined as the probability for a particle issued from zero to be at position x after n steps whilst staying positive, is the key ingredient needed to derive a variety of joint distributions of extremes and times at which they are reached. Along with exact expressions, we extract universal asymptotic behaviors of such quantities. For bounded, semi-infinite jump processes killed upon first crossing of zero, we introduce the strip probability µ_{0,[under x]̲}(n), defined as the probability that a particle issued from zero remains positive and reaches its maximum x on its nth^{} step exactly. We show that µ_{0,[under x]̲}(n) is the essential building block to address EVS of semi-infinite jump processes, and obtain exact expressions and universal asymptotic behaviors of various joint distributions.

Leftward, rightward, and complete exit-time distributions of jump processes.

First-passage properties of continuous stochastic processes confined in a one-dimensional interval are well described. However, for jump processes (discrete random walks), the characterization of the corresponding observables remains elusive, despite their relevance in various contexts. Here we derive exact asymptotic expressions for the leftward, rightward, and complete exit-time distributions from the interval [0,x] for symmetric jump processes starting from x_{0}=0, in the large x and large time limit. We show that both the leftward probability F_{[under 0]̲,x}(n) to exit through 0 at step n and rightward probability F_{0,[under x]̲}(n) to exit through x at step n exhibit a universal behavior dictated by the large-distance decay of the jump distribution parametrized by the Levy exponent µ. In particular, we exhaustively describe the n≪(x/a_{µ})^{µ} and n≫(x/a_{µ})^{µ} limits and obtain explicit results in both regimes. Our results finally provide exact asymptotics for exit-time distributions of jump processes in regimes where continuous limits do not apply.

Splitting Probabilities of Symmetric Jump Processes.

We derive a universal, exact asymptotic form of the splitting probability for symmetric continuous jump processes, which quantifies the probability π_{0,[under x]_}(x_{0}) that the process crosses x before 0 starting from a given position x_{0}∈[0,x] in the regime x_{0}≪x. This analysis provides in particular a fully explicit determination of the transmission probability (x_{0}=0), in striking contrast with the trivial prediction π_{0,[under x]_}(0)=0 obtained by taking the continuous limit of the process, which reveals the importance of the microscopic properties of the dynamics. These results are illustrated with paradigmatic models of jump processes with applications to light scattering in heterogeneous media in realistic 3D slab geometries. In this context, our explicit predictions of the transmission probability, which can be directly measured experimentally, provide a quantitative characterization of the effective random process describing light scattering in the medium.

Joint statistics of space and time exploration of one-dimensional random walks.

The statistics of first-passage times of random walks to target sites has proved to play a key role in determining the kinetics of space exploration in various contexts. In parallel, the number of distinct sites visited by a random walker and related observables has been introduced to characterize the geometry of space exploration. Here, we address the question of the joint distribution of the first-passage time to a target and the number of distinct sites visited when the target is reached, which fully quantifies the coupling between the kinetics and geometry of search trajectories. Focusing on one-dimensional systems, we present a general method and derive explicit expressions of this joint distribution for several representative examples of Markovian search processes. In addition, we obtain a general scaling form, which holds also for non-Markovian processes and captures the general dependence of the joint distribution on its space and time variables. We argue that the joint distribution has important applications to various problems, such as a conditional form of the Rosenstock trapping model, and the persistence properties of self-interacting random walks.

Core-binding factor leukemia hijacks the T-cell-prone PU.1 antisense promoter.

The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we show that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core-binding factor (CBF) fusions RUNX1-ETO and CBFß-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense toward antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared with normal karyotype AML or healthy CD34+ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus use a physiological mechanism used by T cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.

Distribution of the span of one-dimensional confined random processes before hitting a target.

We derive the distribution of the number of distinct sites visited by a random walker before hitting a target site of a finite one-dimensional (1D) domain. Our approach holds for the general class of Markovian processes with connected span-i.e., whose trajectories have no "holes." We show that the distribution can be simply expressed in terms of splitting probabilities only. We provide explicit results for classical examples of random processes with relevance to target search problems, such as simple symmetric random walks, biased random walks, persistent random walks, and resetting random walks. As a by-product, explicit expressions for the splitting probabilities of all these processes are given. Extensions to reflecting boundary conditions, continuous processes, and an example of a random process with a nonconnected span are discussed.

Muography of different structures using muon scattering and absorption algorithms.

In recent decades, muon imaging has found a plethora of applications in many fields. This technique succeeds to infer the density distribution of big inaccessible structures where conventional techniques cannot be used. The requirements of different applications demand specific implementations of image reconstruction algorithms for either multiple scattering or absorption-transmission data analysis, as well as noise-suppression filters and muon momentum estimators. This paper presents successful results of image reconstruction techniques applied to simulated data of some representative applications. In addition to well-known reconstruction methods, a novel approach, the so-called µCT, is proposed for the inspection of spent nuclear fuel canisters. Results obtained based on both µCT and the maximum-likelihood expectation maximization reconstruction algorithms are presented.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.

INFN muon tomography demonstrator: past and recent results with an eye to near-future activities.

A short description of the muon tomography demonstrator at the INFN Laboratori Nazionali di Legnaro near Padua, Italy, is given and the principal achievements owing to the data collected at that experimental facility are presented. In particular, the feasibility studies for several applications based on the muon-tomographic technology, within national and European projects, are discussed. The experimental problems and the procedures used to improve the performance are underlined. In addition, new activities and the related detector optimization are illustrated.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.

Echocardiographic Pulmonary Hypertension Predicts Post-transplantation Renal Allograft Failure.

BACKGROUND: Pulmonary hypertension in the setting of renal transplantation has been associated with early allograft dysfunction and increased mortality, but this relationship has not been extensively studied. METHODS: We performed a retrospective cohort study of adult patients who underwent their first renal transplantation in the years 2003-2009 and had pre-transplantation echocardiograms. Pulmonary hypertension was defined as right ventricular systolic pressure ≥40 mm Hg in the absence of left-sided valvular disease and/or left ventricular ejection fraction ≤50%. Eighty-two of 205 patients (40%) met the inclusion criteria. The relationship between pulmonary hypertension and death-censored allograft failure (hemodialysis dependence or retransplantation) and serum creatinine was assessed with the use of Cox hazard regression and generalized mixed models. RESULTS: The presence of pulmonary hypertension was associated with a 3-fold increase in the risk of death-censored allograft failure (95% confidence interval, 1.20-7.32; P = .02). Failure rates were 19% at 24 months and 51% at 96 months for those with pulmonary hypertension versus 7% at 24 months and 20% at 86 months for those without pulmonary hypertension (P = .01). Among those without graft failure, there was an increase in creatinine levels after transplantation (P = .01). Effect estimates were unchanged by adjustment for multiple covariates and when pulmonary hypertension was defined as right ventricular systolic pressure ≥36 mm Hg. CONCLUSIONS: Pulmonary hypertension before renal transplantation carries a 3-fold increased risk of death-censored allograft failure. The relationship between the pulmonary circulation and renal allograft failure warrants further study.

Isotopic constraints on water source mixing, network leakage and contamination in an urban groundwater system.

Water supply in developing countries is prone to large water losses due to leaky distribution networks and defective sewers, which may affect groundwater quality and quantity in urban areas and result in complex subsurface mixing dynamics. In this study, a multi-stable isotope approach was used to investigate spatiotemporal fluctuations of surface and sub-surface water source partitioning and mixing, and to assess nitrogen (N) contamination in the urban water cycle of As-Salt, Jordan. Water import from the King Abdullah Canal (KAC), mains waters from the network, and wastewater are characterized by distinct isotopic signatures, which allowed us to quantify city effluents into the groundwater. Temporal variations in isotopic signatures of polluted groundwater are explained by seasonally fluctuating inflow, and dilution by water that originates from Lake Tiberias and enters the urban water cycle via the KAC. Isotopic analysis (N and O) and comparison between groundwater nitrate and nitrate from mains water, water imports and wastewater confirmed that septic waste from leaky sewers is the main contributor of nitrate contamination. The nitrate of strongly contaminated groundwater was characterized by highest δ15NNO3 values (13.3±1.8‰), whereas lowest δ15NNO3 values were measured in unpolluted groundwater (6.9‰). Analogously, nitrate concentration and isotopic ratios were used for source partitioning and qualitatively confirmed δDH2O and δ18OH2O-based estimates. Dual water isotope endmember mixing calculations suggest that city effluents from leaky networks and sewers contribute 30-64% to the heavily polluted groundwater. Ternary mixing calculations including also chloride revealed that 5-18% of the polluted groundwater is wastewater. Up to two thirds of the groundwater originates from mains, indicating excessive water loss from the network, and calling for improved water supply management.

Muon-Induced Neutrons Do Not Explain the DAMA Data.

We present an accurate model of the muon-induced background in the DAMA/LIBRA experiment. Our work challenges proposed mechanisms which seek to explain the observed DAMA signal modulation with muon-induced backgrounds. Muon generation and transport are performed using the MUSIC/MUSUN code, and subsequent interactions in the vicinity of the DAMA detector cavern are simulated with Geant4. We estimate the total muon-induced neutron flux in the detector cavern to be Φ(n)(ν)=1.0 × 10(-9) cm(-2) s(-1). We predict 3.49 × 10(-5) counts/day/kg/keV, which accounts for less than 0.3% of the DAMA signal modulation amplitude.

Ultra-narrow linewidth, stable and tunable laser source for optical communication systems and spectroscopy.

A novel ultra-narrow linewidth, stable and tunable single-line laser source is demonstrated and experimentally performed. The single spectral line laser is achieved by selecting and amplifying one spectral comb line of a femtosecond-fiber laser via polarization pulling assisted stimulated Brillouin scattering. Stabilization and tuning is performed by additional modulation. First proof of concept results show possible linewidths below 1 Hz and an SNR of 47 dB with a tunability of more than 100 nm and a relative stability of ±160 mHz over 5 h. Such a laser source gives high potential for many different applications like spectroscopy and optical communications.

Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial.

BACKGROUND: Acute pulmonary embolism (PE) can worsen quality of life due to persistent dyspnea or exercise intolerance. OBJECTIVE: Test if tenecteplase increases the probability of a favorable composite patient-oriented outcome after submassive PE. METHODS: Normotensive patients with PE and right ventricular (RV) strain (by echocardiography or biomarkers) were enrolled from eight hospitals. All patients received low-molecular-weight heparin followed by random assignment to either a single weight-based bolus of tenecteplase or placebo, administered in a double-blinded fashion. The primary composite outcome included: (i) death, circulatory shock, intubation or major bleeding within 5 days or (ii) recurrent PE, poor functional capacity (RV dysfunction with either dyspnea at rest or exercise intolerance) or an SF36(®) Physical Component Summary (PCS) score < 30 at 90-day follow-up. RESULTS: Eighty-three patients were randomized; 40 to tenecteplase and 43 to placebo. The trial was terminated prematurely. Within 5 days, adverse outcomes occurred in three placebo-treated patients (death in one and intubation in two) and one tenecteplase-treated patient (fatal intracranial hemorrhage). At 90 days, adverse outcomes occurred in 13 unique placebo-treated patients and five unique tenecteplase-treated patients Thus, 16 (37%) placebo-treated and six (15%) tenecteplase-treated patients had at least one adverse outcome (exact two-sided P = 0.017). CONCLUSIONS: Treatment of patients with submassive pulmonary embolism with tenecteplase was associated with increased probability of a favorable composite outcome.

Integrating groundwater into urban water management.

The management of urban groundwater resources is directly linked to urban water supply and drainage concepts. A proper integration of groundwater into urban water management plans is recommended for long-term planning. The paper describes the development of a new modelling suite which addresses the urban water and solute balance in a holistic way. Special focus has been placed on the assessment of the impact of sewer leakage on groundwater in four case study cities. Tools for the prediction of sewer leakage including the assessment of uncertainties are now available. Field investigations in four European case study cities were able to trace the influence of sewer leakage on urban groundwater using microbiological indicators and pharmaceutical residues.

Evidence for the role of p38 MAP kinase in hypoxia-induced pulmonary vasoconstriction.

Mitogen-activated protein (MAP) kinases regulate smooth muscle cell contraction. Hypoxia contracts pulmonary arteries by mechanisms that are incompletely understood. We hypothesized that hypoxic contraction of pulmonary arteries involves activation of the MAP kinases. To test this hypothesis, we studied the effects of SB-202190, a p38 MAP kinase inhibitor, PD-98059 and UO-126, two structurally different MEKK inhibitors, and anisomycin, a stimulator of p38 MAP kinase on acute hypoxia-induced contraction in rat conduit pulmonary artery rings precontracted with phenylephrine or KCl. Hypoxia induced a transient contraction, followed by a relaxation, and then a slowly developing sustained contraction. Hypoxia also significantly increased phosphorylation of p38 MAP kinase. SB-202190 did not affect the transient phase but abrogated the sustained phase of hypoxic contraction, whereas anisomycin enhanced both phases of contraction. SB-202190 also attenuated and anisomycin enhanced the phenylephrine-induced contraction. In contrast, PD-98059 and UO-126 had minimal effects on either hypoxic or phenylephrine-induced contraction. None of the treatments modified KCl-induced contraction. We conclude that p38, but not the ERK1/ERK2 MAP kinase pathway, mediates the sustained phase of hypoxic contraction in isolated rat pulmonary arteries.

Reduced oxygen tension increases atrial natriuretic peptide release from atrial cardiocytes.

To test the hypothesis that reduced oxygen tension stimulates cardiac atrial natriuretic peptide (ANP) secretion, we measured ANP release and expression in neonatal rat atrial and ventricular cardiac myocytes exposed to 45 min and 3, 6, and 24 hr of 3% or 21% oxygen. In atrial cardiocytes, the percentage of increase in culture media ANP concentration from baseline was greater in cells exposed to 3% than in cells exposed to 21% oxygen after 3 hr (814% +/- 52% vs. 567% +/- 33%, P < 0.05) and 6 hr of exposure (1639% +/- 91% vs. 1155% +/- 73%, P < 0.05). No differences in the percentage of increase in culture media ANP concentration was seen at 45 min (284% +/- 27% vs. 201% +/- 16%, P = NS) or 24 hr (2499% +/- 250% vs. 2426% +/- 195%). There was a significant increase in cellular ANP content between 3 and 24 hr in atrial cardiocytes exposed to 21% oxygen (105% +/- 40% vs. 296% +/- 60%, P < 0.05), but not in atrial cardiocytes exposed to 3% oxygen (118% +/- 20% vs. 180% +/- 26%, P = NS). Steady-state ANP mRNA levels in atrial cardiocytes were not affected by oxygen tension. In ventricular cardiocytes, oxygen tension did not affect ANP secretion, cellular ANP content, or steady-state ANP mRNA levels. We conclude that reduced oxygen tension increases release of ANP from atrial, but not ventricular cardiocytes and that this mechanism may contribute to the elevation in plasma ANP seen during acute hypoxia.

Vasoresponsiveness of sarcoidosis-associated pulmonary hypertension.

OBJECTIVE: To assess short-term and long-term responses to treatment with pulmonary vasodilators in patients with sarcoidosis-related pulmonary hypertension. METHODS: A prospective, observational study was performed on eight patients with moderate-to-severe sarcoidosis-related pulmonary hypertension. Patients underwent a short-term vasodilator trial, using inhaled nitric oxide (iNO), IV epoprostenol, and/or oral calcium-channel blockers. A favorable short-term response was considered a > or = 20% decrease in pulmonary vascular resistance (PVR). Five patients received long-term treatment with iNO (with one patient receiving epoprostenol in addition) and underwent follow-up hemodynamic and/or 6-min walk testing. Two patients received long-term treatment with calcium-channel blockers. RESULTS: Baseline (+/- SE) mean pulmonary artery pressure (mPAP) was 55 +/- 4 mm Hg and PVR was 896 +/- 200 dyne.s.cm(-5). A favorable short-term response was seen in seven of eight patients receiving iNO, four of six patients receiving epoprostenol, and two of five patients receiving calcium-channel blockers. With iNO, PVR decreased 31 +/- 5% (p = 0.006) and mPAP decreased 18 +/- 4% (p = 0.003); with epoprostenol, PVR decreased 25 +/- 6% (p = 0.016) and mPAP decreased 6 +/- 2% (p = not significant). Decreased systemic vascular resistance was the only significant response to treatment with calcium-channel blockers. Follow-up 6-min walk test results improved in all five patients receiving long-term treatment with iNO. Follow-up hemodynamic responses in three patients showed preserved vasoresponsiveness. These three patients subsequently died, as did the two patients receiving calcium-channel blockers. The two remaining patients continue to receive iNO. CONCLUSION: In the short term, pulmonary hypertension in patients with sarcoidosis is responsive to treatment with pulmonary vasodilators; these patients may benefit from long-term iNO therapy.

Pharmacokinetics of human growth hormone administered subcutaneously with two different injection systems.

The bioavailability of recombinant human growth hormone (somatropin, CAS 12629-01-5) was compared between a transcutaneous jet injection device and subcutaneous cannula injection. Thirteen healthy male subjects received 8.64 IU somatropin once with jet and once with cannula injection in a randomized cross-over study. Baseline-corrected somatropin serum concentrations were evaluated with non-compartmental and compartmental methods. The 90% confidence intervals with two one-sided t-tests around the ratios of injection devices were 91-120% for maximum concentration, 94-110% for area-under-curve until 14 h, and 92-103% for area-under-curve to infinity. Somatropin has a known metabolic half-life of ca. 20-30 min while the observed terminal half-lives were 2-4 h. Absorption and elimination rate constants were similar. Times of maximum concentrations, terminal half-lives and lag times to start of absorption appeared to be shorter and the absorption rate constant appeared to be larger for jet than for cannula injection. In conclusion, the kinetics of somatropin from subcutaneous tissue had a "flip-flop" characteristic. Bioavailability of somatropin after jet injection was equivalent to cannula injection.

GT160-246, a toxin binding polymer for treatment of Clostridium difficile colitis.

GT160-246, a high-molecular-weight soluble anionic polymer, was tested in vitro and in vivo for neutralization of Clostridium difficile toxin A and B activities. Five milligrams of GT160-246 per ml neutralized toxin-mediated inhibition of protein synthesis in Vero cells induced by 5 ng of toxin A per ml or 1.25 ng of toxin B per ml. In ligated rat ileal loops, 1 mg of GT160-246 neutralized fluid accumulation caused by 5 microg of toxin A. At doses as high as 80 mg/loop, cholestyramine provided incomplete neutralization of fluid accumulation caused by 5 microg of toxin A. GT160-246 protected 80% of the hamsters from mortality caused by infection with C. difficile, whereas cholestyramine protected only 10% of animals. Treatment of C. difficile-infected hamsters with metronidazole initially protected 100% of the hamsters from mortality, but upon removal of treatment, 80% of the hamsters had relapses and died. In contrast, removal of GT160-246 treatment did not result in disease relapse in the hamsters. GT160-246 showed no antimicrobial activity in tests with a panel of 16 aerobic bacteria and yeast and 22 anaerobic bacteria and did not interfere with the in vitro activities of most antibiotics. GT160-246 offers a novel, nonantimicrobial treatment of C. difficile disease in humans.

[Irritable bowel syndrome]. / Síndrome de intestino irritable.

Irritable bowel syndrome is a functional disease with highly variable symptoms and difficult to diagnose. The clinical picture is fundamental to reach a correct diagnosis and discard other gastrointestinal diseases. It etiology is not well known; psychological problems and stress probably play an important role in the development of the disease. Irritable bowel syndrome impairs the quality of life of patients and is a frequent cause of consultation in primary care. Its therapy is basically symptomatic and requires psychological support. The physician must warn his/her patients that immediate results are rarely obtained and that a prolonged clinical follow up may be necessary.