Particle-number distribution in large fluctuations at the tip of branching random walks.

We investigate properties of the particle distribution near the tip of one-dimensional branching random walks at large times t, focusing on unusual realizations in which the rightmost lead particle is very far ahead of its expected position, but still within a distance smaller than the diffusion radius ∼sqrt[t]. Our approach consists in a study of the generating function G_{Δx}(λ)=∑_{n}λ^{n}p_{n}(Δx) for the probabilities p_{n}(Δx) of observing n particles in an interval of given size Δx from the lead particle to its left, fixing the position of the latter. This generating function can be expressed with the help of functions solving the Fisher-Kolmogorov-Petrovsky-Piscounov (FKPP) equation with suitable initial conditions. In the infinite-time and large-Δx limits, we find that the mean number of particles in the interval grows exponentially with Δx, and that the generating function obeys a nontrivial scaling law, depending on Δx and λ through the combined variable [Δx-f(λ)]^{3}/Δx^{2}, where f(λ)≡-ln(1-λ)-ln[-ln(1-λ)]. From this property, one may conjecture that the growth of the typical particle number with the size of the interval is slower than exponential, but, surprisingly enough, only by a subleading factor at large Δx. The scaling we argue is consistent with results from a numerical integration of the FKPP equation.

Diffractive Electron-Nucleus Scattering and Ancestry in Branching Random Walks.

We point out an analogy between diffractive electron-nucleus scattering events and realizations of one-dimensional branching random walks selected according to the height of the genealogical tree of the particles near their boundaries. This correspondence is made transparent in an event-by-event picture of diffraction, emphasizing the statistical properties of gluon evolution, from which new quantitative predictions straightforwardly follow: we are able to determine the distribution of the total invariant mass produced diffractively, which is an interesting observable that can potentially be measured at a future electron-ion collider.

Long-Term Outcomes in Belatacept- Versus Cyclosporine-Treated Recipients of Extended Criteria Donor Kidneys: Final Results From BENEFIT-EXT, a Phase III Randomized Study.

In the Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial-Extended Criteria Donors (BENEFIT-EXT), extended criteria donor kidney recipients were randomized to receive belatacept-based (more intense [MI] or less intense [LI]) or cyclosporine-based immunosuppression. In prior analyses, belatacept was associated with significantly better renal function compared with cyclosporine. In this prospective analysis of the intent-to-treat population, efficacy and safety were compared across regimens at 7 years after transplant. Overall, 128 of 184 belatacept MI-treated, 138 of 175 belatacept LI-treated and 108 of 184 cyclosporine-treated patients contributed data to these analyses. Hazard ratios (HRs) comparing time to death or graft loss were 0.915 (95% confidence interval [CI] 0.625-1.339; p = 0.65) for belatacept MI versus cyclosporine and 0.927 (95% CI 0.634-1.356; p = 0.70) for belatacept LI versus cyclosporine. Mean estimated GFR (eGFR) plus or minus standard error at 7 years was 53.9 ± 1.9, 54.2 ± 1.9, and 35.3 ± 2.0 mL/min per 1.73 m2 for belatacept MI, belatacept LI and cyclosporine, respectively (p < 0.001 for overall treatment effect). HRs comparing freedom from death, graft loss or eGFR <20 mL/min per 1.73 m2 were 0.754 (95% CI 0.536-1.061; p = 0.10) for belatacept MI versus cyclosporine and 0.706 (95% CI 0.499-0.998; p = 0.05) for belatacept LI versus cyclosporine. Acute rejection rates and safety profiles of belatacept- and cyclosporine-based treatment were similar. De novo donor-specific antibody incidence was lower for belatacept (p ≤ 0.0001). Relative to cyclosporine, belatacept was associated with similar death and graft loss and improved renal function at 7 years after transplant and had a safety profile consistent with previous reports.

Phenomenological picture of fluctuations in branching random walks.

We propose a picture of the fluctuations in branching random walks, which leads to predictions for the distribution of a random variable that characterizes the position of the bulk of the particles. We also interpret the 1/sqrt[t] correction to the average position of the rightmost particle of a branching random walk for large times t≫1, computed by Ebert and Van Saarloos, as fluctuations on top of the mean-field approximation of this process with a Brunet-Derrida cutoff at the tip that simulates discreteness. Our analytical formulas successfully compare to numerical simulations of a particular model of a branching random walk.

Length variations in the NA stalk of an H7N1 influenza virus have opposite effects on viral excretion in chickens and ducks.

A deletion of ∼20 amino acids in the stalk of neuraminidase is frequently observed upon transmission of influenza A viruses from waterfowl to domestic poultry. A pair of recombinant H7N1 viruses bearing either a short- or long-stalk neuraminidase was genetically engineered. Inoculation of the long-stalk-neuraminidase virus resulted in a higher cloacal excretion in ducks and led conversely to lower-level oropharyngeal excretion in chickens, associated with a higher-level local immune response and better survival. Therefore, a short-stalk neuraminidase is a determinant of viral adaptation and virulence in chickens but is detrimental to virus replication and shedding in ducks.

[Interspecies transmission, adaptation to humans and pathogenicity of animal influenza viruses]. / Transmission inter-espèces, adaptation à l'homme et pathogénicité des virus influenza d'origine animale.

The emergence in 2009 of a novel A(H1N1)v influenza virus of swine origin and the regular occurrence since 2003 of human cases of infection with A(H5N1) avian influenza viruses underline the zoonotic and pandemic potential of type A influenza viruses. Influenza viruses from the wild aquatic birds reservoir usually do not replicate efficiently in humans. Domestic poultry and swine can act as intermediate hosts for the acquisition of determinants that increase the potential of transmission and adaptation to humans, through the accumulation of mutations or by genetic reassortment. The rapid evolution of influenza viruses following interspecies transmission probably results from the selection of genetic variations that favor optimal interactions between viral proteins and cellular factors, leading to an increased multiplication potential and a better escape to the host antiviral response. Whereas influenza viruses usually cause asymptomatic infections in wild aquatic birds, they may be highly pathogenic in other species. Molecular determinants of host-specificity and pathogenesis have been identified in most viral genes, notably in genes that encode viral surface glycoproteins, proteins involved in the viral genome replication, and proteins that counteract the host immune response. However, our knowledge of these numerous and interdependant determinants remains incomplete, and the molecular mechanisms involved are still to be understood.

A genetically engineered waterfowl influenza virus with a deletion in the stalk of the neuraminidase has increased virulence for chickens.

A deletion of about 20 amino acids in the stalk of the neuraminidase (NA) is frequently detected upon transmission of influenza A viruses from waterfowl to domestic poultry. Using reverse genetics, a recombinant virus derived from a wild duck influenza virus isolate, A/Mallard/Marquenterre/Z237/83 (MZ), and an NA stalk deletion variant (MZ-delNA) were produced. Compared to the wild type, the MZ-delNA virus showed a moderate growth advantage on avian cultured cells. In 4-week-old chickens inoculated intratracheally with the MZ-delNA virus, viral replication in the lungs, liver, and kidneys was enhanced and interstitial pneumonia lesions were more severe than with the wild-type virus. The MZ-delNA-inoculated chickens showed significantly increased levels of mRNAs encoding interleukin-6 (IL-6), transforming growth factor-beta4 (TGF-beta4), and CCL5 in the lungs and a higher frequency of apoptotic cells in the liver than did their MZ-inoculated counterparts. Molecular mechanisms possibly underlying the growth advantage of the MZ-delNA virus were explored. The measured enzymatic activities toward a small substrate were similar for the wild-type and deleted NA, but the MZ-delNA virus eluted from chicken erythrocytes at reduced rates. Pseudoviral particles expressing the MZ hemagglutinin in combination with the MZ-NA or MZ-delNA protein were produced from avian cultured cells with similar efficiencies, suggesting that the deletion in the NA stalk does not enhance the release of progeny virions and probably affects an earlier step of the viral cycle. Overall, our data indicate that a shortened NA stalk is a strong determinant of adaptation and virulence of waterfowl influenza viruses in chickens.

Effect of selection on ancestry: an exactly soluble case and its phenomenological generalization.

We consider a family of models describing the evolution under selection of a population whose dynamics can be related to the propagation of noisy traveling waves. For one particular model that we shall call the exponential model, the properties of the traveling wave front can be calculated exactly, as well as the statistics of the genealogy of the population. One striking result is that, for this particular model, the genealogical trees have the same statistics as the trees of replicas in the Parisi mean-field theory of spin glasses. We also find that in the exponential model, the coalescence times along these trees grow like the logarithm of the population size. A phenomenological picture of the propagation of wave fronts that we introduced in a previous work, as well as our numerical data, suggest that these statistics remain valid for a larger class of models, while the coalescence times grow like the cube of the logarithm of the population size.

[Tolerance and efficacy of early nicotine substitution after acute coronary syndromes]. / Tolérance et efficacité de la substitution nicotinique précoce au décours d'un syndrome coronaire aigu.

The object of this study was to assess the cardiovascular tolerance and efficacy of early nicotine substitution therapy in 100 patients admitted to the Coronary Care Unit for acute coronary syndromes (ACS). The files of the first 100 consecutive patients having received nicotine substitution therapy immediately after an ACS were consulted retrospectively and a questionnaire was sent to all patients. A reply was obtained in 90% of cases. In this series, there was a 7% rate of cardiovascular events in the days following hospital discharge, comparable to previously reported results. The smoking relapse rate at six months after the ACS was 38.9%, a percentage which was less than in previously reported series. Although consultations to help stop smoking and nicotine substitution did not seem to have significant benefits in this study, the authors recommend continuing and improving the management of coronary patients who smoke.

PS-341 or a combination of arsenic trioxide and interferon-alpha inhibit growth and induce caspase-dependent apoptosis in KSHV/HHV-8-infected primary effusion lymphoma cells.

Kaposi's sarcoma (KS)-associated herpes virus (KSHV) is the causative agent of primary effusion lymphoma and of KS. Primary effusion lymphoma (PEL) is an aggressive proliferation of B cells. Conventional chemotherapy has limited benefits in PEL patients, and the prognosis is very poor. We previously reported that treatment of human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma cells either with arsenic trioxide (As) combined to interferon-alpha (IFN-alpha) or with the bortezomib (PS-341) proteasome inhibitor induces cell cycle arrest and apoptosis, partly due to the reversal of the constitutive nuclear factor-kappaB (NF-kappaB) activation. PEL cells also display an activated NF-kappaB pathway that is necessary for their survival. This prompted us to investigate the effects of PS-341, or of the As/IFN-alpha combination on PEL cells. A dramatic inhibition of cell proliferation and induction of apoptosis was observed in PS-341 and in As/IFN-alpha treated cells. This was associated with the dissipation of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and was reversed by the z-VAD caspase inhibitor. PS-341 and As/IFN-alpha treatment abrogated NF-kappaB translocation to the nucleus and decreased the levels of the anti-apoptotic protein Bcl-X(L). Altogether, these results provide a rational basis for a future therapeutic use of PS-341 or combined As and IFN-alpha in PEL patients.

Phenomenological theory giving the full statistics of the position of fluctuating pulled fronts.

We propose a phenomenological description for the effect of a weak noise on the position of a front described by the Fisher-Kolmogorov-Petrovsky-Piscounov equation or any other traveling-wave equation in the same class. Our scenario is based on four hypotheses on the relevant mechanism for the diffusion of the front. Our parameter-free analytical predictions for the velocity of the front, its diffusion constant and higher cumulants of its position agree with numerical simulations.

[Medications in smoking cessation]. / Médicaments d'aide au sevrage tabagique.

Physicians can aid their patients' smoking cessation by providing psychological support, advice, behavioral strategies, and drugs. Success depends on appropriate management, including selection of the right moment to begin treatment and an understanding of the development of the withdrawal syndrome, smoking urges, and the possibility of failure. The standard pharmacological treatment for nicotine dependence uses different forms of nicotine substitutes and bupropion, while we await data about other drugs currently under study. The score on the "simplified" Fagerström questionnaire usually determines the initial nicotine dose. Six forms of nicotine substitutes are available. They provide either prolonged nicotine release (transcutaneous patches) that prevents withdrawal symptoms, or rapid release through the buccal and nasal mucosa (chewing gum, suckers, inhalers and nasal sprays) to anticipate the positive effects represented by cigarettes and the urges occurring during withdrawal. The efficacy of these substitutes, widely studied, is approximately twice that of placebo. Their use is no longer contraindicated in patients with heart disease, when necessary. Bupropion should be used in treating nicotine dependence either as a first-line treatment, or if nicotine substitutes (150 mg/d the first week, 300 mg/d thereafter) fail. The combination of bupropion and nicotine substitutes can be considered, either from the outset for heavy or very heavy smokers, or afterwards, if withdrawal symptoms or urges to smoke persist in subjects treated by only one of these two drug classes. One of the new drugs under evaluation is rimonabant, the first representatives of a new class of drugs, selective CB1 endocannabinoid receptor antagonists. Promising results about its use in smoking cessation were released in 2004.

Geometric scaling as traveling waves.

We show the relevance of the nonlinear Fisher and Kolmogorov-Petrovsky-Piscounov (KPP) equation to the problem of high energy evolution of the QCD amplitudes. We explain how the traveling wave solutions of this equation are related to geometric scaling, a phenomenon observed in deep-inelastic scattering experiments. Geometric scaling is for the first time shown to result from an exact solution of nonlinear QCD evolution equations. Using general results on the KPP equation, we compute the velocity of the wave front, which gives the full high energy dependence of the saturation scale.

Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial.

PURPOSE: This phase III trial compared the efficacy and safety of doxorubicin and paclitaxel (AT) to 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line therapy for women with metastatic breast cancer. PATIENTS AND METHODS: A total of 267 women with metastatic breast cancer were randomized to receive either AT (doxorubicin 50 mg/m(2) followed 24 hours later by paclitaxel 220 mg/m(2)) or FAC (5-fluorouracil 500 mg/m(2), doxorubicin 50 mg/m(2), cyclophosphamide 500 mg/m(2)), each administered every 3 weeks for up to eight cycles. Patients had to have measurable disease and an Eastern Cooperative Oncology Group performance status of 0 to 2. Only one prior non-anthracycline, nontaxane-containing adjuvant chemotherapy regimen was allowed. RESULTS: Overall response rates for patients randomized to AT and FAC were 68% and 55%, respectively (P =.032). Median time to progression and overall survival were significantly longer for AT compared with FAC (time to progression 8.3 months v 6.2 months [P =.034]; overall survival 23.3 months v 18.3 months [P =.013]). Therapy was generally well-tolerated (median of eight cycles delivered in each arm). Grade 3 or 4 neutropenia was more common with AT than with FAC (89% v 65%; P <.001); however, the incidence of fever and infection was low. Grade 3 or 4 arthralgia and myalgia, peripheral neuropathy, and diarrhea were more common with AT, whereas nausea and vomiting were more common with FAC. The incidence of cardiotoxicity was low in both arms. CONCLUSION: AT conferred a significant advantage in response rate, time to progression, and overall survival compared with FAC. Treatment was well-tolerated with no unexpected toxicities.

Adverse events with transvenous left ventricular pacing in patients with severe heart failure: early experience from a single centre.

AIMS: Assessment of complications following implantation of transvenous ventricular electrodes to pace the left ventricle. METHODS AND RESULTS: Twenty-eight patients with severe cardiac failure and left bundle branch block were prospectively followed for adverse effects of implantation of a left ventricular transvenous pacing system. Immediate follow-up was associated with loss of left ventricular pacing in nine patients (32%). This was due to lead dislodgement in four cases (corrected by re-operation in three of these cases), and due to increased threshold in five cases (corrected by programming a higher pacing amplitude in all five cases, but with intermittent diaphragmatic contraction in one case). After 1 month, one patient died, one patient with severe coronary heart disease suffered a myocardial infarction, and left ventricular pacing was lost in two patients. Pericardial effusion, new significant ventricular arrhythmias or other adverse effects were not observed. After a mean follow-up of 16 +/- 9.2 months, pacing leads remained stable and no late complications related to the transvenous left ventricular epicardial pacing were observed. CONCLUSION: Placement of a permanent lead in a tributary of the coronary sinus is feasible without serious adverse effects during the first month. The only frequent adverse event was lead dislodgement; a finding which emphasizes the need for development of specially designed leads for this application.

Prevalence of factor V Leiden in patients with myocardial infarction and normal coronary angiography.

Factor V Leiden is associated with an increased risk of venous thrombosis and myocardial infarction in young women, but not in men in this latter case. The aim of this study was to evaluate the prevalence of this mutation in patients with myocardial infarction but normal coronary angiography. We compared 3 groups of patients: one group consisted of 107 patients with premature myocardial infarction but no significant coronary artery stenosis; another group of 244 patients with myocardial infarction and significant coronary artery stenosis; a third group of 400 healthy controls. Factor V Leiden was found in 13 patients (12.1%) who had a myocardial infarction without significant coronary artery stenosis, 11 patients (4.5%) who had a myocardial infarction with significant coronary artery stenosis (p = 0.01) and in 20 controls (5%) (p = 0.01). Odds ratio associated with factor V Leiden were respectively 2.93 (CI95: 1.18-7.31 ) and 2.63 (CI95: 1.19-5.78) when we compared myocardial infarction patients without significant coronary artery stenosis to controls or to patients with significant coronary artery stenosis. In myocardial infarction patients without significant coronary artery stenosis, prevalence of factor V Leiden is significantly higher than in controls. This new finding supports the hypothesis that thrombosis plays a key role in this selected situation.

Evaluation of different ventricular pacing sites in patients with severe heart failure: results of an acute hemodynamic study.

BACKGROUND: Multisite ventricular pacing has recently been proposed as an additional treatment for patients with severe congestive heart failure. To further assess the potential value of this technique, we compared the acute hemodynamic changes associated with pacing the right ventricular apex (RVA) or outflow tract (RVOT) alone, the left ventricle (LV) alone, or biventricular (BIV) pacing of the RVA and LV together. METHODS AND RESULTS: Acute hemodynamic findings were measured in 27 patients with severe heart failure despite optimal therapy and either first-degree AV block and/or an intraventricular conduction defect. In the 23 patients with a high pulmonary capillary wedge pressure (PCWP) (>15 mm Hg), data were collected after transvenous pacing at different ventricular sites in either the VDD mode (AV delay=100 ms) or the VVI mode in patients with atrial fibrillation (n=6). The mean baseline cardiac index was 1.82 L x min(-1) x m(-2). Mean+/-SD baseline systolic blood pressure (SBP) (118.5+/-15.2 mm Hg), PCWP (26.4+/-6.6 mm Hg), and V-wave amplitude (39.1+/-14.6 mm Hg) were similar before and after either RVA or RVOT pacing. In contrast, LV-based pacing (either LV alone or BIV pacing) resulted in higher SBP (P<.03) and lower PCWP (P<.01) and V-wave amplitude (P<.001) than either baseline or RV pacing measurements. With LV pacing alone, SBP, PCWP, and V waves were 126.5+/-15.1, 20.7+/-5.9, and 25.5+/-8.1 mm Hg, respectively. The results with LV pacing alone were similar to those obtained with BIV pacing. CONCLUSIONS: In patients with severe congestive heart failure, both LV pacing alone and BIV pacing resulted in a similar and significant acute improvement in SBP, PCWP, and V-wave amplitude compared with baseline measurements and RV pacing alone. These results provide a strong basis for initiating long-term studies examining the chronic effects of LV-based pacing in patients with medically refractory congestive heart failure.

[Torsades de pointe with spiramycine and metiquazine therapy. Apropos of a case]. / Torsades de pointes sous traitement par spiramycine et méquitazine. A propos d'un cas.

The authors report the case of a 21 year old woman with a congenital long Q7 syndrome who had several syncopal attacks at least one of which was caused by torsades de pointe. This sudden complication was attributed to the simultaneous prescription of Spiramycine and Mequitazine over a 48 hour period. These two drugs are not considered to be predisposing factors for torsades de pointe despite the fact that they belong to two families of drugs which can trigger this type of arrhythmia. The withdrawal of this treatment led to the complete regression of the syncopal episodes with a follow-up of two years and a significant shortening of the initial QTc interval which remained, nevertheless, longer than normal. This case underlines the potential risks of drug associations of these two families of drugs, especially in patients with the congenital long Qt syndrome.