Comments on: Methylene blue? therapeutic alternative in the management of septic shock refractory to norepinephrine

It is a comment on an interesting case report focusing on the use of methylene blue in septic shock refractory to noreprinephrine. In septic shock, the response to pathogen-associated molecular patterns (PAMPS) and damage-associated molecu- lar patterns (DAMPS) generates a combination of vasodilation and increased capillary permeability. Capillary leak, coupled with greater vessel capacitance mediated by vasoplegia, may result in absolute or more commonly relative hypovolemia. The L-arginine nitric oxide (NO) pathway plays a pivotal role in regulating cardiovascular hemodynamics and vascular permeability. Methylene blue inhibits inducible NO synthase (NOS) and guanylate cyclase, thereby reversing NO induced vasodilation. In septic shock, it was firstly used at the beginning of the 1990s. This drug has resulted beneficial and safe in randomized clinical trials and case reports. Recently, its clinical use has been deeply reviewed, and we are strongly convinced that it would deserve further attention and prospective, randomized, clinical trials

Fractal-like Distributions over the Rational Numbers in High-throughput Biological and Clinical Data

Recent developments in extracting and processing biological and clinical data are allowing quantitative approaches to studying living systems. High-throughput sequencing, expression profiles, proteomics, and electronic health records are some examples of such technologies. Extracting meaningful information from those technologies requires careful analysis of the large volumes of data they produce. In this note, we present a set of distributions that commonly appear in the analysis of such data. These distributions present some interesting features: they are discontinuous in the rational numbers, but continuous in the irrational numbers, and possess a certain self-similar (fractal-like) structure. The first set of examples which we present here are drawn from a high-throughput sequencing experiment. Here, the self-similar distributions appear as part of the evaluation of the error rate of the sequencing technology and the identification of tumorogenic genomic alterations. The other examples are obtained from risk factor evaluation and analysis of relative disease prevalence and co-mordbidity as these appear in electronic clinical data. The distributions are also relevant to identification of subclonal populations in tumors and the study of the evolution of infectious diseases, and more precisely the study of quasi-species and intrahost diversity of viral populations

Vasopressor-Sparing Action of Methylene Blue in Severe Sepsis and Shock: A Narrative Review

Shock is a serious acute circulatory failure leading to inadequate oxygen delivery to the cells. Its treatment is mainly based on circulating fluid optimization, and vasopressors to provide an adequate mean arterial pressure and microcirculatory flow. Norepinephrine is the drug of choice, but high dosages may be responsible for several side effects, including increased myocardial oxygen consumption, dysrhythmias, and peripheral and organ ischemia. Moreover, some patients are “non-responders” to first-line norepinephrine treatment. Hence, other drugs have been proposed to reach and maintain the hemodynamic target. In general, they are described as catecholamine-sparing agents. Among others, the most used are vasopressin, corticosteroids, and angiotensin II. Methylene blue (MB) represents a further option, even though its use is still a topic of controversy. This review article tries to summarize what is known and unknown about the actions of MB in patients in shock. It reduces excessive production of nitric oxide via blockade of guanylate cyclase in shock states. At present, it appears the MB provides positive results in septic shock, if administered early. Further randomized controlled trials are warranted regarding its use to provide more precise indications to physicians involved in the treatment of such patients

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor

Study of the a_0(980) meson via the radiative decay phi->eta pi^0 gamma with the KLOE detector

We have studied the phi->a_0(980) gamma process with the KLOE detector at the Frascati phi-factory DAPhNE by detecting the phi->eta pi^0 gamma decays in the final states with eta->gamma gamma and eta->pi^+ pi^- pi^0. We have measured the branching ratios for both final states: Br(phi->eta pi^0 gamma)=(7.01 +/- 0.10 +/- 0.20)x10^-5 and (7.12 +/- 0.13 +/- 0.22)x10^-5 respectively. We have also extracted the a_0(980) mass and its couplings to eta pi^0, K^+ K^-, and to the phi meson from the fit of the eta pi^0 invariant mass distributions using different phenomenological models.Comment: 17 pages, 6 figures, submitted to Physics Letters B. Corrected typos in eq.

Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma

PR domain containing 1 with zinc finger domain (PRDM1)/B lymphocyte–induced maturation protein 1 (BLIMP1) is a transcriptional repressor expressed in a subset of germinal center (GC) B cells and in all plasma cells, and required for terminal B cell differentiation. The BLIMP1 locus lies on chromosome 6q21-q22.1, a region frequently deleted in B cell lymphomas, suggesting that it may harbor a tumor suppressor gene. We report here that the BLIMP1 gene is inactivated by structural alterations in 24% (8 out of 34) activated B cell–like diffuse large cell lymphoma (ABC-DLBCL), but not in GC B cell–like (n = 0/37) or unclassified (n = 0/21) DLBCL. BLIMP1 alterations included gene truncations, nonsense mutations, frameshift deletions, and splice site mutations that generate aberrant transcripts encoding truncated BLIMP1 proteins. In all cases studied, both BLIMP1 alleles were inactivated by deletions or mutations. Furthermore, most non–GC type DLBCL cases (n = 20/26, 77%) lack BLIMP1 protein expression, despite the presence of BLIMP1 mRNA. These results indicate that a sizable fraction of ABC-DLBCL carry an inactive BLIMP1 gene, and suggest that the same gene is inactivated by epigenetic mechanisms in an additional large number of cases. These findings point to a role for BLIMP1 as a tumor suppressor gene, whose inactivation may contribute to lymphomagenesis by blocking post–GC differentiation of B cells toward plasma cells

Study of the process e+e- -> omega pi0 in the phi-meson mass region with the KLOE detector

We have studied the e+e- -> omegapi0 cross section in the sqrt(s) interval 1000-1030 MeV using the pi+pi-pi0pi0 and pi0pi0gamma final states with a sample of ~600 pb^-1 collected with the KLOE detector at DAFNE. By fitting the observed interference pattern around M_phi for both final states, we extract the ratio of the decay widths Gamma(omega->pi0gamma)/Gamma(omega->pi+pi-pi0) = 0.0897 +- 0.0016 and derive the branching fractions BR(omega -> pi+pi-pi0)= (90.24 +- 0.19)%, BR(omega -> pi0gamma) = (8.09 +- 0.14)%. The parameters describing the e+e- -> omegapi0 reaction around M_\phi are also used to extract the branching fraction for the OZI and G-parity violating phi -> omegapi0 decay: BR(phi->omegapi0) = (4.4 +- 0.6)x10^-5.Comment: 12 Pages, 4 figures, submitted to Physics Letter

System Test of the ATLAS Muon Spectrometer in the H8 Beam at the CERN SPS

An extensive system test of the ATLAS muon spectrometer has been performed in the H8 beam line at the CERN SPS during the last four years. This spectrometer will use pressurized Monitored Drift Tube (MDT) chambers and Cathode Strip Chambers (CSC) for precision tracking, Resistive Plate Chambers (RPCs) for triggering in the barrel and Thin Gap Chambers (TGCs) for triggering in the end-cap region. The test set-up emulates one projective tower of the barrel (six MDT chambers and six RPCs) and one end-cap octant (six MDT chambers, A CSC and three TGCs). The barrel and end-cap stands have also been equipped with optical alignment systems, aiming at a relative positioning of the precision chambers in each tower to 30-40 micrometers. In addition to the performance of the detectors and the alignment scheme, many other systems aspects of the ATLAS muon spectrometer have been tested and validated with this setup, such as the mechanical detector integration and installation, the detector control system, the data acquisition, high level trigger software and off-line event reconstruction. Measurements with muon energies ranging from 20 to 300 GeV have allowed measuring the trigger and tracking performance of this set-up, in a configuration very similar to the final spectrometer. A special bunched muon beam with 25 ns bunch spacing, emulating the LHC bunch structure, has been used to study the timing resolution and bunch identification performance of the trigger chambers. The ATLAS first-level trigger chain has been operated with muon trigger signals for the first time

Search for the K_S -> e+e- decay with the KLOE detector

We present the result of a direct search for the decay K_S -> e+e-, obtained with a sample of e+e- -> phi -> K_S K_L events produced at DAFNE, the Frascati phi-factory, for an integrated luminosity of 1.9 fb^-1. The search has been performed using a pure K_S beam tagged by the simultaneous detection of a K_L interaction in the calorimeter. Background rejection has been optimized by using both kinematic and particle identification cuts. We find BR(K_S -> e+e-) < 9x10^-9 at 90% CL, which improves by an order of magnitude on the previous best limit.Comment: 13 pages, 11 figures, submitted to Physics Letters