Search for diffuse neutrino flux from astrophysical sources with MACRO

Many galactic and extragalactic astrophysical sources are currently considered promising candidates as high energy neutrino emitters. Astrophysical neutrinos can be detected as upward-going muons produced in charged-current interactions with the medium surrounding the detector. The expected neutrino fluxes from various models start to dominate on the atmospheric neutrino background at neutrino energies above some tens of TeV. We present the results of a search for an excess of high energy upward-going muons among the sample of data collected by MACRO during ~5.8 years of effective running time. No significant evidence for this signal was found. As a consequence, an upper limit on the flux of upward-going muons from high-energy neutrinos was set at the level of 1.7 10^(-14) cm^(-2) s^(-1) sr^(-1). The corresponding upper limit for the diffuse neutrino flux was evaluated assuming a neutrino power law spectrum. Our result was compared with theoretical predictions and upper limits from other experiments.Comment: 19 pages, 8 figures, 2 table

Chinese herbal recipe versus diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial [ISRCTN70292892]

BACKGROUND: Duhuo Jisheng Wan (DJW) is perhaps the best known and most widely used Chinese herbal recipe for arthralgia, but the clinical study to verify its efficacy is lacking. The purpose of this study was to compare the efficacy of DJW versus diclofenac in symptomatic treatment of osteoarthritis (OA) of the knee. METHODS: This study was a randomized, double-blind, double-dummy, controlled trial. The 200 patients suffering from OA of the knee, were randomized into the DJW and diclofenac group. The patients were evaluated after a run-in period of one week (week 0) and then weekly during 4 weeks of treatment. The clinical assessments included visual analog scale (VAS) score that assessed pain and stiffness, Lequesne's functional index, time for climbing up 10 steps, as well as physician's and patients' overall opinions on improvement. RESULTS: Ninety four patients in each group completed the study. In the first few weeks of treatment, the mean changes in some variables (VAS, which assessed walking pain, standing pain and stiffness, as well as Lequesne's functional index) of the DJW group were significantly lower than those of the diclofenac group. Afterwards, these mean changes became no different throughout the study. Most of the physician's and patients' overall opinions on improvement at each time point did not significantly differ between the two groups. Approximately 30% of patients in both groups experienced mild adverse events. CONCLUSION: DJW demonstrates clinically comparable efficacy to diclofenac after 4 weeks of treatment. However, the slow onset of action as well as approximately equal rate of adverse events to diclofenac might limit its alternative role in treatment of OA of the knee

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Activation of DNA-PK by Ionizing Radiation Is Mediated by Protein Phosphatase 6

DNA-dependent protein kinase (DNA-PK) plays a critical role in DNA damage repair, especially in non-homologous end-joining repair of double-strand breaks such as those formed by ionizing radiation (IR) in the course of radiation therapy. Regulation of DNA-PK involves multisite phosphorylation but this is incompletely understood and little is known about protein phosphatases relative to DNA-PK. Mass spectrometry analysis revealed that DNA-PK interacts with the protein phosphatase-6 (PP6) SAPS subunit PP6R1. PP6 is a heterotrimeric enzyme that consists of a catalytic subunit, plus one of three PP6 SAPS regulatory subunits and one of three ankyrin repeat subunits. Endogenous PP6R1 co-immunoprecipitated DNA-PK, and IR enhanced the amount of complex and promoted its import into the nucleus. In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation. Knockdown of other phosphatases PP5 or PP1γ1 and subunits PP6R3 or ARS-A did not reduce IR activation of DNA-PK, demonstrating specificity for PP6R1. Finally, siRNA knockdown of PP6R1 or PP6 but not other phosphatases increased the sensitivity of glioblastoma cells to radiation-induced cell death to a level similar to DNA-PK deficient cells. Our data demonstrate that PP6 associates with and activates DNA-PK in response to ionizing radiation. Therefore, the PP6/PP6R1 phosphatase is a potential molecular target for radiation sensitization by chemical inhibition

Paracetamol in therapeutic dosages and acute liver injury: causality assessment in a prospective case series

Background: Acute liver injury (ALI) induced by paracetamol overdose is a well known cause of emergency hospital admission and death. However, there is debate regarding the risk of ALI after therapeutic dosages of the drug. The aim is to describe the characteristics of patients admitted to hospital with jaundice who had previous exposure to therapeutic doses of paracetamol. An assessment of the causality role of paracetamol was performed in each case. Methods: Based on the evaluation of prospectively gathered cases of ALI with detailed clinical information, thirty-two cases of ALI in non-alcoholic patients exposed to therapeutic doses of paracetamol were identified. Two authors assessed all drug exposures by using the CIOMS/RUCAM scale. Each case was classified into one of five categories based on the causality score for paracetamol. Results: In four cases the role of paracetamol was judged to be unrelated, in two unlikely, and these were excluded from evaluation. In seven of the remaining 26 cases, the RUCAM score associated with paracetamol was higher than that associated with other concomitant medications. The estimated incidence of ALI related to the use of paracetamol in therapeutic dosages was 0.4 per million inhabitants older than 15 years of age and per year (99%CI, 0.2-0.8) and of 10 per million paracetamol users-year (95% CI 4.3-19.4). Conclusions:Our results indicate that paracetamol in therapeutic dosages may be considered in the causality assessment in non-alcoholic patients with liver injury, even if the estimated incidence of ALI related to paracetamol appears to be low

Astrophysical Origins of Ultrahigh Energy Cosmic Rays

In the first part of this review we discuss the basic observational features at the end of the cosmic ray energy spectrum. We also present there the main characteristics of each of the experiments involved in the detection of these particles. We then briefly discuss the status of the chemical composition and the distribution of arrival directions of cosmic rays. After that, we examine the energy losses during propagation, introducing the Greisen-Zaptsepin-Kuzmin (GZK) cutoff, and discuss the level of confidence with which each experiment have detected particles beyond the GZK energy limit. In the second part of the review, we discuss astrophysical environments able to accelerate particles up to such high energies, including active galactic nuclei, large scale galactic wind termination shocks, relativistic jets and hot-spots of Fanaroff-Riley radiogalaxies, pulsars, magnetars, quasar remnants, starbursts, colliding galaxies, and gamma ray burst fireballs. In the third part of the review we provide a brief summary of scenarios which try to explain the super-GZK events with the help of new physics beyond the standard model. In the last section, we give an overview on neutrino telescopes and existing limits on the energy spectrum and discuss some of the prospects for a new (multi-particle) astronomy. Finally, we outline how extraterrestrial neutrino fluxes can be used to probe new physics beyond the electroweak scale.Comment: Higher resolution version of Fig. 7 is available at http://www.angelfire.com/id/dtorres/down3.html. Solicited review article prepared for Reports on Progress in Physics, final versio

High-energy Neutrino Astronomy: The Cosmic Ray Connection

This is a review of neutrino astronomy anchored to the observational fact that Nature accelerates protons and photons to energies in excess of $10^{20}$ and $10^{13}$ eV, respectively. Although the discovery of cosmic rays dates back close to a century, we do not know how and where they are accelerated. Basic elementary-particle physics dictates a universal upper limit on their energy of $5\times10^{19}$ eV, the so-called Greisen-Kuzmin-Zatsepin cutoff; however, particles in excess of this energy have been observed by all experiments, adding one more puzzle to the cosmic ray mystery. Mystery is fertile ground for progress: we will review the facts as well as the speculations about the sources including gamma ray bursts, blazars and top-down scenarios. The important conclusion is that, independently of the specific blueprint of the source, it takes a kilometer-scale neutrino observatory to detect the neutrino beam associated with the highest energy cosmic rays and gamma rays. We also briefly review the ongoing efforts to commission such instrumentation.Comment: 83 pages, 18 figures, submitted to Reports on Progress in Physic