Read-across of 90-Day Rat Oral Repeated-Dose Toxicity: A Case Study for Selected 2-Alkyl-1-alkanols

2-Alkyl-1-alkanols offer an example whereby the category approach to read-across can be used to predict repeated-dose toxicity for a variety of derivatives. Specifically, the NOAELs of 125 mg/kg bw/d for 2-ethyl-1-hexanol and 2-propyl-1-heptanol, the source substances, can be read across with confidence to untested 2-alkyl-1-alkanols in the C5 to C13 category based on a LOAEL of low systemic toxicity. These branched alcohols, while non-reactive and exhibiting unspecific, reversible simple anaesthesia or nonpolar narcosis mode of toxic action, have metabolic pathways that have significance to repeated-dose toxic potency. In this case study, the chemical category is limited to the readily bioavailable analogues. The read-across premise includes rapid absorption via the gastrointestinal tract, distribution in the circulatory system and first-pass metabolism in the liver via Phase 2 glucuronidation prior to urinary elimination. 2-Ethyl-1-hexanol and 2-propyl-1-heptanol, the source substances, have high quality 90-day oral repeated-dose toxicity studies (OECD TG 408) that exhibit qualitative and quantitative consistency. Findings include only mild changes consistent with low-grade effects including decreased body weight and slightly increased liver weight, which in some cases is accompanied by clinical chemical and haematological changes but generally without concurrent histopathological effects at the LOAEL. These findings are supported by results from the TG 408 assessment of a semi-defined mixture of isotridecanols. Chemical similarity between the analogues is readily defined and data uncertainty associated with toxicokinetic and toxicodynamics similarities are low. Uncertainty associated with mechanistic relevance and completeness of the read-across is reduced by the concordance of in vivo and in vitro results, as well as high throughput and in silico methods data. As shown in detail, the 90-day rat oral repeated-dose NOAEL values for the two source substances can be read across to fill the data gaps of the untested analogues in this category with uncertainty deemed equivalent to results from a TG 408 assessment

The First VERITAS Telescope

The first atmospheric Cherenkov telescope of VERITAS (the Very Energetic Radiation Imaging Telescope Array System) has been in operation since February 2005. We present here a technical description of the instrument and a summary of its performance. The calibration methods are described, along with the results of Monte Carlo simulations of the telescope and comparisons between real and simulated data. The analysis of TeV $\gamma$-ray observations of the Crab Nebula, including the reconstructed energy spectrum, is shown to give results consistent with earlier measurements. The telescope is operating as expected and has met or exceeded all design specifications.Comment: Accepted by Astroparticle Physic

VERITAS: the Very Energetic Radiation Imaging Telescope Array System

The Very Energetic Radiation Imaging Telescope Array System (VERITAS) represents an important step forward in the study of extreme astrophysical processes in the universe. It combines the power of the atmospheric Cherenkov imaging technique using a large optical reflector with the power of stereoscopic observatories using arrays of separated telescopes looking at the same shower. The seven identical telescopes in VERITAS, each of aperture 10 m, will be deployed in a filled hexagonal pattern of side 80 m; each telescope will have a camera consisting of 499 pixels with a field of view of 3.5 deg VERITAS will substantially increase the catalog of very high energy (E > 100GeV) gamma-ray sources and greatly improve measurements of established sources.Comment: 44 pages, 16 figure

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)

Pengaruh Pemberian Ketotifen terhadap Jumlah Sel Fibroblas dan Kepadatan Sel Kolagen pada Luka Insisi Tikus Wistar

Ingga Hadian, S-501202027. PENGARUH PEMBERIAN KETOTIFEN TERHADAP JUMLAH SEL FIBROBLAS DAN KEPADATAN SEL KOLAGEN PADA LUKA INSISI TIKUS WISTAR. Pembimbing I : DR. Untung Alfianto, dr, Sp.Bs, Pembimbing II : dr. Ardana Tri Arianto. Msi. Med. Sp.An-KNA. Program studi Magister Kedokteran Keluarga, Minat Utama Ilmu Biomedik, Fakultas Kedokteran Universitas Sebelas Maret, Surakarta, 2016. Latar Belakang : Sel mast merupakan salah satu yang berperan dalam proses inflamasi pada penyembuhan luka. Sel mast dikaitkan dengan kejadian luka kronis, sehingga sel mast diduga ikut memelihara proses inflamasi secara berlebihan. Hambatan pada degranulasi sel mast diharapkan akan mempercepat penyembuhan luka yang ditandai dengan meningkatnya jumlah sel fibroblas dan kepadatan sel kolagen. Ketotifen mampu mengurangi dreganulasi sel Mast dan mengurangi pelepasan Histamin, protease sel Mast, myeloperoxidase, leukotriens, PAF dan bermacam-macam Prostaglandin. Ketotifen juga menghambat agregasi polimorfonuklear serta mengurangi respon inflamasi dan mempercepat migrasi fibroblas di fase proliferasi. Tujuan :Mengetahui perbedaan jumlah sel fibroblas dan kepadatan sel kolagen pada tikus wistar yang diberikan Ketotifen oral dosis 0.3 mg/kg dibandingkan plasebo pada penyembuhan luka insisi tikus wistar. Metode : Penelitian ini termasuk true eksperimental laboratorik dengan desain Randomized Controlled Trial yang menggunakan tikus wistar sebagai obyek penelitian. 14 tikus Wistar dibagi dalam 2 kelompok, masing masing kelompok terdiri atas 7 tikus Wistar. Kelompok 1 merupakan kelompok kontrol yang dilakukan insisi sepanjang 2cm pada kulit punggung tikus dan diberikan plasebo per oral selama 6 hari. Kelompok 2 merupakan kelompok perlakuan yang dilakukan insisi sepanjang 2cm pada kulit punggung tikus dan diberikan Ketotifen 0,3 mg/kgBB per oral setiap 12 jam selama 6 hari. Analisis data untuk membandingkan rerata antar kedua kelompok yaitu kelompok perlakuan dan kelompok kontrol menggunakan uji independent samples t-test, dengan tingkat kemaknaan p < 0,05 (dikatakan bermakna secara statistik). Hasil : Pada kelompok kontrol didapatkan rerata persentase kepadatan sel kolagen sebesar 26,05 %, sedangkan pada kelompok Ketotifen didapatkan rerata persentase kepadatan sel kolagen sebesar 36,13 %. Untuk jumlah sel fibroblas pada kelompok kontrol didapatkan rerata sebesar 423 per lapang pandang, sedangkan pada kelompok Ketotifen didapatkan rerata sebesar 555,43 per lapang pandang. Kesimpulan : Ketotifen mempercepat penyembuhan luka ditandai dengan peningkatan sel fibroblas dan sel kolagen. Kata Kunci : Sel Mast, Ketotifen, Sel fibroblas, Serabut Kolagen. ABSTRACT Ingga Hadian, S-501202027. EFFECTS OF KETOTIFEN ON FIBROBLAST CELL COUNT AND COLLAGEN DENSITY ON INCISED WISTAR RATS. DR. Untung Alfianto, dr., Sp.BS, dr. Ardana Tri Arianto, Msi, Med, Sp.An-KNA. Background: Mast cells have a pivotal role in every healing process that involves inflammation of the cells, usually in wounds of chronic nature. If the degranulation process of the mast cells are inhibited, the healing process of the wound will accelerate, indicated by a raise in fibroblast cells and collagen density. Ketotifen are shown to inhibit the degranulation process and decreasing the release of histamin, mast cells proteases, myeloperoxidases, leukotriens, PAF, and various prostaglandins. Ketotifen can also inhibit the aggregation of polymorphonuclear cells, increasing the rate of fibroblast migration in the proliferation phase. This study was aimed to identify the effects of ketotifen on fibroblast cell count and collagen density tested on a wistar rats model. Methods: This study was a true laboratoric experimental study with randomized controlled trial using wistar rats model as objects. 14 rats were divided into two groups, each group contained seven rats. The first group was the control group, where the rats were incised 2 cm above the back skin, and were given per oral placebo for 6 days. The second group were given the same treatment, only the rats were given ketotifen 0.3 mg/kg per oral, every 12 hours lasting 6 days. The data were then collected and tested with independent sample t-test, with p value less than 0,05 is statistically significant. Results: In the control group, the mean percentage of the thickest collagen density were marked at 26.05%, whereas in the treatment group collagen density were marked at 36.13%. The mean fibroblast cell count were marked at 423 and 555.43 each viewing field, on the control group and the treatment group respectively. Conclusion: Ketotifen can accelerate the healing process, marked by the significant increase in collagen density and fibroblast cell count. Keywords: mast cells, ketotifen, fibroblast cells, collagen fibers

Multiwavelength observations of a TeV-Flare from W comae

We report results from an intensive multiwavelength campaign on the intermediate-frequency-peaked BL Lacertae object W Com (z = 0.102) during a strong outburst of very high energy gamma-ray emission in 2008 June. The very high energy gamma-ray signal was detected by VERITAS on 2008 June 7-8 with a flux F(>200 GeV) =(5.7 0.6) × 10-11 cm-2 s -1, about three times brighter than during the discovery of gamma-ray emission from W Com by VERITAS in 2008 March. The initial detection of this flare by VERITAS at energies above 200 GeV was followed by observations in high-energy gamma rays (AGILE; E γ≥ 100 MeV), X-rays (Swift and XMM-Newton), and at UV, and ground-based optical and radio monitoring through the GASP-WEBT consortium and other observatories. Here we describe the multiwavelength data and derive the spectral energy distribution of the source from contemporaneous data taken throughout the flare. © 2009. The American Astronomical Society. All rights reserved

Insights into the high-energy γ-ray emission of Markarian 501 from extensive multifrequency observations in the Fermi era

We report on the γ-ray activity of the blazar Mrk 501 during the first 480 days of Fermi operation. We find that the average Large Area Telescope (LAT) γ-ray spectrum of Mrk 501 can be well described by a single power-law function with a photon index of 1.78 ± 0.03. While we observe relatively mild flux variations with the Fermi-LAT (within less than a factor of two), we detect remarkable spectral variability where the hardest observed spectral index within the LAT energy range is 1.52 ± 0.14, and the softest one is 2.51 ± 0.20. These unexpected spectral changes do not correlate with the measured flux variations above 0.3 GeV. In this paper, we also present the first results from the 4.5 month long multifrequency campaign (2009 March 15-August 1) on Mrk 501, which included the Very Long Baseline Array (VLBA), Swift, RXTE, MAGIC, and VERITAS, the F-GAMMA, GASP-WEBT, and other collaborations and instruments which provided excellent temporal and energy coverage of the source throughout the entire campaign. The extensive radio to TeV data set from this campaign provides us with the most detailed spectral energy distribution yet collected for this source during its relatively low activity. The average spectral energy distribution of Mrk 501 is well described by the standard one-zone synchrotron self-Compton (SSC) model. In the framework of this model, we find that the dominant emission region is characterized by a size ≲0.1 pc (comparable within a factor of few to the size of the partially resolved VLBA core at 15-43 GHz), and that the total jet power (≃1044 erg s-1) constitutes only a small fraction (∼10-3) of the Eddington luminosity. The energy distribution of the freshly accelerated radiating electrons required to fit the time-averaged data has a broken power-law form in the energy range 0.3 GeV-10 TeV, with spectral indices 2.2 and 2.7 below and above the break energy of 20 GeV. We argue that such a form is consistent with a scenario in which the bulk of the energy dissipation within the dominant emission zone of Mrk 501 is due to relativistic, proton-mediated shocks. We find that the ultrarelativistic electrons and mildly relativistic protons within the blazar zone, if comparable in number, are in approximate energy equipartition, with their energy dominating the jet magnetic field energy by about two orders of magnitude. © 2011. The American Astronomical Society