Mechanisms and management of diabetic painful distal symmetrical polyneuropathy

Although a number of the diabetic neuropathies may result in painful symptomatology, this review focuses on the most common: chronic sensorimotor distal symmetrical polyneuropathy (DSPN). It is estimated that 15–20% of diabetic patients may have painful DSPN, but not all of these will require therapy. In practice, the diagnosis of DSPN is a clinical one, whereas for longitudinal studies and clinical trials, quantitative sensory testing and electrophysiological assessment are usually necessary. A number of simple numeric rating scales are available to assess the frequency and severity of neuropathic pain. Although the exact pathophysiological processes that result in diabetic neuropathic pain remain enigmatic, both peripheral and central mechanisms have been implicated, and extend from altered channel function in peripheral nerve through enhanced spinal processing and changes in many higher centers. A number of pharmacological agents have proven efficacy in painful DSPN, but all are prone to side effects, and none impact the underlying pathophysiological abnormalities because they are only symptomatic therapy. The two first-line therapies approved by regulatory authorities for painful neuropathy are duloxetine and pregabalin. α-Lipoic acid, an antioxidant and pathogenic therapy, has evidence of efficacy but is not licensed in the U.S. and several European countries. All patients with DSPN are at increased risk of foot ulceration and require foot care, education, and if possible, regular podiatry assessment

Changing Natural History of HER2–Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies

Patients with breast cancer brain metastases historically have a poor prognosis. In this single-institution cohort study of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases, we found no improvement in survival after brain recurrence over time despite wide adoption of HER2–targeted therapies. This highlights the importance of continued development of novel brain penetrant therapies for patients with HER2–positive metastatic disease to extend survival and improve quality of life. Background: Given the wide adoption of human epidermal growth factor receptor 2 (HER2)-targeted therapies for advanced HER2–positive breast cancer, we studied the natural history of patients with HER2–positive breast cancer brain metastases (BCBM) over time. Patients and Methods: Patients with HER2–positive BCBM identified from a prospectively maintained database at the University of North Carolina were divided into 3 cohorts by year of BCBM diagnosis. Cohorts were selected by year of HER2–targeted therapy US Food and Drug Administration approval. Overall survival (OS), time to first metastasis, time to BCBM, and BCBM survival were estimated by the Kaplan-Meier method. Associations between OS after BCBM and clinical variables were assessed by Cox proportional hazards regression models. Results: One hundred twenty-three patients were identified. Median age was 51 years, and 58% were white and 31% African American. OS from initial breast cancer diagnosis improved over time: 3.6 years (95% confidence interval [CI], 2.8-6.1) in the 1998-2007 cohort, 6.6 years (95% CI, 4.5-8.6) in the 2008-2012 cohort, and 7.6 years (95% CI, 4.4-9.6) in the 2013-2015 cohort (P =.05). While time from initial diagnosis to first metastasis did not differ (P =.12), time to BCBM increased over time (2.6 years [95% CI, 1.3-3.5] for 1998-2007; 2.6 years [95% CI, 2.1-4.3] for 2008-2012, and 3.3 years [95% CI, 2.2-6] for 2013-2015; P =.05). Although OS from BCBM did not significantly differ by cohort, patients who received HER2–targeted therapy after BCBM had a prolonged OS (2.1 years [95% CI, 1.6-2.6] vs. 0.65 years [95% CI, 0.4-1.3]; P =.001). Conclusion: OS from initial breast cancer diagnosis significantly improved over time for patients with HER2–positive breast cancer who develop BCBM, now exceeding 7 years; survival from BCBM diagnosis may now exceed 2 years

Milagrito: a TeV air-shower array

Milagrito, a large, covered water-Cherenkov detector, was the world's first air-shower-particle detector sensitive to cosmic gamma rays below 1 TeV. It served as a prototype for the Milagro detector and operated from February 1997 to May 1998. This paper gives a description of Milagrito, a summary of the operating experience, and early results that demonstrate the capabilities of this technique.Comment: 38 pages including 24 figure

A low level of extragalactic background light as revealed by big gamma-rays from blazars

The diffuse extragalactic background light consists of the sum of the starlight emitted by galaxies through the history of the Universe, and it could also have an important contribution from the 'first stars', which may have formed before galaxy formation began. Direct measurements are difficult and not yet conclusive, owing to the large uncertainties caused by the bright foreground emission associated with zodiacal light1. An alternative approach2, 3, 4, 5 is to study the absorption features imprinted on the -ray spectra of distant extragalactic objects by interactions of those photons with the background light photons6. Here we report the discovery of -ray emission from the blazars7 H 2356 - 309 and 1ES 1101 - 232, at redshifts z = 0.165 and z = 0.186, respectively. Their unexpectedly hard spectra provide an upper limit on the background light at optical/near-infrared wavelengths that appears to be very close to the lower limit given by the integrated light of resolved galaxies8. The background flux at these wavelengths accordingly seems to be strongly dominated by the direct starlight from galaxies, thus excluding a large contribution from other sources—in particular from the first stars formed9. This result also indicates that intergalactic space is more transparent to -rays than previously thought

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

The Great Markarian 421 Flare of 2010 February: Multiwavelength Variability and Correlation Studies

We report on variability and correlation studies using multiwavelength observations of the blazar Mrk 421 during the month of 2010 February, when an extraordinary flare reaching a level of ∼27 Crab Units above 1 TeV was measured in very high energy (VHE) γ-rays with the Very Energetic Radiation Imaging Telescope Array System (VERITAS) observatory. This is the highest flux state for Mrk 421 ever observed in VHE γ-rays. Data are analyzed from a coordinated campaign across multiple instruments, including VHE γ-ray (VERITAS, Major Atmospheric Gamma-ray Imaging Cherenkov), high-energy γ-ray (Fermi-LAT), X-ray (Swift, Rossi X-ray Timing Experiment, MAXI), optical (including the GASP-WEBT collaboration and polarization data), and radio (Metsahovi, Owens Valley Radio Observatory, University of Michigan Radio Astronomy Observatory). Light curves are produced spanning multiple days before and after the peak of the VHE flare, including over several flare "decline" epochs. The main flare statistics allow 2 minute time bins to be constructed in both the VHE and optical bands enabling a cross-correlation analysis that shows evidence for an optical lag of ∼25-55 minutes, the first time-lagged correlation between these bands reported on such short timescales. Limits on the Doppler factor (δ ⪆ 33) and the size of the emission region (δ-1RB≲ 3.8 × 1013cm) are obtained from the fast variability observed by VERITAS during the main flare. Analysis of 10 minute binned VHE and X-ray data over the decline epochs shows an extraordinary range of behavior in the flux-flux relationship, from linear to quadratic to lack of correlation to anticorrelation. Taken together, these detailed observations of an unprecedented flare seen in Mrk 421 are difficult to explain with the classic single-zone synchrotron self-Compton model.</p

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