Abnormal structural and functional brain connectivity in gray matter heterotopia

available in PMC 2013 June 01Purpose:  Periventricular nodular heterotopia (PNH) is a malformation of cortical development associated with epilepsy and dyslexia. Evidence suggests that heterotopic gray matter can be functional in brain malformations and that connectivity abnormalities may be important in these disorders. We hypothesized that nodular heterotopia develop abnormal connections and systematically investigated the structural and functional connectivity of heterotopia in patients with PNH. Methods:  Eleven patients were studied using diffusion tensor tractography and resting-state functional connectivity MRI with bold oxygenation level–dependent (BOLD) imaging. Fiber tracks with a terminus within heterotopic nodules were visualized to determine structural connectivity, and brain regions demonstrating resting-state functional correlations to heterotopic nodules were analyzed. Relationships between these connectivity results and measures of clinical epilepsy and cognitive disability were examined. Key Findings:  A majority of heterotopia (69%) showed structural connectivity to discrete regions of overlying cortex, and almost all (96%) showed functional connectivity to these regions (mean peak correlation coefficient 0.61). Heterotopia also demonstrated connectivity to regions of contralateral cortex, other heterotopic nodules, ipsilateral but nonoverlying cortex, and deep gray matter structures or the cerebellum. Patients with the longest durations of epilepsy had a higher degree of abnormal functional connectivity (p = 0.036). Significance:  Most heterotopic nodules in PNH are structurally and functionally connected to overlying cortex, and the strength of abnormal connectivity is higher among patients with the longest duration of epilepsy. Along with prior evidence that cortico-cortical tract defects underlie dyslexia in this disorder, the current findings suggest that altered connectivity is likely a critical substrate for neurologic dysfunction in brain malformations.National Institutes of Health (U.S.) (NIH/NINDS R01 NS073601)National Institutes of Health (U.S.) (NIH/NINDS K23 NS049159)Epilepsy Foundation of AmericaHarvard University (William F. Milton Fund

Worldwide variations in artificial skyglow

Despite constituting a widespread and significant environmental change, understanding of artificial nighttime skyglow is extremely limited. Until now, published monitoring studies have been local or regional in scope, and typically of short duration. In this first major international compilation of monitoring data we answer several key questions about skyglow properties. Skyglow is observed to vary over four orders of magnitude, a range hundreds of times larger than was the case before artificial light. Nearly all of the study sites were polluted by artificial light. A non-linear relationship is observed between the sky brightness on clear and overcast nights, with a change in behavior near the rural to urban landuse transition. Overcast skies ranged from a third darker to almost 18 times brighter than clear. Clear sky radiances estimated by the World Atlas of Artificial Night Sky Brightness were found to be overestimated by ~25%; our dataset will play an important role in the calibration and ground truthing of future skyglow models. Most of the brightly lit sites darkened as the night progressed, typically by ~5% per hour. The great variation in skyglow radiance observed from site-to-site and with changing meteorological conditions underlines the need for a long-term international monitoring program

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pmed.100213