Terminal spreading depolarization and electrical silence in death of human cerebral cortex

Objective: Restoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could help predict the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization. This potentially reversible, spreading wave typically starts 2 to 5 minutes after the onset of severe ischemia, marking the onset of a toxic intraneuronal change that eventually results in irreversible injury. Methods: To investigate this in the human brain, we performed recordings with either subdural electrode strips (n = 4) or intraparenchymal electrode arrays (n = 5) in patients with devastating brain injury that resulted in activation of a Do Not Resuscitate–Comfort Care order followed by terminal extubation. Results: Withdrawal of life‐sustaining therapies produced a decline in brain tissue partial pressure of oxygen (ptiO2) and circulatory arrest. Silencing of spontaneous electrical activity developed simultaneously across regional electrode arrays in 8 patients. This silencing, termed “nonspreading depression,” developed during the steep falling phase of ptiO2 (intraparenchymal sensor, n = 6) at 11 (interquartile range [IQR] = 7–14) mmHg. Terminal spreading depolarizations started to propagate between electrodes 3.9 (IQR = 2.6–6.3) minutes after onset of the final drop in perfusion and 13 to 266 seconds after nonspreading depression. In 1 patient, terminal spreading depolarization induced the initial electrocerebral silence in a spreading depression pattern; circulatory arrest developed thereafter. Interpretation: These results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults. Ann Neurol 2018;83:295–31

Diagnosis of pericardial cysts using diffusion weighted magnetic resonance imaging: A case series

<p>Abstract</p> <p>Introduction</p> <p>Congenital pericardial cysts are benign lesions that arise from the pericardium during embryonic development. The diagnosis is based on typical imaging features, but atypical locations and signal magnetic resonance imaging sequences make it difficult to exclude other lesions. Diffusion-weighted magnetic resonance imaging is a novel method that can be used to differentiate tissues based on their restriction to proton diffusion. Its use in differentiating pericardial cysts from other pericardial lesions has not yet been described.</p> <p>Case presentation</p> <p>We present three cases (a 51-year-old Caucasian woman, a 66-year-old Caucasian woman and a 77-year-old Caucasian woman) with pericardial cysts evaluated with diffusion-weighted imaging using cardiac magnetic resonance imaging. Each lesion demonstrated a high apparent diffusion coefficient similar to that of free water.</p> <p>Conclusion</p> <p>This case series is the first attempt to investigate the utility of diffusion-weighted magnetic resonance imaging in the assessment of pericardial cysts. Diffusion-weighted imaging may be a useful noninvasive diagnostic tool for pericardial cysts when conventional imaging findings are inconclusive.</p

Focused Ion Beam Fabrication

Contains reports on ten research projects.U.S. Army Research Office Contract DAAL03-88-K-0108Hughes Research Laboratories FellowshipSEMATECHCharles S. Draper Laboratory Contract DL-H-261827U.S. Army Research Office Contract DAAL03-87-K-0126IBM General Technologies DivisionIBM Research Divisio

Focused Ion Beam Fabrication

Contains reports on thirteen research projects and a list of publications.Defense Advanced Research Projects Agency/U.S. Army Research Office Contract DAAL03-88-K-0108National Science Foundation Grant ECS 89-21728MIT Lincoln Laboratory Innovative Research ProgramSEMATECH Contract 90-MC-503Micrion Contract M08774U.S. Army Research Office Contract DAAL03-87-K-0126IBM Corporatio

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Ordered Processing of the Human Immunodeficiency Virus Type 1 GagPol Precursor Is Influenced by the Context of the Embedded Viral Protease

Ordered and accurate processing of the human immunodeficiency virus type 1 (HIV-1) GagPol polyprotein precursor by a virally encoded protease is an indispensable step in the appropriate assembly of infectious viral particles. The HIV-1 protease (PR) is a 99-amino-acid enzyme that is translated as part of the GagPol precursor. Previously, we have demonstrated that the initial events in precursor processing are accomplished by the PR domain within GagPol in cis, before it is released from the polyprotein. Despite the critical role that ordered processing of the precursor plays in viral replication, the forces that define the order of cleavage remain poorly understood. Using an in vitro assay in which the full-length HIV-1 GagPol is processed by the embedded PR, we examined the effect of PR context (embedded within GagPol versus the mature 99-amino-acid enzyme) on precursor processing. Our data demonstrate that the PR domain within GagPol is constrained in its ability to cleave some of the processing sites in the precursor. Further, we find that this constraint is dependent upon the presence of a proline as the initial amino acid in the embedded PR; substitution of an alanine at this position produces enhanced cleavage at additional sites when the precursor is processed by the embedded, but not the mature, PR. Overall, our data support a model in which the selection of processing sites and the order of precursor processing are defined, at least in part, by the structure of GagPol itself

Optimal parameters for clinical implementation of breast cancer patient setup using Varian DTS software

Digital tomosynthesis (DTS) was evaluated as an alternative to cone‐beam computed tomography (CBCT) for patient setup. DTS is preferable when there are constraints with setup time, gantry‐couch clearance, and imaging dose using CBCT. This study characterizes DTS data acquisition and registration parameters for the setup of breast cancer patients using nonclinical Varian DTS software. DTS images were reconstructed from CBCT projections acquired on phantoms and patients with surgical clips in the target volume. A shift‐and‐add algorithm was used for DTS volume reconstructions, while automated cross‐correlation matches were performed within Varian DTS software. Triangulation on two short DTS arcs separated by various angular spread was done to improve 3D registration accuracy. Software performance was evaluated on two phantoms and ten breast cancer patients using the registration result as an accuracy measure; investigated parameters included arc lengths, arc orientations, angular separation between two arcs, reconstruction slice spacing, and number of arcs. The shifts determined from DTS‐to‐CT registration were compared to the shifts based on CBCT‐to‐CT registration. The difference between these shifts was used to evaluate the software accuracy. After findings were quantified, optimal parameters for the clinical use of DTS technique were determined. It was determined that at least two arcs were necessary for accurate 3D registration for patient setup. Registration accuracy of 2 mm was achieved when the reconstruction arc length was > 5° for clips with HU ≥ 1000°; larger arc length (≥ 8°) was required for very low HU clips. An optimal arc separation was found to be ≥ 20° and optimal arc length was 10°. Registration accuracy did not depend on DTS slice spacing. DTS image reconstruction took 10–30 seconds and registration took less than 20 seconds. The performance of Varian DTS software was found suitable for the accurate setup of breast cancer patients. Optimal data acquisition and registration parameters were determined. PACS numbers: 87.57.‐s, 87.57.nf, 87.57.n