Posterior reversible encephalopathy syndrome (PRES) and CT perfusion changes

Posterior reversible encephalopathy syndrome (PRES) can present with focal neurologic deficits, mimicking a stroke and can often represent a diagnostic challenge when presenting atypically. A high degree of suspicion is required in the clinical setting in order to yield the diagnosis. Cerebral CT perfusion (CTP) is utilized in many institutions as the first line in acute stroke imaging. CTP has proved to be a very sensitive measure of cerebral blood flow dynamics, most commonly employed to delineate the infarcted tissue from penumbra (at-risk tissue) in ischemic strokes. But abnormal CTP is also seen in stroke mimics such as seizures, hypoglycemia, tumors, migraines and PRES. In this article we describe a case of PRES in an elderly bone marrow transplant recipient who presented with focal neurological deficits concerning for a cerebrovascular accident. CTP played a pivotal role in the diagnosis and initiation of appropriate management. We also briefly discuss the pathophysiology of PRES

Hybrid Wing Body Aircraft Acoustic Test Preparations and Facility Upgrades

NASA is investigating the potential of acoustic shielding as a means to reduce the noise footprint at airport communities. A subsonic transport aircraft and Langley's 14- by 22-foot Subsonic Wind Tunnel were chosen to test the proposed "low noise" technology. The present experiment studies the basic components of propulsion-airframe shielding in a representative flow regime. To this end, a 5.8-percent scale hybrid wing body model was built with dual state-of-the-art engine noise simulators. The results will provide benchmark shielding data and key hybrid wing body aircraft noise data. The test matrix for the experiment contains both aerodynamic and acoustic test configurations, broadband turbomachinery and hot jet engine noise simulators, and various airframe configurations which include landing gear, cruise and drooped wing leading edges, trailing edge elevons and vertical tail options. To aid in this study, two major facility upgrades have occurred. First, a propane delivery system has been installed to provide the acoustic characteristics with realistic temperature conditions for a hot gas engine; and second, a traversing microphone array and side towers have been added to gain full spectral and directivity noise characteristics

Genome Scan of M. tuberculosis Infection and Disease in Ugandans

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an enduring public health problem globally, particularly in sub-Saharan Africa. Several studies have suggested a role for host genetic susceptibility in increased risk for TB but results across studies have been equivocal. As part of a household contact study of Mtb infection and disease in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB, by studying three phenotypes. First, we analyzed culture confirmed TB disease compared to latent Mtb infection (LTBI) or lack of Mtb infection. Second, we analyzed resistance to Mtb infection in the face of continuous exposure, defined by a persistently negative tuberculin skin test (PTST-); this outcome was contrasted to LTBI. Third, we analyzed an intermediate phenotype, tumor necrosis factor-alpha (TNFα) expression in response to soluble Mtb ligands enriched with molecules secreted from Mtb (culture filtrate). We conducted a full microsatellite genome scan, using genotypes generated by the Center for Medical Genetics at Marshfield. Multipoint model-free linkage analysis was conducted using an extension of the Haseman-Elston regression model that includes half sibling pairs, and HIV status was included as a covariate in the model. The analysis included 803 individuals from 193 pedigrees, comprising 258 full sibling pairs and 175 half sibling pairs. Suggestive linkage (p<10−3) was observed on chromosomes 2q21-2q24 and 5p13-5q22 for PTST-, and on chromosome 7p22-7p21 for TB; these findings for PTST- are novel and the chromosome 7 region contains the IL6 gene. In addition, we replicated recent linkage findings on chromosome 20q13 for TB (p = 0.002). We also observed linkage at the nominal α = 0.05 threshold to a number of promising candidate genes, SLC11A1 (PTST- p = 0.02), IL-1 complex (TB p = 0.01), IL12BR2 (TNFα p = 0.006), IL12A (TB p = 0.02) and IFNGR2 (TNFα p = 0.002). These results confirm not only that genetic factors influence the interaction between humans and Mtb but more importantly that they differ according to the outcome of that interaction: exposure but no infection, infection without progression to disease, or progression of infection to disease. Many of the genetic factors for each of these stages are part of the innate immune system

Observations of teleseismic P wave coda for underground explosions

The early P wave coda (5–15 sec after the first arrival) of underground explosions at the Nevada Test Site is studied in the time domain using 2082 teleseismic short-period recordings, with the intent of identifying near-source contributions to the signals in the frequency range 0.2–2.0 Hz. Smaller magnitude events tend to have relatively high coda levels in the 0.4–0.8 Hz frequency band for both Yucca Flat and Pahute Mesa explosions. Coda complexity in this low-frequency passband is negatively correlated with burial depth for Pahute Mesa events but is only weakly correlated with depth for Yucca Flat events. Enhanced excitation of relatively long-period scattered waves for smaller, less deeply buried events is required to explain this behavior. Coda complexity in the 0.8–1.1 Hz band is positively correlated with magnitude and depth for Pahute Mesa events, but has no such dependence for Yucca Flat events. This may result from systematic variations between the spectra of direct signals and coda arrivals caused by pP interference for the largest events, all of which were detonated at Pahute Mesa. Another possible explanation is a frequency-dependent propagation effect on the direct signals of the larger events, most of which were located in the center of the mesa overlying strong lateral velocity gradients in the crust and upper mantle. Event average complexity varies spatially for both test sites, particularly in the 0.8–1.1 Hz band, providing evidence for frequency-dependent focussing or scattering by near-source structure. Both the direct arrivals and the early coda have strong azimuthal amplitude patterns that are produced by defocussing by mantle heterogeneity. The direct arrivals have stronger coherent azimuthal patterns than the early coda for Pahute Mesa events, indicating more pronounced deep crustal and shallow mantle defocussing for the direct signals. However, for Yucca Flat events the direct arrivals have less coherent azimuthal patterns than the coda, suggesting that a highly variable component of near-source scattering preferentially affecting the downgoing energy is superimposed on a pattern produced by mantle heterogeneity that affects the entire signal. This complicated behavior of the direct arrivals may be the result of triplications and caustics produced by the complex basement structure known to underlie the Yucca Flat test site. The presence of strong azimuthal patterns in the early coda indicates that source strength estimates based on early coda are subject to biases similar to those affecting estimates based on direct arrivals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43106/1/24_2005_Article_BF01772598.pd

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice

A História da Alimentação: balizas historiográficas

Os M. pretenderam traçar um quadro da História da Alimentação, não como um novo ramo epistemológico da disciplina, mas como um campo em desenvolvimento de práticas e atividades especializadas, incluindo pesquisa, formação, publicações, associações, encontros acadêmicos, etc. Um breve relato das condições em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biológica, a econômica, a social, a cultural e a filosófica!, assim como da identificação das contribuições mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histórica, foi ela organizada segundo critérios morfológicos. A seguir, alguns tópicos importantes mereceram tratamento à parte: a fome, o alimento e o domínio religioso, as descobertas européias e a difusão mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rápido balanço crítico da historiografia brasileira sobre o tema