The role of histone arginine methylation in gene expression of airway smooth muscle cells in asthma

Introduction and objectives: Asthma is estimated to affect at least 300 million people globally. About 25% of the patients do not respond to therapy; therefore we need to develop novel treatments. ASM cells have a crucial role in asthma, contributing to airway remodelling, inflammation and airflow obstruction. We have previously shown that epigenetic histone modifications, particularly histone lysine acetylation and methylation regulate the secretion of inflammatory mediators from ASM cells. Here we tested the hypothesis that histone arginine changes are also involved. Protein arginine N-methyltransferases (PRMTs) are the enzymes which catalyse histone arginine methylation (HRme, the addition of a methyl group to arginine residues on the N-terminal tails of histones), and inhibiting them represents a strategy to reduce the secretion of inflammatory mediators from ASM cells. Methods: Studies were performed in cultured human ASM cells from asthmatic and non-asthmatic donors at passage 6. PRMT expression in human ASM cells was investigated by qPCR. Protein levels of four PRMTs in human ASM cells were investigated by western blotting. The effect of inhibiting PRMTs on the secretion of eotaxin, IL-6, CXCL8 and IP-10 from healthy ASM cells, under basal conditions and following stimulation with TNF-α (1ng/ml), was investigated by ELISA. Results: We found that ASM cells express the PRMT1, PRMT2, PRMT3, CARM1, PRMT5, PRMT6, PRMT7 and FBX011 mRNA and PRMT1, CARM1, PRMT5, and PRMT6 protein. The analysis showed no difference in the levels of expression between cells isolated from asthmatic and non-asthmatic donors. Two PRMT inhibitors, namely TCE5003 – a PRMT1 inhibitor, and 217531 - a CARM1 inhibitor, significantly reduced the secretion of inflammatory mediators from ASM cells. Conclusions: ASM cells express a number of PRMTs at mRNA and protein levels. The inhibition of PRMTs results in the reduced secretion of inflammatory mediators from ASM cells. PRMTs may have an important role in regulating chemokine production from ASM cells in asthma, and are a promising target for future investigations in asthma

Alpha-stat acid-base regulation during cardiopulmonary bypass improves neuropsychologic outcome in patients undergoing coronary artery bypass grafting

AbstractNeuropsychologic impairment in patients undergoing cardiopulmonary bypass may be associated with cerebral blood flow changes arising from different management protocols for carbon dioxide tension during bypass. Seventy patients having coronary artery bypass grafting were randomized to either pH-stat or alpha-stat acid-base management during cardiopulmonary bypass with a membrane oxygenator. In each patient, cerebral blood flow (xenon 133 clearance), middle cerebral artery blood flow velocity (transcranial Doppler sonography), and cerebral oxygen metabolism (cerebral metabolic rate and cerebral extraction ratio) were measured during four phases of the operation: before bypass, during bypass (at hypothermia and at normothermia), and after bypass. A battery of neuropsychologic tests were also conducted before and 6 weeks after the operation. During hypothermic (28º C) bypass, cerebral blood flow was significantly (p < 0.001) greater in the pH-stat group (41 ml•100 gm -1 •min -1 ; 95% confidence interval 39 to 43 ml•100 gm -1 •min -1 ) than in the alpha-stat group (24 ml•100 gm -1 •min -1 ; confidence interval 22 to 26 ml•100 gm -1 •min -1 ) at constant pressure and flow. Arterial carbon dioxide tensions were 41 mm Hg (40 to 41 mm Hg) and 26 mm Hg (25 to 27 mm Hg), respectively; pH was 7.36 (7.34 to 7.38) and 7.53 (7.51 to 7.55), respectively. Middle cerebral artery flow velocity was significantly (p < 0.05) reduced in the alpha-stat group to 87% (77% to 96%) of the prebypass value, whereas it was significantly (p < 0.05) increased (152%; 141% to 162%) in the pH-stat group. Cerebral extraction ratio for oxygen demonstrated relative cerebral hyperemia during hypothermic (28º C) bypass in both the pH-stat and alpha-stat groups (0.12 [0.11 to 0.14] and 0.25 [0.22 to 0.28], respectively); however, hyperemia was significantly more pronounced in the pH-stat group, indicating greater disruption in cerebral autoregulation. Neuropsychologic impairment criteria of deterioration in results of three or more tests revealed that a significantly (Fisher's exact test, p = 0.02) higher proportion of patients in the pH-stat group fared poorly than in the alpha-stat group at 6 weeks (17/35, 48.6% [32% to 65.1%], and 7/35, 20% [6.7% to 33.2.2%], respectively). In conclusion, patients receiving alpha-stat management had less disruption of cerebral autoregulation during cardiopulmonary bypass, accompanied by a reduced incidence of postoperative cerebral dysfunction. (J THORAC CARDIOVASC SURG 1996;111:1267-79

Efficacy of different fungicides against dry rot pathogen of potato caused by Fusarium sp. under in vitro condition

Potato crop is affected by numerous diseases in field, as well as in storage conditions, particularly in cold storage. Dry rot of potato is caused by Fusarium sp. Dry rot of seed tubers can reduce crop establishment by killing developing potato sprouts, and crop losses can be up to 25%, while more than 60% of tubers can be infected in storage. It is a rich source of energy, which supplement food source of a country. In this experiment, four systemic and four non-systemic fungicides were tested at different concentrations in vitro for their comparative efficacy against inhibition of the growth of Fusarium sp. through poisoned food technique. To manage these diseases effectively, different concentrations of fungicides were tested. Results revealed against Fusarium sp. that carbendazim and benomyl significantly inhibited the fungal growth even at its lower concentration (100 ppm) and proved statistically superior over the rest of the fungicides tested at different concentrations and among non-systemic fungicides, MEMC significantly inhibited the fungal growth even at its lower concentration (1000 ppm)

The glueball spectrum from an anisotropic lattice study

The spectrum of glueballs below 4 GeV in the SU(3) pure-gauge theory is investigated using Monte Carlo simulations of gluons on several anisotropic lattices with spatial grid separations ranging from 0.1 to 0.4 fm. Systematic errors from discretization and finite volume are studied, and the continuum spin quantum numbers are identified. Care is taken to distinguish single glueball states from two-glueball and torelon-pair states. Our determination of the spectrum significantly improves upon previous Wilson action calculations.Comment: 14 pages, 8 figures, uses REVTeX and epsf.sty (final version published in Physical Review D

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

BACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .)

Calibration and Control of a Redundant Robotic Workcell for Milling Tasks

This article deals with the tuning of a complex robotic workcell of eight joints devoted to milling tasks. It consists of a KUKA (TM) manipulator mounted on a linear track and synchronised with a rotary table. Prior to any machining, the additional joints require an in situ calibration in an industrial environment. For this purpose, a novel planar calibration method is developed to estimate the external joint configuration parameters by means of a laser displacement sensor and avoiding direct contact with the pattern. Moreover, a redundancy resolution scheme on the joint rate level is integrated within a computer aided manufacturing system for the complete control of the workcell during the path tracking of a milling task. Finally, the whole system is tested in the prototyping of an orographic model.Andres De La Esperanza, FJ.; Gracia Calandin, LI.; Tornero Montserrat, J. (2011). Calibration and Control of a Redundant Robotic Workcell for Milling Tasks. International Journal of Computer Integrated Manufacturing. 24(6):561-573. doi:10.1080/0951192X.2011.566284S56157324

Field Measurements of Terrestrial and Martian Dust Devils

Surface-based measurements of terrestrial and martian dust devils/convective vortices provided from mobile and stationary platforms are discussed. Imaging of terrestrial dust devils has quantified their rotational and vertical wind speeds, translation speeds, dimensions, dust load, and frequency of occurrence. Imaging of martian dust devils has provided translation speeds and constraints on dimensions, but only limited constraints on vertical motion within a vortex. The longer mission durations on Mars afforded by long operating robotic landers and rovers have provided statistical quantification of vortex occurrence (time-of-sol, and recently seasonal) that has until recently not been a primary outcome of more temporally limited terrestrial dust devil measurement campaigns. Terrestrial measurement campaigns have included a more extensive range of measured vortex parameters (pressure, wind, morphology, etc.) than have martian opportunities, with electric field and direct measure of dust abundance not yet obtained on Mars. No martian robotic mission has yet provided contemporaneous high frequency wind and pressure measurements. Comparison of measured terrestrial and martian dust devil characteristics suggests that martian dust devils are larger and possess faster maximum rotational wind speeds, that the absolute magnitude of the pressure deficit within a terrestrial dust devil is an order of magnitude greater than a martian dust devil, and that the time-of-day variation in vortex frequency is similar. Recent terrestrial investigations have demonstrated the presence of diagnostic dust devil signals within seismic and infrasound measurements; an upcoming Mars robotic mission will obtain similar measurement types

Identification of clonal hematopoiesis mutations in solid tumor patients undergoing unpaired next-generation sequencing assays

Purpose: In this era of precision-based medicine, for optimal patient care, results reported from commercial next-generation sequencing (NGS) assays should adequately reflect the burden of somatic mutations in the tumor being sequenced. Here, we sought to determine the prevalence of clonal hematopoiesis leading to possible misattribution of tumor mutation calls on unpaired Foundation Medicine NGS assays. Experimental Design: This was a retrospective cohort study of individuals undergoing NGS of solid tumors from two large cancer centers. We identified and quantified mutations in genes known to be frequently altered in clonal hematopoiesis (DNMT3A, TET2, ASXL1, TP53, ATM, CHEK2, SF3B1, CBL, JAK2) that were returned to physicians on clinical Foundation Medicine reports. For a subset of patients, we explored the frequency of true clonal hematopoiesis by comparing mutations on Foundation Medicine reports with matched blood sequencing. Results: Mutations in genes that are frequently altered in clonal hematopoiesis were identified in 65% (1,139/1,757) of patients undergoing NGS. When excluding TP53, which is often mutated in solid tumors, these events were still seen in 35% (619/1,757) of patients. Utilizing paired blood specimens, we were able to confirm that 8% (18/226) of mutations reported in these genes were true clonal hematopoiesis events. The majority of DNMT3A mutations (64%, 7/11) and minority of TP53 mutations (4%, 2/50) were clonal hematopoiesis. Conclusions: Clonal hematopoiesis mutations are commonly reported on unpaired NGS testing. It is important to recognize clonal hematopoiesis as a possible cause of misattribution of mutation origin when applying NGS findings to a patient's care

Medical students' personal experience of high-stakes failure:case studies using interpretative phenomenological analysis

Abstract (provisional): Background Failing a high-stakes assessment at medical school is a major event for those who go through the experience. Students who fail at medical school may be more likely to struggle in professional practice, therefore helping individuals overcome problems and respond appropriately is important. There is little understanding about what factors influence how individuals experience failure or make sense of the failing experience in remediation. The aim of this study was to investigate the complexity surrounding the failure experience from the student’s perspective using interpretative phenomenological analysis (IPA). Methods The accounts of 3 medical students who had failed final re-sit exams, were subjected to in-depth analysis using IPA methodology. IPA was used to analyse each transcript case-by-case allowing the researcher to make sense of the participant’s subjective world. The analysis process allowed the complexity surrounding the failure to be highlighted, alongside a narrative describing how students made sense of the experience. Results The circumstances surrounding students as they approached assessment and experienced failure at finals were a complex interaction between academic problems, personal problems (specifically finance and relationships), strained relationships with friends, family or faculty, and various mental health problems. Each student experienced multi-dimensional issues, each with their own individual combination of problems, but experienced remediation as a one-dimensional intervention with focus only on improving performance in written exams. What these students needed to be included was help with clinical skills, plus social and emotional support. Fear of termination of the their course was a barrier to open communication with staff. Conclusions These students’ experience of failure was complex. The experience of remediation is influenced by the way in which students make sense of failing. Generic remediation programmes may fail to meet the needs of students for whom personal, social and mental health issues are a part of the picture