First administration to man of Org 25435, an intravenous anaesthetic: A Phase 1 Clinical Trial

BACKGROUND: Org 25435 is a new water-soluble alpha-amino acid ester intravenous anaesthetic which proved satisfactory in animal studies. This study aimed to assess the safety, tolerability and efficacy of Org 25435 and to obtain preliminary pharmacodynamic and pharmacokinetic data. METHODS: In the Short Infusion study 8 healthy male volunteers received a 1 minute infusion of 0.25, 0.5, 1.0, or 2.0 mg/kg (n = 2 per group); a further 10 received 3.0 mg/kg (n = 5) or 4.0 mg/kg (n = 5). Following preliminary pharmacokinetic modelling 7 subjects received a titrated 30 minute Target Controlled Infusion (TCI), total dose 5.8-20 mg/kg. RESULTS: Within the Short Infusion study, all subjects were successfully anaesthetised at 3 and 4 mg/kg. Within the TCI study 5 subjects were anaesthetised and 2 showed signs of sedation. Org 25435 caused hypotension and tachycardia at doses over 2 mg/kg. Recovery from anaesthesia after a 30 min administration of Org 25435 was slow (13.7 min). Pharmacokinetic modelling suggests that the context sensitive half-time of Org 25435 is slightly shorter than that of propofol in infusions up to 20 minutes but progressively longer thereafter. CONCLUSIONS: Org 25435 is an effective intravenous anaesthetic in man at doses of 3 and 4 mg/kg given over 1 minute. Longer infusions can maintain anaesthesia but recovery is slow. Hypotension and tachycardia during anaesthesia and slow recovery of consciousness after cessation of drug administration suggest this compound has no advantages over currently available intravenous anaesthetics

A Study into the Application of a FRP Deck in Railway Bridges

Fibre reinforced polymer is a new material that is more and more used in civil engineering works. This lightweight and high-strength material comes with a lot of advantages. The application of this lightweight material in bridge structures can result in a reduction of the out-of-service time of railways. On the other hand, the low stiffness of this material offers a big challenge. The stiffness requirements of railway bridges are strict to ensure safe and comfortable passing of trains. This thesis looks at the application of a FRP deck in railway bridges. The literature study describes (1) the material FRP, (2) state-of-the-art in (FRP) bridges and (3) a dynamic model for (railway) bridges. The main properties of FRP materials are listed including common manufacturing processes. According to a state-of-the-art study two designs are presented: (1) A sandwich deck, commonly used in FRP bridges, and (2) a through deck, commonly used in railway bridges. Furthermore, the requirements and loadings for railway bridges are listed. The dynamic model for railway bridges is based on a mass-spring rigid body system with Rayleigh damping. This model is used to verify the finite element models. A material study is performed to determine the most suitable material properties for FRP railway bridges. Glass fibres and polyester resin are choses based on individual material properties, market prices and common use in civil engineering structures. Foam has no structural integrity but is used as permanent form work. The lay-up of fibres is based on the literature study and differ for flanges and webs. The lay-up for flanges is: [12.5% - 90° | 12.5% - ±45° | 62.5% - 0° | 12.5% - ±45°]s The lay-up for webs is: [25% - 90° | 20% - ±45° | 35% - 0° | 20% - ±45°]s The volume fraction of both laminates is 50%. These lay ups in combination with the conversion factors and safety factors result in a FRP material suitable for FRP railway bridges. The design study describes the sandwich and through design with the materials from the material study. Two finite element model are made using Sofistik. These finite element models are verified using analytical models. A static and dynamic analysis is performed on both designs. Based on the results from the static analysis the maximum deflection and maximum stresses of the Sandwich Design do not exceed the limits, and the maximum deflection and maximum stresses of the Through Design do exceed the limits. Based on the dynamic analysis both designs do exceed the limits. Furthermore, in consultation with a FRP manufacturer, the laminate thickness must be reduced to ensure both designs are manufacturable. Based on the results of the design study and the requirements presented in the literature study a new design is created. This design includes the following improvements: (1) reduction of the span by transferring the forces in transverse direction, (2) extra height of the design, (3) more webs, (4) extra supports, (5) reduction of the laminate thickness to 30 mm and (6) the use of pre-camber. This final design is transformed into a finite element model. A static and dynamic analysis is performed. Based on the results of the static analysis the maximum deflection and maximum stresses do not exceed the limits. The dynamic analysis results in maximum acceleration of 19.48 m/s2, which exceeds the limit and results in a unity check of 5.57. The final design doesn’t meet the requirements based on the results of the dynamic analysis. An important remark on the dynamic results is made in the discussion. The dynamic load model, consisting of point loads, is applied directly on the bridge deck, omitting the dynamic behaviour of the ballast bed. Taking into account the ballast bed in the dynamic analysis might result in a significant reduction of the maximum acceleration of the bridge deck due to the spreading and damping effect of the ballast bed. In conclusion, according to the results of the static analysis of the final design it is possible to apply a FRP deck in railway bridges. Improvement of the dynamic numerical model is needed before drawing conclusions on the dynamic behaviour of the final design.Civil Engineering | Structural Engineerin

Suppression of the inflammatory response in experimental arthritis is mediated via estrogen receptor alpha but not estrogen receptor beta

Introduction: The immune modulatory role of estrogens in inflammation is complex. Both pro- and anti-inflammatory effects of estrogens have been described. Estrogens bind both estrogen receptor (ER)alpha and beta. The contribution of ER alpha and ER beta to ER-mediated immune modulation was studied in delayed type hypersensitivity (DTH) and in experimental arthritis Methods: ER-mediated suppression of rat adjuvant arthritis (AA) was studied using ethinyl-estradiol (EE) and a selective ER beta agonist (ERB-79). Arthritis was followed for 2 weeks. Next, effects of ER agonists (ethinyl-estradiol, an ER alpha selective agonist (ERA-63) and a selective ER beta agonist (ERB-79) on the development of a tetanus toxoid (TT)-specific delayed type hypersensitivity response in wild type (WT) and in ER alpha- or ER beta-deficient mice were investigated. Finally, EE and ERA-63 were tested for their immune modulating potential in established collagen induced arthritis in DBA/1J mice. Arthritis was followed for three weeks. Joint pathology was examined by histology and radiology. Local synovial cytokine production was analyzed using Luminex technology. Sera were assessed for COMP as a biomarker of cartilage destruction. Results: EE was found to suppress clinical signs and symptoms in rat AA. The selective ER beta agonist ERB-79 had no effect on arthritis symptoms in this model. In the TT-specific DTH model, EE and the selective ER alpha agonist ERA-63 suppressed the TT-specific swelling response in WT and ER beta KO mice but not in ER alpha KO mice. As seen in the AA model, the selective ER beta agonist ERB-79 did not suppress inflammation. Treatment with EE or ERA-63 suppressed clinical signs in collagen induced arthritis (CIA) in WT mice. This was associated with reduced inflammatory infiltrates and decreased levels of proinflammatory cytokines in CIA joints. Conclusions: ER alpha, but not ER beta, is key in ER-mediated suppression of experimental arthritis. It remains to be investigated how these findings translate to human autoimmune disease

Clusters of genes encoding fructan biosynthesizing enzymes in wheat and barley

Fructans are soluble carbohydrates with health benefits and possible roles in plant adaptation. Fructan biosynthetic genes were isolated using comparative genomics and physical mapping followed by BAC sequencing in barley. Genes encoding sucrose:sucrose 1-fructosyltransferase (1-SST), fructan:fructan 1-fructosyltransferase (1-FFT) and sucrose:fructan 6-fructosyltransferase (6-SFT) were clustered together with multiple copies of vacuolar invertase genes and a transposable element on two barley BAC. Intron–exon structures of the genes were similar. Phylogenetic analysis of the fructosyltransferases and invertases in the Poaceae showed that the fructan biosynthetic genes may have evolved from vacuolar invertases. Quantitative real-time PCR was performed using leaf RNA extracted from three wheat cultivars grown under different conditions. The 1-SST, 1-FFT and 6-SFT genes had correlated expression patterns in our wheat experiment and in existing barley transcriptome database. Single nucleotide polymorphism (SNP) markers were developed and successfully mapped to a major QTL region affecting wheat grain fructan accumulation in two independent wheat populations. The alleles controlling high- and low- fructan in parental lines were also found to be associated in fructan production in a diverse set of 128 wheat lines. To the authors’ knowledge, this is the first report on the mapping and sequencing of a fructan biosynthetic gene cluster and in particular, the isolation of a novel 1-FFT gene from barley.Bao-Lam Huynh; Diane E. Mather; Andreas W. Schreiber; John Toubia; Ute Baumann; Zahra Shoaei; Nils Stein; Ruvini Ariyadasa; James C. R. Stangoulis; James Edwards; Neil Shirley; Peter Langridge; Delphine Fleur

Early rhythm-control therapy in patients with atrial fibrillation

BACKGROUND Despite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control therapy can reduce this risk. METHODS In this international, investigator-initiated, parallel-group, open, blinded-outcome-assessment trial, we randomly assigned patients who had early atrial fibrillation (diagnosed ≤1 year before enrollment) and cardiovascular conditions to receive either early rhythm control or usual care. Early rhythm control included treatment with antiarrhythmic drugs or atrial fibrillation ablation after randomization. Usual care limited rhythm control to the management of atrial fibrillation–related symptoms. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome; the second primary outcome was the number of nights spent in the hospital per year. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm-control therapy. Secondary outcomes, including symptoms and left ventricular function, were also evaluated. RESULTS In 135 centers, 2789 patients with early atrial fibrillation (median time since diagnosis, 36 days) underwent randomization. The trial was stopped for efficacy at the third interim analysis after a median of 5.1 years of follow-up per patient. A first-primary-outcome event occurred in 249 of the patients assigned to early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence interval, 0.66 to 0.94; P=0.005). The mean (±SD) number of nights spent in the hospital did not differ significantly between the groups (5.8±21.9 and 5.1±15.5 days per year, respectively; P=0.23). The percentage of patients with a primary safety outcome event did not differ significantly between the groups; serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care. Symptoms and left ventricular function at 2 years did not differ significantly between the groups. CONCLUSIONS Early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions