The NORwegian study on DIstrict treatment of ST-Elevation Myocardial Infarction (NORDISTEMI)

Objectives. Thrombolysis is the treatment of choice for patients with ST-elevation myocardial infarction (STEMI) living in rural areas with long transfer delays to percutaneous coronary intervention (PCI). This trial compares two different strategies following thrombolysis: to transfer all patients for immediate coronary angiography and intervention, or to manage the patients more conservatively. Design. The NORwegian study on DIstrict treatment of STEMI (NORDISTEMI) is an open, prospective, randomized controlled trial in patients with STEMI of less than 6 hours of duration and more than 90 minutes expected time delay to PCI. A total of 266 patients will receive full-dose thrombolysis, preferably prehospitally, and then be randomized to either strategy. Our primary endpoint is the one year combined incidence of death, reinfarction, stroke or new myocardial ischaemia. The study is registered with ClinicalTrials.gov, number NCT00161005. Results. By April 2006, 109 patients have been randomized. Thrombolysis has been given prehospitally to 52% of patients. The median transport distance from first medical contact to catheterization laboratory was 155 km (range 90–396 km). Results of the study are expected in 2008.

Trial registration: ClinicalTrials.gov identifier: NCT00161005.     

Dysprosium magnesium silicate apatite featuring field and temperature stable slow magnetization relaxation

Dy–Mg silicate Dy₈Mg₂(SiO₄)₆O₂ has been prepared by high-temperature solid state reaction. It has an apatite type structure (P6₃/m) with the Dy atoms fully occupying the 6h site and being in random distribution with the Mg atoms at the 4f site. The compound reveals dual magnetization relaxation with widely varying contributions from fast (FR) and slow (SR) relaxation paths controlled by field and temperature. The SR path is stabilized by a strong magnetic field, exhibits a weak dependence of relaxation time τ on field and temperature, and sustains large τ of a few seconds up to a temperature of 40 K and under a field of 50 kOe. The analysis of the electronic structure and comparison with the known Dy-doped phosphate apatites suggests that the Orbach and Raman processes are suppressed.

The compound reveals dual magnetization relaxation with largely varying contributions from fast and slow relaxation paths controlled by field and temperature. The relaxation times retain values of a few seconds up to 40 K.     

fMRI evaluation of hemispheric language dominance using various methods of laterality index calculation

Several functional MR imaging studies evaluating the lateralisation of linguistic functions in patients who underwent Wada testing have been reported. There is extensive variance in the Laterality index (LI) calculation across the studies, and the optimal calculation method remains unclear. We attempted to calculate the LI in different ways in the same subjects, in order to find the LI calculation method with the highest correlation to the Wada test. Fifteen patients (10 females, 5 males) suffering from medically intractable temporal lobe epilepsy (TLE) (12 left, 3 right) were admitted for the study. The patients underwent a standardized bilateral intracarotid short-acting barbiturate test. Language testing included spontaneous speech, oral comprehension, reading, object and picture naming, and repetition. All the tasks were scored separately in order to increase the possibility of correlation between Wada and LI. A silent phonemic verbal fluency task (VFT) was used as a language paradigm for functional measurement. Regions of interest (ROIs), with a known association with language function (Broca’s area, the lateral prefrontal cortex, etc.), were defined. First, the LIs were calculated from the ROIs using a previously reported method (simple suprathreshold count). Next, we used several new methods of LI calculation (t–weighting of voxels, methods independent of the choice of the statistical threshold, etc.) The most significant correlation with Wada was proven in the LIs that were evaluated from Broca’s area (up to R = 0.94, P = 1 × 10⁻⁷). However, the new LI calculation methods used in the present study did not produce a statistically significant benefit in comparison to previously reported methods.     

Topography of signaling molecules as detected by electron microscopy on plasma membrane sheets isolated from non-adherent mast cells

Immunolabeling of isolated plasma membrane (PM) sheets combined with high-resolution electron microscopy is a powerful technique for understanding the topography of PM-bound signaling molecules. However, this technique has been mostly confined to analysis of membrane sheets from adherent cells. Here we present a rapid, simple and versatile method for isolation of PM sheets from non-adherent cells, and show its use for examination of the topography of Fcepsilon receptor I (FcepsilonRI) and transmembrane adaptors, LAT (linker for activation of T cells) and NTAL (non-T cell activation linker), in murine bone marrow-derived mast cells (BMMC). The data were compared with those obtained from widely used but tumor-derived rat basophilic leukemia (RBL) cells. In non-activated cells, FcepsilonRI was distributed either individually or in small clusters of comparable size in both cell types. In multivalent antigen-activated BMMC as well as RBL cells, FcepsilonRI was internalized to a similar extent, but, strikingly, internalization in BMMC was not preceded by formation of large (~200 nm) aggregates of FcepsilonRI, described previously in activated RBL cells. On the other hand, downstream adaptor proteins, LAT and NTAL, were localized in independent domains in both BMMC and RBL cells before and after FcepsilonRI triggering. The combined data demonstrate unexpected properties of FcepsilonRI signaling assemblies in BMMC and emphasize the importance of studies of PM sheets isolated from non-tumor cells.     

A semi-analytical radiobiological model may assist treatment planning in light ion radiotherapy

A semi-analytical model of light ions' Bragg peaks is presented and used in conjunction with a detailed probabilistic radiobiological module to predict the biological effectiveness of light ion irradiation for hadrontherapy applications. The physical Bragg peak model is based on energy-loss calculations with the SRIM code and phenomenological formulae for the energy-loss straggling. Effects of nuclear reactions are accounted for on the level of reducing the number of primary particles only. Reaction products are not followed at all and their contribution to dose deposition is neglected. Beam widening due to multiple scattering and calculations of spread-out Bragg peaks are briefly discussed. With this simple physical model, integral depth-dose distributions are calculated for protons, carbon, oxygen and neon ions. A good agreement with published experimental data is observed for protons and lower energy ions (with ranges in water up to approximately 15 cm), while less satisfactory results are obtained for higher energy ions due to the increased role of nuclear reaction products, neglected in this model. A detailed probabilistic radiobiological module is used to complement the simple physical model and to estimate biological effectiveness along the penetration depth of Bragg peak irradiation. Excellent agreement is found between model predictions and experimental data for carbon beams, indicating potential applications of the present scheme in treatment planning in light ion hadrontherapy. Due to the semi-analytical character of the model, leading to high computational speed, applications are foreseen in particular in the fully biological optimization of multiple irradiation fields and intensity-modulated beams.     

Rotational Rheology of Bovine Serum Albumin Solutions: Confounding Effects of Impurities,Mechanistic Considerations and Potential Implications on Protein Formulation Development

Purpose

To show and rationalize the confounding effects on the rotational/oscillatory rheology of surface active impurities in commercial protein formulations such as bovine serum albumin, BSA.

Methods

Bulk and interfacial rotational/oscillatory rheology were used to study the viscosity, complex viscosity, storage/elastic modulus, G’ and loss/viscous modulus, G”, as a function of time of aqueous formulations of BSA and their purified components.

Results

Viscosity/time profiles at steady shear for different commercial BSA products and lots showed viscosity increase, decrease and time-independent profiles at low shear rates. All lots showed shear thinning. BSA monomer and dimers/aggregates, in general, showed similar profiles. Addition of low levels of surfactant or high shear rates rendered all solutions to be Newtonian-like. Interfacial viscosity studies paralleled those on the rotational rheometer. G’?>?G” with viscosity increase and G’?<?G” with viscosity decrease over time.

Conclusions

We provide a rational explanation for the time-dependent and source-dependent rheological behavior of aqueous formulations of commercially available BSA proteins based on the migration of protein and surface active impurities to the air/water interface within the rheometer plates leading to the formation and breakdown of protein networks. Highly purified proteins is warranted in rheological studies of protein drug product candidates.

     

Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial

American Journal of Cardiovascular Drugs - SERAPHIN was a double-blind, placebo-controlled, event-driven phase III trial that evaluated the effects of long-term treatment with macitentan, an oral...     

Reproducibility of sonographic measurement of the substantia nigra

The aim of this study was to evaluate inter-reader, intra-investigator and inter-investigator reproducibility and correlations in the assessment of substantia nigra (SN) echogenicity and area measurement by a physician-sonographer (PS), a sonographic laboratory assistant (SLA) and a physician without sonographic experience (PN). A total of 22 patients with extrapyramidal symptoms were examined using transcranial sonography (TCS). SN images were encoded and evaluated by the three readers. A second TCS examination was performed after 7+/-2 d. A second investigator performed TCS examination 1 mo later. Spearman rank correlation and Pearson's correlation coefficient were used when assessing the agreement between readers. All three readers identified the same 15 patients with SN echogenicity III or more. Inter-reader SN echogenicity and area measurement correlations were r=0.55 to 0.82 and r=0.31 to 0.74 between PS and SLA and r=0.55 to 0.77 and 0.49 to 0.62 between PS and PN, respectively (p<0.05 in all cases). Intra-reader echogenicity and area measurement correlations (r=0.85 to 0.96 and r=0.51 to 0.69) were statistically significant only for PS (p<0.001). All intra- and inter-investigator correlations of SN area measurement (r=0.69 to 0.88 and r=0.5 to 0.61) and SN echogenicity (r=0.64 to 0.92 and r=0.51 to 0.69) were statistically significant (p<0.05). Semiquantitative evaluation of SN echogenicity and area using TCS is highly dependent on the experience of the sonographer. Only an experienced sonographer was able to produce very reproducible results with statistically significant correlations; SLA and PN intra-reader correlations were poor.     

Does status epilepticus modify the effect of ifenprodil on cortical epileptic afterdischarges in immature rats?

Background

Ifenprodil as a specific antagonist of NMDA receptors containing a dominant NR2B subunit exhibits age-dependent anticonvulsant action. Possible changes of this action due to status epilepticus (SE) elicited at early stage of development were studied using cortical epileptic afterdischarges (ADs) as a model.