A Flow-Through Dissolution Approach to In Vivo/In Vitro Correlation of Adinazolam Release from Sustained Release Formulations

A Copley^TM fraction collector and a Disotest^TM flow-through system were coupled to provide an automatic discrete sampling flow-through dissolution system for use both in the “open-loop” and “closed-loop” mode. The system was used to investigate the release characteristics of adinazolam in sustained release formulations using a pH 1.2 simulated gastric fluid (without enzymes) dissolution medium (USP XXI). These experimental formulations are designed to provide relatively slow to rapid drug release. The dissolution effluent was analysed off-line by reverse phase HPLC to determine the adinazolam concentration at programmed timed intervals. The differential dissolution profiles produced when the system is used in the “open-loop” configuration are more discriminating in describing the release characteristics of the formulations according to the relative release rates than the “closed-loop” cumulative profiles. Using the characteristic dissolution time parameter from the Weibull function, a better correlation with in vivo bioavailability data was achieved for the data from the system in the “open-loop” mode than when it was used in the “closed-loop” mode. In the “open-loop” mode the Weibull function characteristic dissolution time parameter yielded the best quantitative correlation with a correlation coefficient of 0.92 compared to a value of 0.85 for the “closed-loop” configuration     

How accurately does the public perceive differences in transport risks?: An exploratory analysis of scales representing perceived risk

This paper probes the extent to which the public accurately perceives differences in transport risks. The paper is based on a survey of a random sample of the Norwegian population, conducted in September 2003. In the survey, respondents were asked: “How safe do you think it is to travel by means of (bus, train, etc.)?” Answers were given as: very safe, safe, a little unsafe, and very unsafe. A cursory examination of the answers suggested that the Norwegian public was quite well informed about differences in the risk of accident between different modes of transport, as well as between groups formed according to age and gender for each mode of transport. This paper probes the relationship between statistical estimates of risk and summary representations of perceived risk more systematically. It is found that the differences in fatality rate between different modes of transport are quite well perceived by the Norwegian public, irrespective of the way in which perceived risk is represented numerically. The relationship between statistical estimates of risk and numerical representations of perceived risk for each mode of transport is more sensitive to the choice of a numerical representation of perceived risk. A scale in which the answer “very safe” is assigned the value of 0.01 and the answer “very unsafe” is assigned the value of 10 is found to perform quite well. When the perception of risk is represented numerically according to this scale, a positive correlation between statistically estimated risk and perceived risk is found in seven of the eight comparisons that were made to determine how well variation in accident rates according to age and gender for car occupants, car drivers, cyclists and pedestrians are perceived.     

An experimental study on the dynamic axial plastic buckling of cylindrical shells

This paper deals with an experimental study on the dynamic plastic post-buckling behaviour of a stationary AMΓ aluminium alloy cylindrical shell under axial impact. According to current theory, it is believed that within a certain velocity range, the shell will buckle in a uniform axisymmetrical sinusoidal mode. However, we found that when the impact velocity is less than a certain critical value V_c1, the shell will exhibit only uniform plastic deformation in both the axial and radial directions and does not produce the sinusoidal waves. On the other hand, when the impact velocity exceeds another critical value V_c2, the shell will change from the axisymmetric mode into a nonuniform type of large deformation, the number of waves decreases slightly and the shell begins to lose its load-carrying capacity. Experimental results on cylinders with three different thicknesses are presented and discussed. An approximate theoretical formula for estimating V_c2 based on strain rate reversal is also given.     

Engineering Multiwalled Carbon Nanotubes Inside a Transmission Electron Microscope Using Nanorobotic Manipulation

This paper provides a review of recent experimental techniques developed for shell engineering individual multiwalled carbon nanotubes (MWNTs). Basic processes for the nanorobotic manipulation of MWNTs inside a transmission electron microscope are investigated. MWNTs, bamboo-structured carbon nanotubes (CNTs), Cu-filled CNTs, and CNTs with quantum dots attached are used as test structures for manipulation. Picking is realized using van der Waals forces, “sticky” probes, electron-beam-induced deposition, and electric breakdown. Cap opening and shell shortening are presented using field emission current. Controlled peeling and thinning of the shells of MWNTs are achieved by electric breakdown, and changes in MWNT structures are correlated with electrical measurements. These processes are fundamental for the characterization of nanoscale materials, the structuring of nanosized building blocks, and the prototyping of nanoelectromechanical systems.      

Cracked shells under skew-symmetric loading

In this paper, the general problem of a shell containing a through crack in one of the principal planes of curvature and under general skew-symmetric loading is considered. By employing a Reissner type shell theory which takes into account the effect of transverse shear strains, all boundary conditions on the crack surfaces are satisfied separately. Consequently, unlike those obtained from the classical shell theory, the angular distributions of the stress components around the crack tips are shown to be identical to the distributions obtained from the plane and anti-plane elasticity solutions. Extensive results are given for axially and circumferentially cracked cylindrical shells, spherical shells, and toroidal shells under uniform in-plane shearing, out of plane shearing, and torsion. Taking advantage of the fact that the problem is formulated for “specially” orthotropic materials, the effect of orthotropy on the results is also studied in some detail.     

Gamma Approximation for Preventive Maintenance Scheduling

This paper presents an approximation model for determining minimum cost preventive maintenance schedules where accurate failure data are not available except the “average” (mean) and the “typical” value (mode) of the component lifetime.     

A mechanistic model for the effect of stress ratio on the LEFM fatigue crack growth behavior of metals and alloys—II. Crack-brittle materials

A recently proposed mechanistic model for the effect of stress ratio, R, on the LEFM (long) fatigue crack growth behavior of “crack-ductile” materials is extended here to explain and predict similar behavior under similar conditions of “crack-brittle” materials characterised by the presence of “static” modes of fatigue fracture in stages II and III. It is shown that in these materials the stage I behavior is similar, but the stages II and III behave differently from crack-ductile materials. Mechanism-based existence of two types of stage II curves characterised respectively by “ pure shear mode ” (SM-II) and “mixed-mode” (MM-II), both plotting linear but having different slopes, is introduced. It is shown that while stage SM-II is insensitive, stage MM-II is significantly sensitive to R, in the same material. Similar to stage I, another “ moving pivot-point ” exists at the transition from SM-II to MM-II, which slides down the “ master shear-curve ” with increasing R. Assuming a critical K_max for the initiation of static modes, a critical R for saturation of these modes, and Paris-type growth relations, a quantitative predictive model containing growth equations for stages SM-II and MM-II, has been developed. Stage III is discussed only qualitatively. Reasonably good agreement was found between predicted curves at selected R-values and a relatively large volume of experimental data for steels, Al-alloys and Ti-alloys. This simple, alternative model may be used for obtaining quick, fairly accurate and conservative estimates of R-influenced crack growth rates for design applications in preference to crack-closure which frequently requires elaborate and tedious experimental procedures.     

Emulsion Formulations: Study of the Influence of Parameters with Experimental Designs

Parameters of formulation of emulsions were performed by the aid of experimental designs. The aim of the work was to investigate five factors at two levels: temperature of manufacture, time of phase introduction, rate of homogenization, mode of cooling, and operators. The study of the flow behavior of the emulsions corresponds to the quantitive response. This work allowed us to show the dominating influence of the factor “mode of cooling”. The progressive cooling at room temperature gives a better stability than the brutal cooling with a water bath corresponding to a shorter homogenization. A further aim was to study the influence of an additional factor: the nature of the sulfactant with the best mode of cooling, progressive cooling. In that case, we can conclude that the main factor, the nature of the surfactant, influences the response.     

An improved model for the prediction of intra-cell buckling in CFRP sandwich panels under in-plane compressive loading

Local instability in the form of “intra-cell buckling” or “dimpling” is a well-known failure mode in honeycomb-cored sandwich panels with very thin faces. Most work reported on the subject suggests relatively simple design formulae for the estimation of the intra-cell buckling load. It is however widely known that these classical design formulae in some cases considerably underpredict the intra-cell buckling load. In this paper a series of experimental results obtained for different CFRP/honeycomb sandwich panel configurations loaded in compression are presented. The results confirm that the “classical” design formulae provide overly conservative results. During the tests the intra-cell buckling patterns were monitored carefully, and it was observed that the hitherto assumed buckling patterns did not correspond to the experimental observations. Based on these findings a new simplified design formula is suggested, which for the investigated CFRP/honeycomb sandwich panels provides significantly more accurate predictions than the “classical” design formulae.     

Growth and structure in abalone shell

The growth and self-assembly of aragonitic calcium carbonate found in the shell of abalone (Haliotis) is described. This was accomplished through the close examination of laboratory-grown flat pearl samples and cross-sectional slices of the nacreous shell. Further understanding of the sequenced assembly has been obtained. It has been confirmed that the growth of the aragonite component of the composite occurs by the successive nucleation of aragonite crystals and their arrest by means of a protein-mediated mechanism; it takes place in the “Christmas-tree pattern” [Nature 49 (1994) 371]. It is shown that the protein layer is virtually absent where plates on a same plane abut (along lateral surfaces of tiles). This suggests a mechanism of c-axis aragonite growth arrest by the deposition of a protein layer of approximately 20–30 nm that is periodically activated and determines the thickness of the aragonite platelets, which are remarkably constant (0.5 μm). This platelet size was measured for animals with shell diameters of 10, 50, and 200 mm and was found to be constant. The overall growth process is expressed in terms of parameters incorporating the anisotropy of growth velocity in aragonite (V_c, the velocity along c axis, and V_ab, the velocity in basal plane). Comparison of laboratory-raised and naturally-grown abalone indicates growth regulated by the level of proteinaceous saturation. Naturally-grown abalone exhibits mesolayers (growth bands) 0.3 mm apart; it is proposed that they result from seasonal interruptions in feeding patterns, creating thicker (10–20 μm) layers of protein. These mesolayers play a critical role in the mechanical properties, and are powerful crack deflectors. The viscoplastic deformation of the organic inter-tile layers is responsible for the significant improvement of tensile strength over the tensile strength of monolithic aragonite.     

First toxicity report of tetrodotoxin and 5,6,11-trideoxyTTX in the trumpet shell Charonia lampas lampas in Europe

Tetrodotoxin (TTX) is one of the most potent toxins already isolated, which occurs in a wide variety of animals. In this work, the occurrence of TTX and analogues was examined using mass spectrometry, confocal microscopy, liquid chromatography-mass spectrometry (LC-MS), and mouse bioassay in a trumpet shell (Charonia lampas lampas) and in the fluids of a patient poisoned by consuming this shell. Retention time data in the LC-MS system within the enhanced mass spectrum (EMS) mode indicated the presence of TTX and the analogue 5,6,11-trideoxyTTX; the enhanced product ion (EPI) mode confirmed the existence of both toxins with the formation of characteristic daughter ions from the fragment pattern of each molecule. TTX and 5,6,11-trideoxyTTX were only detected in the digestive gland of the trumpet shell and also in the urine and serum of the patient. The concentration of 5,6,11-trideoxyTTX checked in the samples by LC-MS was 3 times higher than TTX. However, the results obtained by mouse bioassay showed that the analogue is much less toxic than TTX. In vitro toxicity was checked using cerebellar cells; in these experiments the trumpet shell sample showed high toxicity, but the level was lower than in vivo results probably due to some competition between analogues. This paper shows for first time the presence and toxicity of TTX and 5,6,11-trideoxyTTX in a trumpet shell collected in the European coasts. The LC-MS method is a useful tool to confirm the presence of TTX and the further identification of TTX analogues.     

The assessment of the damage probability of storage tanks in domino events triggered by fire

An approach aimed to the quantitative assessment of the risk caused by escalation scenarios triggered by fire was developed. Simplified models for the estimation of the vessel time to failure (ttf) with respect to the radiation intensity on the vessel shell were obtained using a multi-level approach to the analysis of vessel wall failure under different fire conditions. Each vessel “time to failure” calculated by this approach for the specific fire scenario of concern was compared to a reference time required for effective mitigation actions and related to the escalation probability. The failure probability of each vessel was correlated to the probability of scenarios involving multiple vessel failure as a consequence of the primary fire, thus allowing a comprehensive assessment of domino scenarios triggered by fire. The application of the methodology to the analysis of several case-studies allowed the estimation of the quantitative contribution of escalation events triggered by fire to the overall individual and societal risk indexes.     

Intelligent Real-Time Adaptation for Power Efficiency in Sensor Networks

This paper presents an intelligent, dynamic power conservation scheme for sensor networks in which the sensor network operation is adaptive to both changes in the objects under measurement and the network itself. The conservation scheme switches sensor nodes between a sleep and an active mode in a manner such that the nodes can maximize the time they spend in a power-efficient sleep state, which corresponds to a nonmeasuring and/or nontransmitting mode, while not missing important events. A switching decision is made based on changes (or their absence) in the signals sensed from the environment by an intelligent agent that has been trained to determine whether or not a special event has occurred. This intelligent agent is based on a novel neural network topology that allows for a significant reduction in the resource consumption required for its training and operation without compromising its change detection performance. The scheme was implemented to control a sensor network built from a number of Telos rev. B motes currently available on the market. A few new utilities including an original neural network-based intelligent agent, a “visualizer,” a communication manager, and a scheduler have been designed, implemented, and tested. Power consumption measurements taken in a laboratory environment confirm that use of the designed system results in a significant extension of sensor network lifetime (versus “always on” systems) from a few days to a few years.      

Spin-Transparency of the Fullerene Shell of Endometallofullerene La@C82

For La@C₈₂ embedded into the polycarbonate film, an intensive ¹H-electron-nuclear double resonance (ENDOR) has been revealed. Since La-EMF does not contain hydrogen atoms, it evidences for the electron spin density on the matrix protons. Furthermore, for the solutions of La-EMF in hexamethylphosphoramide (HMPA), the paramagnetic shift of the ³¹P NMR signal of bulk solvent molecules has been revealed. These findings testify the partial localization of unpaired electron outside the fullerene cage. The “transparency” of the fullerene shell to the electron spin density may serve the important factor in designing the fullerene-based materials.     

A shell/3D modeling technique for the analysis of delaminated composite laminates

A shell/3D modeling technique was developed for which a local three-dimensional solid finite element model is used only in the immediate vicinity of the delamination front. The goal was to combine the accuracy of the full three-dimensional solution with the computational efficiency of a plate or shell finite element model. Multi-point constraints provided a kinematically compatible interface between the local three-dimensional model and the global structural model which has been meshed with plate or shell finite elements. Double cantilever beam (DCB), end notched flexure (ENF), and single leg bending (SLB) specimens were modeled using the shell/3D technique to study the feasibility for pure mode I (DCB), mode II (ENF) and mixed mode I/II (SLB) cases. Mixed mode strain energy release rate distributions were computed across the width of the specimens using the virtual crack closure technique. Specimens with a unidirectional layup and with a multidirectional layup where the delamination is located between two non-zero degree plies were simulated. For a local three-dimensional model, extending to a minimum of about three specimen thicknesses on either side of the delamination front, the results were in good agreement with mixed mode strain energy release rates obtained from computations where the entire specimen had been modeled with solid elements. For large built-up composite structures modeled with plate elements, the shell/3D modeling technique offers a great potential for reducing the model size, since only a relatively small section in the vicinity of the delamination front needs to be modeled with solid elements.     

Looking for errors of omission and commission or The Hunting of the Snark revisited

Since the early 1990s, considerable effort has been spent to understand what is meant by an “error of commission” (EOC), to complement the traditional notion of an “error of omission” (EOO). This paper argues that the EOO–EOC dyad, as an artefact of the PSA event tree, is insufficient for human reliability analysis (HRA) for several reasons: (1) EOO–EOC fail to distinguish between manifestation and cause; (2) EOO–EOC refer to classes of incorrect actions rather than to specific instances; (3) there is no unique way of classifying an event using EOO–EOC; (4) the set of error modes that cannot reasonably be classified as EOO is too diverse to fit into any single category of its own. Since the use of EOO–EOC leads to serious problems for HRA, an alternative is required. This can be found in the concept of error modes, which has a long history in risk analysis. A specific system for error mode prediction was tested in a simulator experiment. The analysis of the results showed that error modes could be qualitatively predicted with sufficient accuracy (68% correct) to propose this method as a way to determine how operator actions can fail in PSA-cum-HRA. Although this still leaves the thorny issue of quantification, a consistent prediction of error modes provides a better starting point for determining probabilities than the EOO–EOC dyad. It also opens a possibility for quantification methods where the influence of the common performance conditions is prior to and more important than individual failure rates.     

Colonic drug delivery: influence of cross-linking agent on pectin beads properties and role of the shell capsule type

For colonic delivery, pectin beads obtained by ionotropic gelation method have been already reported as an interesting approach. This study investigated the influence of the cross-linking agent (calcium or zinc) and the type of shell capsule used (classical or enteric capsules) on pectin beads properties and on their performance to target the colon (in vitro dissolution studies with subsequent pH change to mimic overall gastro-intestinal tract). Zinc pectinate beads seemed to be relatively similar to calcium's ones in morphological point, except on the surface aspect. When beads were introduced in classical hard capsules, ketoprofen release was not significantly different between CPG and ZPG beads, and it was too premature and too quick due to a chemical erosion of the pectinate matrix (acid + basic attacks). However, zinc pectinate beads showed slower ketoprofen release compared with calcium pectinate beads when enteric hard capsules were used. This interesting finding could be due to the strength of the network formed during the process between the zinc cations and the LM-pectin following the “egg-box” model. This network was stronger and induced a reduction of swelling and hydration when contact with dissolution medium, then subsequently a decrease of drug release. Thus, the zinc pectinate beads could protect sufficiently drug entrapped from the upper gastro-intestinal conditions and drug release will be controlled by pectin degradation with colonic microflora. Finally, these zinc pectinate beads in enteric hard capsules are promising as a carrier for specific colonic delivery of drugs after oral administration.     

On the experimental investigation of crash energy absorption in laminate splaying collapse mode of FRP tubular components

In this experimental work the crash energy absorption of fibre reinforced plastic (FRP) tubular components that collapse in laminate splaying mode is investigated by means of a new testing method, the “curling test”. This test method was used trying rectangular carbon, aramid and glass FRP strips—in which the reinforcing fibres were in the form of reinforcing woven fabric (carbon and aramid FRP specimens) and multi-axial fibre reinforcements (glass FRP specimens). Apart from the analysis of the system of bending and friction forces acting on the specimens during the curling tests in comparison with the forces acting in the case the laminate splaying collapse mode and the observations related to the deformation and crushing induced on the FRP specimens by this force combination, the analysis of the test results focused on the influence of the most important geometric and laminate material properties—such as thickness, flexural rigidity, number of reinforcing fibre layers, laminate stacking sequence and constituent material mechanical properties—on the specific energy absorption and the peak load.     

整车低频加速噪声研究及改进

某款车在加速过程中,2 000~3 000 r/min存在明显的低频噪声,通过对车内噪声频谱和空滤辐射噪声关系的分析,指出空滤壳体模态偏低是其主要原因。利用CAE和试验相结合的方式,详细描述改进方案和措施。通过空滤壳体刚度的加强实现模态的提升,从而降低整车噪声在该区域内的噪声峰值,消除低频噪声,主观评价改善明显。     

A novel gamma-ray imaging concept using “edge-on” microchannel plate detector

The “edge-on” illuminated microchannel plate (MCP) position-sensitive detector (PSD) is used for gamma-ray imaging for the first time. The superior position resolution of the MCP is combined with high detection efficiency due to the “edge-on” illumination mode. The results of imaging a 15 μCi ¹³⁷Cs source (662 keV quantum energy) are presented.