Gabapentin: pharmacokinetics, efficacy, and safety

Gabapentin is a new antiepileptic drug (AED) with an attractive pharmacokinetic profile. It is absorbed by an active and saturable transport system, and has a high volume of distribution. Gabapentin is not bound to plasma proteins, does not induce hepatic enzymes and is not metabolized. At steady state, it has a half-life of 6-8 h, and is eliminated unchanged by renal route with a plasma clearance proportional to the creatinine clearance. It is devoid of significant drug-drug interactions when administered with the established AEDs or with oral contraceptives. Gabapentin used as an add-on AED significantly reduced the frequency of partial seizures and secondarily generalized tonic-clonic seizures in three large double-blind, placebo-controlled, parallel-group clinical trails. It is well tolerated, with transient somnolence and dizziness being the most frequent adverse effects. Although the mechanism of action of gabapentin is not fully established, there is strong evidence to suggest a novel mechanism of action. Gabapentin is a unique and promising drug that could improve the quality of life of patients with epilepsy and is a welcome addition to the armamentarium of currently available AEDs for the treatment of patients with seizures of partial onset.     

Concurrent right diaphragmatic hernia and esophageal atresia

The occurrence of a coexisting congenital diaphragmatic hernia (CDH) and esophageal atresia (EA) with distal tracheoesophageal fistula is extremely rare and is considered highly lethal. Only 19 cases of CDH with EA have been reported in the world literature to date. This is a very challenging clinical problem, and the neonate is likely to deteriorate rapidly. Such a case is reported with a successful outcome, probably the first survivor with a right CDH and EA. Management guidelines for such a case are discussed.     

Bayesian Model Calibration Using Geotechnical Centrifuge Tests

The predicted performance using a geotechnical prediction model is expected to deviate from reality. A practical approach to assess the model error is through calibration with observed performances in physical model tests. In this paper, a Bayesian framework of model calibration using centrifuge modeling tests is proposed and the procedure of model calibration is illustrated. Two centrifuge tests conducted to investigate the performance of soil slopes under rainfall conditions are used to calibrate a coupled hydromechanical analysis model. It is found that for centrifuge tests with different levels of soil variability, the test with a smaller variability of soil properties is more efficient for model calibration. According to the concept of random field, a centrifuge model with a larger model size and accelerated to a lower acceleration is better for model calibration. When the discrepancy between the performance interpreted from the centrifuge model and the field performance is small, the improvement of the reliability estimation for a new slope is significant. However, when there is little information about the discrepancy, the reliability estimation cannot be significantly improved by the information from centrifuge modeling. The proposed procedure is shown to be able to quantify the calibration effects of centrifuge tests and may be used to achieve a more reliable calibration.     

Vandal Loads and Induced Vibrations on a Footbridge

The paper describes a study to characterize intentional human dynamic loads (vandal loads) and their induced effects on a footbridge. A numerical model to characterize the dynamic behavior of the footbridge has been developed, is experimentally validated, and is used to numerically simulate the response induced by groups of pedestrians synchronized at critical bridge frequencies. The vandal load associated with a single pedestrian is characterized and compared with definitions in the literature. The response is then calculated considering the measured load and compared with the measured response to the excitation induced by a single pedestrian or a group with varying dimensions. The definition of a general load model for vandal excitation, including a tentative definition for synchronization is discussed.     

State Space Formulation for Linear Viscoelastic Dynamic Systems with Memory

A dynamic system with memory is a system for which knowledge of the equations of motion, together with the state at a given time instant t0 is insufficient to predict the evolution of the state at time instants t>t0. To calculate the response of systems with memory starting from an initial time instant t0, complete knowledge of the history of the system for t相似文献   

Spectral and cyanide binding properties of the cytochrome aa3 (600 nm) complex from Bacillus subtilis

The cytochrome aa3 (600 nm) complex, or menaquinol oxidase, from Bacillus subtilis is a member of the cytochrome oxidase superfamily of respiratory membrane protein complexes. We have characterized some spectral properties of this enzyme and its reaction with cyanide. The magnetic circular dichroism (MCD) spectrum of the oxidized enzyme has a single band at 1560 nm in the near-infrared region assigned to bis-histidine-ligated, low-spin ferricytochrome a. The other heme, cytochrome a3, is presumably high-spin in the oxidized enzyme, as isolated. The absence of a trough in the MCD spectrum at 790 nm, observed previously with mammalian cytochrome c oxidase and assigned to CuA (Greenwood et al., Biochem. J. 215, 303-316, 1983), is consistent with the absence of this center from the menaquinol oxidase. When the heme ligand cyanide is added to oxidized menaquinol oxidase, a new MCD band appears at 2010 nm, while the band at 1560 nm is unperturbed. The new band is assigned to low-spin ferricytochrome a3 bound with cyanide. The long-wavelength position of this cyanide-induced band is proposed to arise from the close interaction of cytochrome a3 with the copper atom, CuB. The kinetics of cyanide binding to oxidized cytochrome aa3(600 nm) reveal a spectrally simple, yet kinetically complex process. The reaction is biphasic with second-order rate constants of 45 and 0.61 M-1s-1 at 1 mM KCN, with each phase constituting about 50% of the overall reaction. When the enzyme is subjected to a cycle of anaerobic reduction and air oxidation, the subsequent reaction with cyanide occurs in a single phase at the faster rate. This behavior is ascribed to different conformations of the binuclear center exhibiting different reactivities with cyanide, and is in keeping with that previously established for the structurally more complex mitochondrial cytochrome c oxidase. However, the electronic spectral characteristics of some of the species involved in these reactions are different in the present bacterial case from those of reported eukaryotic systems.     

Approach to the patient with pulmonary disease

The approach to the HIV-infected patient with pulmonary disease is summarized by the algorithms in Figures 3 and 4. These are not intended to be followed in a rigid step-wise fashion. Rather, the practitioner's knowledge of the patient with his or her accompanying medical risks influences the path taken, including the depth and the speed of the evaluation. For example, the patient with cough who is afebrile and breathing at 18 breaths a minute, with a normal chest radiograph and a CD4 count of 350 cells/mm3, is reasonably treated with a macrolide or cephalosporin for bacterial bronchitis and clinical follow-up while awaiting cultures (see Fig. 4). A febrile patient with a cough productive of thin mucus, but known to have a CD4 count of 60 cells/mm3 should be started on anti-PCP therapy while being evaluated for PCP with an induced sputum and if nondiagnostic, a bronchoscope despite a normal chest radiograph. Screening can be as simple as placing an oximeter on the patient's finger in the clinic. If the oxygen saturation of a patient with a normal chest radiograph is low, then the patient should be hospitalized and begun on treatment for PCP while diagnostic evaluation is initiated. If the oxygen saturation is normal, the patient can be exercised to elicit desaturation. If there is no desaturation, PCP is unlikely. If the results are equivocal (i.e., a decrease in saturation, but less than 3%), rest and exercise arterial blood gases can be performed, along with a Dlco-Gallium scanning can be done in patients known to have abnormal Dlco or those who cannot exercise. Patients with focal infiltrates who have acute onset of symptoms (see Fig. 4) commonly have bacterial infections, but the possibility of PCP or TB should not be dismissed. Induced sputum should be examined if TB or PCP is suspected. Patients who are severely ill might go quickly to bronchoscopy without awaiting improvement on empiric therapy. The patient with diffuse infiltrates (see Fig. 4) needs no screening because the presence of disease is apparent from the radiograph. The diagnostic part quickly leads to bronchoscopy for these patients and the initiation of therapy for PCP when suspected. In patients with known pulmonary KS, gallium scanning can be helpful to rule out acute infection, but bronchoscopy is warranted if the patient is severely ill, or at high risk for PCP. This approach should avoid unnecessary procedures in patients with simple bacterial infections, without missing opportunistic infections and tumors.     

Towards an austenite decomposition model for TRIP steels

The current status of developing a fundamental model for describing the overall austenite decomposition kinetics to ferrite and carbide‐free bainite in low carbon TRIP steels alloyed with Mn and Si is reviewed. For ferrite growth, a model is proposed where both interface and carbon diffusion‐controlled ferrite formation are considered in a mixed‐mode approach. The kinetic model is coupled with Thermocalc to obtain necessary thermodynamic information. Spherical geometry with an outer ferrite shell is assumed to capture in a simple way the topological conditions for growth. The mixed‐mode modelling philosophy has been identified to permit a rigorous incorporation of the solute drag effect of substitutional alloying elements, in particular Mn. The Purdy‐Brechet solute drag theory is adopted to characterize the interaction of Mn with the moving austenite‐ferrite interface. The challenges of quantifying the required solute drag parameters are discussed with an emphasis on a potential solute drag interaction of Mn and Si. The model is extended to non‐isothermal processing paths to account for continuous and stepped cooling occurring on the run‐out table of a hot strip mill or on a continuous annealing line. The transformation start temperature during cooling is predicted with a model combining nucleation and early growth which had previously been validated for conventional low carbon steels. The overall model is evaluated by comparing the predictions with experimental data for the ferrite growth kinetics during continuous cooling of a classical TRIP steel with mass contents of 0.19 % C, 1.49 % Mn and 1.95 % Si. Extension of the model to include bainite formation remains a challenge. Both diffusional and displacive model approaches are discussed for the formation of carbide‐free bainite. It is suggested to develop a combined nucleation and growth model which would enable to capture a potential transition from a diffusional to a displacive transformation mode with decreasing temperature.     

Action planning during the presentation of stimulus sequences: effects of compatible and incompatible stimuli

Experimental designs that require the simultaneous perception and reproduction of a stimulus sequence could help to clarify the relationship between perception and action. This contribution examines a specific stimulus-response compatibility with the reproduction of simple stimulus sequences. In the procedure a response just prepared or one to be prepared is confronted with a new incoming stimulus that is compatible or incompatible with the response. Interference is predicted from a framework in which stimulus perception and action control are assumed to share common codes. Five arrows were successively presented at 1-s intervals. The arrows pointed either to the left or to the right with equal probability. One of the five arrows was accompanied by a randomly presented go signal. Subjects then had to reproduce the sequence by pressing corresponding left or right keys while the stimulus presentation continued. Reaction-time latencies and reaction intervals within a sequence were analyzed in six experiments. Results showed increasing reaction-time latencies the later the go signal was presented--that is, the longer the sequence to be reproduced was. In contrast to previous findings, this effect interacted with the compatibility between the arrow displayed together with the go signal and the first reaction. It is argued that the go signal initiates a transfer of a cognitive action plan to a peripheral motor program and that this process is subject to interference the more the current stimulus is at odds with one of the first parameter specification.     

Assessment of Dynamic Stability of Foundations on Saturated Sandy Soils

This paper deals with the dynamic analysis of foundations in saturated soils. In the first part, a mathematical formulation is briefly outlined in which soil is considered as a two-phase medium comprising the soil skeleton and voids filled with a viscous fluid. Such formulation is suitable for describing a solid-fluid transition associated with the liquefaction phenomenon. Subsequently, the notion of dynamic stability is reviewed and a simple criterion is introduced, leading to the definition of a stability factor. The mathematical framework is illustrated by a numerical example involving a foundation subjected to seismic excitation. The effect of viscosity of liquefied material on the stability of the system is examined.     

A simple flotation and McMaster method (author's transl)

A simple and hygienic flotation and McMaster method is described (cf. Fig. 1): The faeces sample (3-5 gm) is mixed with flotation fluid (40-60 ml) in a disposable plastic cup (cup I) and a circular piece of gauze, with a diameter equivalent to twice the height of the cup plus the diameter of its base, is placed over the cup. By a similar cup (cup II), with the bottom cut off and slits made in the side, the gauze is pressed down in cup I. By this procedure the faeces suspension will be filtered through the gauze and appear in cup II. After 10 minutes some drops after transferred from the surface of the filtrate to a slide by means of a test tube, which is dipped to the bottom of the filtrate and quickly moved over to the slide. The optimal procedure was worked out with faeces containing faeces containing eggs of Ostertagia ostertagi. Saturated sodium chloride with 50 g glucose per 100 ml was found to be a suitable flotation fluid for demonstrating eggs of commonly occurring parasites, e.g., trichostronglyids and ascarids. The described flotation technique is more efficacious than the one hitherto employed. The technique is usable also in connection with a McMaster method: 4 gm. faeces are suspended in 56 ml flotation fluid. Immediately following filtration, filtrate is transferred to a McMaster counting chamber by means of a Pasteur pipette.     

Perforated Wall Breakwater with Internal Horizontal Plate

The hydrodynamic performance of a perforated wall breakwater with an internal horizontal plate is studied. It is suggested that a horizontally submerged plate be installed inside the wave chamber to enhance the stability of the structure. Based on the linear wave theory, the 2D problem is formulated to analyze the wave reflection with different porosity, physical dimensions, and wave conditions. The method of matched eigenfunction expansions is used to obtain the solution. Generally, the hydrodynamic performance of a wave chamber is similar with or without an internal horizontal plate. However, the minimum reflection occurs at some particular ratios of the length of the wave chamber to the wavelength, which are less than the corresponding ratios for a wave chamber without the plate, because the waves become shorter over the submerged plate. Thus, the size of the wave chamber can be reduced. It is also found that a moderate porosity is optimal to dissipate the wave energy. By investigating the wave-induced force and moment, such breakwaters with an internal horizontal plate can be designed and constructed with a higher degree of confidence and reliability.     

Construction Risk Analysis Tool for Determining Liquidated Damages Insurance Premiums: Case Study

Construction work is often a risky undertaking for all parties involved, and risk management is essential in dealing with potential exposures. One of the possible options in any risk management approach is the shifting of designated potential risks to financially strong institutions, which, for an agreed premium amount, are willing to assume the financial responsibility for any loss incurred. This paper presents a case study and a methodology for determining the expected loss to an insurance company when insuring for liquidated damages. It is directed to engineers and construction managers faced with providing a surety or owner with a quantification of the risk associated with a project completion date.     

Vapor Flow to Trench in Leaky Aquifer

Soil-vapor extraction has become the most common innovative technology for treating subsurface soils contaminated with volatile and semivolatile organic compounds. This popularity is due partly to the low cost of vapor extraction and partly to the fact that mitigation is completed in situ. Previous applications of this technology have generally considered flow to either vertical or horizontal wells. However, vapor flow to a trench offers the advantages of a more uniform velocity field and lower construction costs at sites with shallow water tables. Therefore, an analytical solution is obtained for steady flow to a trench. The trench is assumed to partially penetrate an anisotropic aquifer and to have a finite horizontal length. The bottom aquifer boundary is assumed to be an impermeable water table, and the top boundary is a semipermeable aquitard. A comparison is made with field measurements to illustrate the application of the solution and to give confidence in its use.     

Electron transfer kinetics during the reduction and turnover of the cytochrome caa3 complex from Bacillus subtilis

The cytochrome caa3 complex from Bacillus subtilis is a member of the cytochrome oxidase superfamily of respiratory enzyme complexes. The key difference in the cytochrome caa3 complex lies in the addition of a domain, homologous with mitochondrial cytochrome c, that is fused to the C-terminal end of its subunit II. Measurements of steady-state and transient reduction kinetics have been carried out on the cytochrome caa3 complex. Reduction of the cyanide-bound enzyme with ascorbate and N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) supports a sequence of electron transfer in which cytochromec is reduced initially, and this is followed by rapid internal electron transfer from cytochrome c to CuA and from CuA to cytochrome a. Steady-state kinetics with exogenous cytochrome c as the substrate demonstrates the capability of the cytochrome caa3 complex to act as a cytochrome c oxidase. The cytochrome c from B. subtilis is the most efficient cytochrome c of those tested. Steady-state kinetics with ascorbate-TMPD as the reductant, in the absence of exogenous cytochrome c, reveals a biphasic pattern even though only a single, covalent cytochrome c interaction site is present. The two-phase kinetics are characterized by a low activity phase associated with a high apparent affinity for TMPD and a high activity phase with a low affinity for TMPD. This pattern is observed over a wide range of ionic strengths and enzyme concentrations, and with both purified and membrane extract forms of cytochrome caa3. It is proposed that the biphasic steady-state kinetics of this oxidase, and other members of the cytochrome oxidase superfamily, do not result directly from different interactions with cytochrome c but are due to a change in the redox kinetics within the centers of the conventional oxidase unit itself. Our results will be related to models that account for the biphasic steady-state kinetics exhibited by cytochrome oxidase.     

Similarity of nucleotide interactions of BiP and GTP-binding proteins

BiP is a member of the Hsp70 heat shock protein family found in the lumen of the endoplasmic reticulum, that binds to a variety of proteins destined to be secreted. Substance P (SP) has been used as a model peptide to study the interaction of BiP with protein substrates. SP stimulates BiP ATPase activity and forms a stable complex with BiP that is dissociated in the presence of levels of ATP > 50 microM. At lower concentrations of ATP, the SP remains bound to BiP, and the results are consistent with the view that a BiP-ATP complex is initially formed that reacts with SP to form a ternary complex, SP-BiP-ATP. Hydrolysis of ATP in this complex yields a SP-BiP-ADP complex. An exchange of ATP with ADP bound to BiP has also been demonstrated, and the results suggest that the interactions of BiP with ATP resemble those seen with GTP-binding proteins and GTP.     

Genetic epidemiology of dyslipidaemia and atherosclerosis

Bacterial vaginosis (BV) is the most common cause of vaginal discharge in women of child-bearing age. A common symptom of this condition is a fishy-smelling vaginal discharge. Trimethylamine (TMA) is the substance which is primarily responsible for this distinctive odour. The ability to metabolize TMA is polymorphically distributed such that the majority of individuals metabolize a large part of the body burden of TMA to the odourless trimethylamine N-oxide (TMAO) which is excreted in urine with a small amount of TMA. However, in certain individuals, N-oxidation of TMA is impaired which results in the excretion of large amounts of TMA in the urine, breath, sweat and vaginal secretions. In the present study the metabolism of TMA to TMAO was determined in women with clinically diagnosed BV, women with fishy-smelling vaginal discharge but with no other evidence of BV and control women with no evidence of fishy-smelling vaginal discharge. An index of TMA N-oxidation was established for all subjects after analysis of a 24 h urine sample for free TMA and total TMA after reduction of TMAO. We show that, irrespective of diagnosis of BV or not, women with fishy-smelling vaginal discharge excrete significantly more free TMA and have a similarly significantly reduced capacity to N-oxidize TMA when compared to healthy control women. Thus, the results of this study suggest that a woman's ability to metabolize TMA to TMAO is an important factor which predisposes to a fishy-smelling vaginal discharge.     

Eye involvement in the spondyloarthropathies

Eye inflammation, especially uveitis, is a prominent feature of spondyloarthropathies. Uveitis associated with ankylosing spondylitis and Reiter's syndrome usually is a unilateral acute anterior uveitis with a high tendency to recur sometimes in the contralateral eye. Uveitis associated with undifferentiated spondyloarthropathy, inflammatory bowel disease, and psoriasis may be less characteristic in its presentation, with a higher tendency to posterior pole involvement, bilaterality, and chronicity. Although acute anterior uveitis is grouped into the spectrum of human leukocyte antigen B27-related disease, other genetic and environmental factors including infections by gram-negative bacteria and gut inflammation can play a role in its pathogenesis. The prognosis of uveitis usually is excellent with topical treatment, and only those with posterior pole involvement or a high tendency to recur or to chronicity might benefit from immunosuppressive therapy.     

Interaction of guanosine nucleotides and their analogs with elongation factor Tu from Thermus thermophilus

Transient kinetic experiments on the interaction of nucleotide-free EF-Tu from Thermus thermophilus with nucleotides using intrinsic protein fluorescence, extrinsic nucleotide fluorescence and fluorescence resonance energy transfer show that nucleotide binding is in general at least a two-step process. The first step is a weak initial binding, which is followed by a relatively slow isomerization of the protein-nucleotide complex in which changes of both intrinsic and extrinsic fluorescence, as well as energy transfer, occur. The values obtained for the equilibrium and kinetic constants confirm the earlier observation that EF-Tu has a higher affinity for GDP than GTP. This is mainly due to a lower dissociation rate constant for GDP, in combination with a somewhat higher effective association rate constant. Modifications of the triphosphate moiety of GTP are quite well tolerated by EF-Tu, with GTP gamma S displaying the same affinity as GTP and with GppNHp and GppCH2p being only ca. 2-3-fold less strongly bound. Caged GTP is bound about 6-fold more weakly than GTP. These results suggest that the binding of GppNHp and GppCH2p is likely to be similar to that of GTP. The photolytic protecting group of caged GTP (or the loss of one of the negative charges on the gamma-phosphate group) appears to interfere to a certain extent with the interaction with the protein, but the affinity is high enough to permit generation of 1:1 complexes for dynamic structural studies. Discrimination between GDP and ADP is dramatic, with a difference of 6 orders of magnitude in affinity.     

A novel insertional mutation in loricrin in Vohwinkel's Keratoderma

A mutation in the gene encoding loricrin has recently been reported in a subset of patients with Vohwinkel's Keratoderma manifesting an associated ichthyosiform dermatosis. We have studied a further kindred with this clinical phenotype. Microsatellite marker analysis was consistent with linkage to chromosome 1q21 and direct sequencing of loricrin identified a heterozygous mutation with an insertion of a T residue at codon 209. This mutation is predicted to produce a mutant protein with a frameshift of its terminal 107 amino acids and to be 22 amino acids longer than the wild-type protein due to a delayed termination codon. The only previously reported mutation is a G insertion producing a frameshift after codon 231. The novel mutation we report is likely to have a similar functional effect on cornified envelope formation, with disturbance of transglutaminase-mediated cross-linking of envelope components, and serves to confirm the predicted role of insertional mutations in Vohwinkel's Keratoderma associated with ichthyosis.