Ni(II)-doped CsCdBrCl2: Variation of spectral and structural properties via mixed-halide coordination

A new addition to the family of single-molecule magnets is reported: an Fete cage stabilized with benzoate and pyridonate ligands. Monte Carlo methods have been used to derive exchange parameters within the cage, and hence model susceptibility behavior.

Hydromorphone-3-glucuronide - A more potent neuro-excitant than its structural analogue, morphine-3-glucuronide

In humans, hydromorphone (HMOR) is metabolised principally by conjugation with glucuronic acid to form hydromorphone-3-glucuronide (H3G), a close structural analogue of morphine-3-glucuronide (M3G), the major metabolite of morphine. In a previous study we described the biochemical synthesis of H3G together with a preliminary evaluation of its pharmacology which revealed that it is a neuro-excitant in rats in a manner analogous to M3G. Thus the aims of the current study were to quantify the neuro-excitatory behaviours evoked by intracerebroventricular (icv) H3G in the rat and to define its potency relative to M3G. Groups of adult male Sprague-Dawley rats received icy injections (1 muL) of H3G (1 - 3 mug), M3G (2 - 7 mug) or vehicle via a stainless steel guide cannula that had been implanted stereotaxically seven days prior to drug administration. Behavioural excitation was monitored by scoring fifteen different behaviours (myoclonic jerks, chewing, wet-dog-shakes, rearing, tonic-clonic-convulsions, explosive motor behaviour, grooming, exploring, general activity, eating, staring, ataxia, righting reflex, body posture, touch evoked agitation) immediately prior to icy injection and at the following post-dosing times: 5, 15, 25, 35, 50, 65 and 80 min. H3G produced dose-dependent behavioural excitation in a manner analogous to that reported previously for M3G by our laboratory and reproduced herein. H3G was found to be approximately 2.5-fold more potent than M3G, such that the mean (+/- S.D.) ED50 values were 2.3 (+/- 0.1) mug and 6.1 (+/- 0.6) mug respectively. Thus, our data clearly imply that if H3G crosses the BBB with equivalent efficiency to M3G, then the myoclonus, allodynia and seizures observed in some patients dosed chronically with large systemic doses of HMOR, are almost certainly due to the accumulation of sufficient H3G in the central nervous system, to evoke behavioural excitation. (C) 2001 Elsevier Science Inc. All rights reserved.

Theory of pseudomodes in quantum optical processes

This paper deals with non-Markovian behavior in atomic systems coupled to a structured reservoir of quantum electromagnetic field modes, with particular relevance to atoms interacting with the field in high-Q cavities or photonic band-gap materials. In cases such as the former, we show that the pseudomode theory for single-quantum reservoir excitations can be obtained by applying the Fano diagonalization method to a system in which the atomic transitions are coupled to a discrete set of (cavity) quasimodes, which in turn are coupled to a continuum set of (external) quasimodes with slowly varying coupling constants and continuum mode density. Each pseudomode can be identified with a discrete quasimode, which gives structure to the actual reservoir of true modes via the expressions for the equivalent atom-true mode coupling constants. The quasimode theory enables cases of multiple excitation of the reservoir to now be treated via Markovian master equations for the atom-discrete quasimode system. Applications of the theory to one, two, and many discrete quasimodes are made. For a simple photonic band-gap model, where the reservoir structure is associated with the true mode density rather than the coupling constants, the single quantum excitation case appears to be equivalent to a case with two discrete quasimodes.

Active site heterogeneity in dimethyl sulfoxide reductase from Rhodobacter capsulatus revealed by raman spectroscopy

Raman spectroscopy has been used to investigate the structure of the molybdenum cofactor in DMSO reductase from Rhodobacter capsulatus. Three oxidized forms of the enzyme, designated 'redox cycled', 'as prepared', and DMSORmodD, have been studied using 752 nm laser excitation. In addition, two reduced forms of DMSO reductase, prepared either anaerobically using DMS or using dithionite, have been characterized. The 'redox cycled' form has a single band in the Mo=O stretching region at 865 cm(-1) consistent with other studies. This oxo ligand is found to be exchangeable directly with (DMSO)-O-18 or by redox cycling. Furthermore, deuteration experiments demonstrate that the oxo ligand in the oxidized enzyme has some hydroxo character, which is ascribed to a hydrogen bonding interaction with Trp 116. There is also evidence from the labeling studies for a modified dithiolene sulfur atom, which could be present as a sulfoxide. In addition to the 865 cm(-1) band, an extra band at 818 cm(-1) is observed in the Mo=O stretching region of the 'as prepared' enzyme which is not present in the 'redox cycled' enzyme. Based on the spectra of unlabeled and labeled DMS reduced enzyme, the band at 818 cm(-1) is assigned to the S=O stretch of a coordinated DMSO molecule. The DMSORmodD form, identified by its characteristic Raman spectrum, is also present in the 'as prepared' enzyme preparation but not after redox cycling. The complex mixture of forms identified in the 'as prepared' enzyme reveals a substantial degree of active site heterogeneity in DMSO reductase.

Non-Markovian quantum optical processes and pseudomodes

Non-Markovian behaviour in atomic systems coupled to a structured reservoir of quantum EM field modes, such as in high Q cavities, is treated using a quasimode description, and the pseudo mode theory for single quantum reservoir excitations is obtained via Fano diagonalisation. The atomic transitions are coupled to a discrete set of (cavity) quasimodes, which are also coupled to a continuum set of (external) quasimodes with slowly varying coupling constants. Each pseudomode corresponds to a cavity quasimode, and the original reservoir structure is obtained in expressions for the equivalent atom-true mode coupling constants. Cases of multiple excitation of the reservoir are now treatable via Markovian master equations for the atom-discrete quasimode system.

Excited to death: different ways to lose your neurones

The selective loss of neurones in a range of neurodegenerative diseases is widely thought to involve the process of excitotoxicity, in which glutamate-mediated neuronal killing is elaborated through the excessive stimulation of cell-surface receptors. Every such disease exhibits a distinct regional and subregional pattern of neuronal loss. so processes must be locally triggered to different extents to account for this. We have studied several mechanisms which could lead to excitotoxic glutamate pathophysiology and compared them in different diseases. Our data suggest that glutamate can reach toxic extracellular levels in Alzheimer disease by malfunctions in cellular transporters, and that the toxicity may be exacerbated by continued glutamate release from presynaptic neurones acting on hypersensitive postsynaptic receptors. Thus the excitotoxicity is direct. In contrast, alcoholic brain damage arises in regions where GABA-mediated inhibition is deficient, and fails properly to dampen trans-synaptic excitation, Thus the excitotoxicity is indirect. A variety of such mechanisms is possible, which may combine in different ways.

Intramolecular electronic energy transfer in bichromophoric macrocyclic complexes

Efficient intramolecular electronic energy transfer (EET) has been demonstrated for three novel bichromophoric compounds utilizing a macrocyclic spacer as the bridge between the electronic energy donor and acceptor fragments. As their free base forms, emission from the electronically excited donor is absent and the acceptor emission is reductively quenched via photoinduced oxidation of proximate amine lone pairs. As their Zn(II) complexes, excitation of the donor results in sensitization of the electronic acceptor emission.

Spermine modulation of the glutamate(NMDA) receptor is differentially responsive to conantokins in normal and Alzheimer's disease human cerebral cortex

The pharmacology of the N -methyl-d-aspartate (NMDA) receptor site was examined in pathologically affected and relatively spared regions of cerebral cortex tissue obtained at autopsy from Alzheimer's disease cases and matched controls. The affinity and density of the [H-3]MK-801 binding site were delineated along with the enhancement of [H-3]MK-801 binding by glutamate and spermine. Maximal enhancement induced by either ligand was regionally variable; glutamate-mediated maximal enhancement was higher in controls than in Alzheimer's cases in pathologically spared regions, whereas spermine-mediated maximal enhancement was higher in controls in areas susceptible to pathological damage. These and other data suggest that the subunit composition of NMDA receptors may be locally variable. Studies with modified conantokin-G (con-G) peptides showed that Ala(7)-con-G had higher affinity than Lys(7)-con-G, and also defined two distinct binding sites in controls. Nevertheless, the affinity for Lys(7)-con-G was higher overall in Alzheimer's brain than in control brain, whereas the reverse was true for Ala(7)-con-G. Over-excitation mediated by specific NMDA receptors might contribute to localized brain damage in Alzheimer's disease. Modified conantokins are useful for identifying the NMDA receptors involved, and may have potential as protective agents.

Modelling of Lamb waves in composite laminated plates excited by interdigital transducers

The technique of permanently attaching interdigital transducers (IDT) to either flat or curved structural surfaces to excite single Lamb wave mode has demonstrated great potential for quantitative non-destructive evaluation and smart materials design, In this paper, the acoustic wave field in a composite laminated plate excited by an IDT is investigated. On the basis of discrete layer theory and a multiple integral transform method, an analytical-numerical approach is developed to evaluate the surface velocity response of the plate due to the IDTs excitation. In this approach, the frequency spectrum and wave number spectrum of the output of IDT are obtained directly. The corresponding time domain results are calculated by applying a standard inverse fast Fourier transformation technique. Numerical examples are presented to validate the developed method and show the ability of mode selection and isolation. A new effective way of transfer function estimation and interpretation is presented by considering the input wave number spectrum in addition to the commonly used input frequency spectrum. The new approach enables the simple physical evaluation of the influences of IDT geometrical features such as electrode finger widths and overall dimension and excitation signal properties on the input-output characteristics of IDT. Finally, considering the convenience of Mindlin plate wave theory in numerical computations as well as theoretical analysis, the validity is examined of using this approximate theory to design IDT for the excitation of the first and second anti-symmetric Lamb modes. (C) 2002 Elsevier Science Ltd. All rights reserved.

Quadriceps concentric and eccentric exercise 1: Changes in contractile and electrical activity following eccentric and concentric exercise

The purpose of this study was to determine whether or not losses of strength or endurance following eccentric and concentric exercise are associated with reduced excitation. The effects of eccentric and concentric work on maximal voluntary isometric contraction (MVC) and surface electromyogram (EMG) of the quadriceps were studied in 10 healthy male subjects following bench-stepping for 20 min with a constant leading leg. Prior to stepping and at 0, 0.25, 0.50, 0.75, 1, 3. 24 and 48 h afterwards the subjects performed a 30 s leg extension MVC with each leg during which the isometric force and the root mean square voltage of the EMG were recorded. In the eccentrically exercised muscles (ECC), MVC0-3 (force during the first 3 s of contraction) fen immediately after the bench-stepping exercise to 88 +/- 2% (mean SE) of the pre-exercise value and remained significantly lower than the concentrically exercised muscles (p < 0.05). The muscle weakness in the ECC could not be attributed to central fatigue as surface EMG amplitude at MVC0-3 increased during the recovery period. Muscle weakness after eccentric exercise appears to be due to contractile failure, which is not associated with a reduction in excitation as assessed by surface EMG. Muscular fatigue over 30 s did not change in the two muscle groups after exercise (p = 0.79), indicating that the ECC were weaker but not more fatiguable after exercise.

Single mode Lamb waves in composite laminated plates generated by piezoelectric transducers

The technique of permanently attaching piezoelectric transducers to structural surfaces has demonstrated great potential for quantitative non-destructive evaluation and smart materials design. For thin structural members such as composite laminated plates, it has been well recognized that guided Lamb wave techniques can provide a very sensitive and effective means for large area interrogation. However, since in these applications multiple wave modes are generally generated and the individual modes are usually dispersive, the received signals are very complex and difficult to interpret. An attractive way to deal with this problem has recently been introduced by applying piezoceramic transducer arrays or interdigital transducer (IDT) technologies. In this paper, the acoustic wave field in composite laminated plates excited by piezoceramic transducer arrays or IDT is investigated. Based on dynamic piezoelectricity theory, a discrete layer theory and a multiple integral transform method, an analytical-numerical approach is developed to evaluate the input impedance characteristics of the transducer and the surface velocity response of the plate. The method enables the quantitative evaluation of the influence of the electrical characteristics of the excitation circuit, the geometric and piezoelectric properties of the transducer array, and the mechanical and geometrical features of the laminate. Numerical results are presented to validate the developed method and show the ability of single wave mode selection and isolation. The results show that the interaction between individual elements of the piezoelectric array has a significant influence on the performance of the IDT, and these effects can not be neglected even in the case of low frequency excitation. It is also demonstrated that adding backing materials to the transducer elements can be used to improve the excitability of specific wave modes. (C) 2002 Elsevier Science Ltd. All rights reserved.

Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a

Voltage-gated sodium channels drive the initial depolarization phase of the cardiac action potential and therefore critically determine conduction of excitation through the heart. In patients, deletions or loss-of-function mutations of the cardiac sodium channel gene, SCN5A, have been associated with a wide range of arrhythmias including bradycardia (heart rate slowing), atrioventricular conduction delay, and ventricular fibrillation. The pathophysiological basis of these clinical conditions is unresolved. Here we show that disruption of the mouse cardiac sodium channel gene, Scn5a, causes intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis whereas heterozygotes show normal survival. Whole-cell patch clamp analyses of isolated ventricular myocytes from adult Scn5a(+/-) mice demonstrate a approximate to50% reduction in sodium conductance. Scn5a(+/-) hearts have several defects including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconcile reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias.

Diverse synaptic mechanisms generate direction selectivity in the rabbit retina

The synaptic conductance of the On-Off direction-selective ganglion cells was measured during visual stimulation to determine whether the direction selectivity is a property of the circuitry presynaptic to the ganglion cells or is generated by postsynaptic interaction of excitatory and inhibitory inputs. Three synaptic asymmetries were identified that contribute to the generation of direction-selective responses: (1) a presynaptic mechanism producing stronger excitation in the preferred direction, (2) a presynaptic mechanism producing stronger inhibition in the opposite direction, and (3) postsynaptic interaction of excitation with spatially offset inhibition. Although the on- and off-responses showed the same directional tuning, the off-response was generated by all three mechanisms, whereas the on- response was generated primarily by the two presynaptic mechanisms. The results indicate that, within a single neuron, different strategies are used within distinct dendritic arbors to accomplish the same neural computation.

On the induced electric field gradients in the human body for magnetic stimulation by gradient coils in MRI

Prior theoretical studies indicate that the negative spatial derivative of the electric field induced by magnetic stimulation may he one of the main factors contributing to depolarization of the nerve fiber. This paper studies this parameter for peripheral nerve stimulation (PNS) induced by time.-varying gradient fields during MRI scans. The numerical calculations are based on an efficient, quasi-static, finite-difference scheme and an anatomically realistic human, full-body model. Whole-body cylindrical and planar gradient sets in MRI systems and various input signals have been explored. The spatial distributions of the induced electric field and their gradients are calculated and attempts are made to correlate these areas with reported experimental stimulation data. The induced electrical field pattern is similar for both the planar coils and cylindrical coils. This study provides some insight into the spatial characteristics of the induced field gradients for PNS in MRI, which may be used to further evaluate the sites where magnetic stimulation is likely to occur and to optimize gradient coil design.

Influence of magnetically-induced E-fields on cardiac electric activity during MRI: A modeling study

In modern magnetic resonance imaging (MRI), patients are exposed to strong, time-varying gradient magnetic fields that may be able to induce electric fields (E-fields)/currents in tissues approaching the level of physiological significance. In this work we present theoretical investigations into induced E-fields in the thorax, and evaluate their potential influence on cardiac electric activity under the assumption that the sites of maximum E-field correspond to the myocardial stimulation threshold (an abnormal circumstance). Whole-body cylindrical and planar gradient coils were included in the model. The calculations of the induced fields are based on an efficient, quasi-static, finite-difference scheme and an anatomically realistic, whole-body model. The potential for cardiac stimulation was evaluated using an electrical model of the heart. Twelve-lead electrocardiogram (ECG) signals were simulated and inspected for arrhythmias caused by the applied fields for both healthy and diseased hearts. The simulations show that the shape of the thorax and the conductive paths significantly influence induced E-fields. In healthy patients, these fields are not sufficient to elicit serious arrhythmias with the use of contemporary gradient sets. However, raising the strength and number of repeated switching episodes of gradients, as is certainly possible in local chest gradient sets, could expose patients to increased risk. For patients with cardiac disease, the risk factors are elevated. By the use of this model, the sensitivity of cardiac pathologies, such as abnormal conductive pathways, to the induced fields generated by an MRI sequence can be investigated. (C) 2003 Wiley-Liss, Inc.