bluuebunny/crossref_metadata_2025 huggingface dataset:
Hereditary chin trembling: A new family with exclusion of the chromosome 9q13‐q21 Locus
Authors: Grimes David A. , Han Fabin , Bulman Dennise , Nicolson Mary Lou , Suchowersky Oksana
Published: December 2002

Hereditary chin trembling is a rare autosomal dominant condition that has been linked to chromosome 9q13‐21 in one kindred. We describe a four‐generation family with this condition and, using linkage analysis, have excluded the 9q13‐21 region as causing the chin trembling in this family. © 2002 Movement Disorder Society
Unilateral pallidal stimulation for segmental cervical and truncal dystonia: Which side?
Authors: Escamilla‐Sevilla Francisco , Mínguez‐Castellanos Adolfo , Arjona‐Morón Ventura , Martín‐Linares José María , Sánchez‐Álvarez Juan Carlos , Ortega‐Morenoa Angel , García‐Gómez Teresa
Published: December 2002

We present a 24‐year‐old man with idiopathic segmental cervical and truncal dystonia of juvenile onset. His condition improved after unilateral stimulation of the internal globus pallidus ipsilateral to the contracting sternocleidomastoid muscle. © 2002 Movement Disorder Society
Juvenile parkinsonism as a manifestation of systemic lupus erythematosus: Case report and review of the literature
Authors: García‐Moreno José Manuel , Chacón José
Published: December 2002

Involvement of the central nervous system in systemic lupus erythematosus (SLE) has been well described. It usually includes psychiatric disturbance, seizures, and cranial nerve disorders. Movement disorders are less common, chorea being the one most frequently described. A parkinsonian syndrome may be an extremely rare manifestation of cerebral lupus. We report on a case of juvenile parkinsonism as a manifestation of SLE and review the literature. © 2002 Movement Disorder Society
Stimulation of cannabinoid receptors reduces levodopa‐induced dyskinesia in the MPTP‐lesioned nonhuman primate model of Parkinson's disease
Authors: Fox Susan H. , Henry Brian , Hill Michael , Crossman Alan , Brotchie Jonathan
Published: December 2002

Long‐term treatment with levodopa in Parkinson's disease results in the development of motor fluctuations, including reduced duration of antiparkinsonian action and involuntary movements, i.e., levodopa‐induced dyskinesia. Cannabinoid receptors are concentrated in the basal ganglia, and stimulation of cannabinoid receptors can increase γ‐aminobutyric acid transmission in the lateral segment of globus pallidus and reduce glutamate release in the striatum. We thus tested the hypothesis that the cannabinoid receptor agonist nabilone (0.01, 0.03, and 0.10 mg/kg) would alleviate levodopa‐induced dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine hydrochloride (MPTP) ‐lesioned marmoset model of Parkinson's disease. Coadministration of nabilone (0.1 mg/kg) with levodopa was associated with significantly less total dyskinesia (dyskinesia score, 12; range, 6–17; primate dyskinesia rating scale) than levodopa alone (22; range, 14–23; P < 0.05). This effect was more marked during the onset period (0–20 minutes post levodopa). There was no reduction in the antiparkinsonian action of levodopa. Furthermore, the intermediate dose of nabilone used (0.03 mg/kg) increased the duration of antiparkinsonian action of levodopa by 76%. Thus, cannabinoid receptor agonists may be useful in the treatment of motor complications in Parkinson's disease. © 2002 Movement Disorder Society
Entacapone‐Induced Hepatotoxicity and Hepatic Dysfunction
Authors: Fisher Alexander , Croft‐Baker James , Davis Michael , Purcell Patrick , McLean Allan J.
Published: December 2002

We describe 2 patients with Parkinson's disease who developed hepatotoxicity associated with the use of entacapone, a novel, mainly peripheral acting inhibitor of catechol‐D‐methyltransferase. Hepatotoxicity resolved rapidly with discontinuation of the drug. Analysis of causality in a further case initially linked to entacapone exposure was confounded by conflicting serial adverse reaction reports. © 2002 Movement Disorder Society
Consequences of nitric oxide generation in epileptic‐seizure rodent models as studied by in vivo EPR
Authors: Kaneko Kenshi , Itoh Kouichi , Berliner Lawrence J. , Miyasaka Kazuo , Fujii Hirotada
Published: December 2002

The role of nitric oxide (NO) in epileptogenesis was studied in pentylenetetrazole (PTZ)‐treated animals using in vivo and ex vivo EPR spectroscopy. NO generation was measured directly in the brain of a PTZ‐induced mouse in vivo by an L‐band EPR spectrometer. An elevation in NO production in the brain was observed during convulsions, and more NO was generated in the tonic seizure vs. the clonic seizure. NO content in several brain tissues (including the cerebral cortex (CR), cerebellum (CL), olfactory bulb (OB), hippocampus (HI), and hypothalamus (HT)) of PTZ‐doped rats was analyzed quantitatively ex vivo by X‐band EPR. To test the involvement of NO in seizure development, pharmacological analyses were performed using the NO synthase (NOS) inhibitors NG‐nitro‐L‐arginine (L‐NNA), NG‐monomethyl‐L‐arginine (L‐NMMA), and 3‐bromo‐7‐nitroindazole (3Br‐7NI). All of these inhibitors suppressed the convulsions, holding them at the clonic level, and prevented development of a tonic convulsion in rats doped with up to 80 mg/kg PTZ. 3Br‐7NI completely inhibited NO production, but L‐NNA and L‐NMMA showed only 70% inhibition of NO production in PTZ‐doped rats. In order to examine the contributions of NO in convulsions, rats were treated with anticonvulsants (phenytoin and diazepam) before PTZ treatment. Both drugs completely suppressed tonic convulsion in PTZ‐doped rats at doses up to 80 mg/kg, but NO levels were similar to those detected in a clonic convulsion. These results support the notion that NO does not directly induce a clonic convulsion, but may be generated as a consequence of onset of seizure. Magn Reson Med 48:1051–1056, 2002. © 2002 Wiley‐Liss, Inc.
Finite difference time domain (FDTD) method for modeling the effect of switched gradients on the human body in MRI
Authors: Zhao Huawei , Crozier Stuart , Liu Feng
Published: December 2002

Numerical modeling of the eddy currents induced in the human body by the pulsed field gradients in MRI presents a difficult computational problem. It requires an efficient and accurate computational method for high spatial resolution analyses with a relatively low input frequency. In this article, a new technique is described which allows the finite difference time domain (FDTD) method to be efficiently applied over a very large frequency range, including low frequencies. This is not the case in conventional FDTD‐based methods. A method of implementing streamline gradients in FDTD is presented, as well as comparative analyses which show that the correct source injection in the FDTD simulation plays a crucial rule in obtaining accurate solutions. In particular, making use of the derivative of the input source waveform is shown to provide distinct benefits in accuracy over direct source injection. In the method, no alterations to the properties of either the source or the transmission media are required. The method is essentially frequency independent and the source injection method has been verified against examples with analytical solutions. Results are presented showing the spatial distribution of gradient‐induced electric fields and eddy currents in a complete body model. Magn Reson Med 48:1037–1042, 2002. © 2002 Wiley‐Liss, Inc.
Transient relationships among BOLD, CBV, and CBF changes in rat brain as detected by functional MRI
Authors: Wu Gaohong , Luo Feng , Li Zhu , Zhao Xiaoli , Li Shi‐Jiang
Published: December 2002

The transient relationship between arterial cerebral blood flow (CBFA) and total cerebral blood volume (CBVT) was determined in the rat brain. Five rats anesthetized with urethane (1.2 g/kg) were examined under graded hypercapnia conditions (7.5% and 10% CO2 ventilation). The blood oxygenation level‐dependent (BOLD) contrast was determined by a gradient‐echo echo‐planar imaging (GE‐EPI) pulse sequence, and CBVT changes were determined after injection of a monocrystalline iron oxide nanocolloid (MION) contrast agent using an iron dose of 12 mg/kg. The relationship between CBVT and CBFA under transient conditions is similar to the power law under steady‐state conditions. In addition, the transient relationship between CBVT and CBFA is region‐specific. Voxels with ≥15% BOLD signal changes from hypercapnia (7.5% CO2 ventilation) have a larger power index (α = 3.26), a larger maximum possible BOLD response (M = 0.85), and shorter T (32 ms) caused by deoxyhemoglobin, compared to voxels with <15% BOLD signal changes (α = 1.82, M = 0.16, and T = 169 ms). It is suggested that the biophysical model of the BOLD signal can be extended under the transient state, with a caution that α and M values are region‐specific. To avoid overestimation of the cerebral metabolic rate of oxygen changes seen using fMRI, caution should be taken to not include voxels with large veins and a large BOLD signal. Magn Reson Med 48:987–993, 2002. © 2002 Wiley‐Liss, Inc.
Can MTR be used to assess cartilage in the presence of Gd‐DTPA2–?
Authors: Henkelman R.M. , Stanisz G.J. , Menezes N. , Burstein D.
Published: December 2002

Magnetization transfer (MT) and T1 and T2 relaxation of normal, trypsinized, and interleukin‐1β (IL‐1β)‐treated cartilage were measured in the absence and presence of Gd‐DTPA2–. Without the addition of Gd‐DTPA2–, neither T1 nor T2 showed any significant change with cartilage damage. However, with Gd‐DTPA2–, trypsinized cartilage exhibited substantially shorter T1 than normal cartilage, as expected due to the glycosaminoglycan (GAG) loss in these samples, and associated increased Gd‐DTPA2– concentration. The T2 results were similar, but less dramatic. The MT pseudo first‐order exchange rate, RM0B, did not depend on the contrast agent concentration, as expected, and was significantly faster for trypsinized and slower for IL‐1β‐treated cartilage. In both cases, the MT fraction of the macromolecular pool M0B decreased while only trypsinized cartilage showed an increase in MT exchange rate R. The MT ratio (MTR) decreased with increasing Gd‐DTPA2– concentration. However, interpretation of the MTR results in the presence of Gd‐DTPA2– was complicated due to competing effects of increased longitudinal relaxivity and MT exchange. Therefore, in a cartilage sample with an unknown degree of GAG depletion and some collagen damage, a full MT analysis might be used to probe the molecular state of cartilage, but it would not be possible to use a simple MTR measurement after the administration of Gd‐DTPA2– to differentially determine the amount of cartilage degradation in the sample. Magn Reson Med 48:1081–1084, 2002. © 2002 Wiley‐Liss, Inc.
Signal behavior in continuously ramped 2D TrueFISP for whole‐body imaging
Authors: Fautz Hans‐Peter , Leupold Jochen , Hennig Jürgen , Scheffler Klaus
Published: December 2002

A fast and robust imaging technique was developed based on a single‐slice TrueFISP acquisition using a slice excitation frequency that is incremented, or spatially “ramped,” with each repetition. The short acquisition time of single slices allows artifact‐free imaging during free breathing, which demonstrates the potential use of this technique for whole‐body screening. Overlapping positioning of consecutively acquired slices was used to provide gapless volume coverage in free‐breathing measurements. The image contrast of ramped TrueFISP was analyzed in detail using simulations and experiments. A high ramp speed results in an increased overall signal intensity and in a modification of the known T2/T1 contrast towards a proton density‐weighted contrast. A further increase in imaging speed is achieved with z‐interleaved phase‐encoding trajectories based on weighted transitions between adjacent views. Magn Reson Med 48:1085–1090, 2002. © 2002 Wiley‐Liss, Inc.
Spin-up from rest in a stratified fluid:
boundary flows
Authors: FLÓR JAN BERT , UNGARISH MARIUS , BUSH JOHN W. M.
Published: December 2002

We present the results of an integrated experimental, numerical and theoretical
examination of spin-up from rest of a stratified fluid. A vertical cylindrical container
of radius R and height 2H containing fluid of viscosity ν and characterized by
a constant buoyancy frequency N is set impulsively to rotate about its symmetry
axis with angular speed Ω = f/2. The characteristic Ekman number E = ν/ΩR2
is small and the Schmidt number S = ν/Ds (where Ds is the diffusivity of salt) is
large. The investigation is focused on elucidating the initial stage of spin-up, which
is characterized by an axisymmetric circulation driven by nonlinear Ekman layers
adjoining the horizontal boundaries. Fluid is drawn by the boundary layers from
the stationary, stratified interior and transported into corner regions. It is shown
that the corner regions are restricted to a height of approximately 0.3Rf/N from
the horizontal boundaries, above which the fluid remains unperturbed apart from
that spun up by diffusion of momentum from the sidewall boundary. Two distinct
regions thus emerge: rotating corner regions, and a quiescent stratified core. After
a time 1.3/(E1/2N), the corner regions cover the bulk of the horizontal boundaries
and the boundary layer suction is suppressed. Our study provides a framework
for understanding the subsequent evolution of the spin-up process, which may be
characterized by axisymmetry-breaking instabilities of the stratified core.
Subsonic gas flow in a straight
and uniform microchannel
Authors: ZOHAR YITSHAK , LEE SYLVANUS YUK KWAN , LEE WING YIN , JIANG LINAN , TONG PIN
Published: December 2002

A nonlinear equation based on the hydrodynamic equations is solved analytically
using perturbation expansions to calculate the flow field of a steady isothermal,
compressible and laminar gas flow in either a circular or a planar microchannel.
The solution takes into account slip-flow effects explicitly by utilizing the classical
velocity-slip boundary condition, assuming the gas properties are known. Consistent
expansions provide not only the cross-stream but also the streamwise evolution of the
various flow parameters of interest, such as pressure, density and Mach number. The
slip-flow effect enters the solution explicitly as a zero-order correction comparable
to, though smaller than, the compressible effect. The theoretical calculations are
verified in an experimental study of pressure-driven gas flow in a long microchannel
of sub-micron height. Standard micromachining techniques were utilized to fabricate
the microchannel, with integral pressure microsensors based on the piezoresistivity
principle of operation. The integrated microsystem allows accurate measurements of
mass flow rates and pressure distributions along the microchannel. Nitrogen, helium
and argon were used as the working fluids forced through the microchannel. The
experimental results support the theoretical calculations in finding that acceleration
and non-parabolic velocity profile effects were found to be negligible. A detailed error
analysis is also carried out in an attempt to expose the challenges in conducting
accurate measurements in microsystems.
Dynamics of vortices on a uniformly
shelving beach
Authors: CENTURIONI L. R.
Published: December 2002

Laboratory experiments are described which investigate the dynamics of a vortex
dipole moving in water towards a planar sloping beach inclined at an angle α to the
horizontal. Results are compared with those of a vortex ring model first developed
by Peregrine (1996). The vortices separate as they travel up the beach, eventually
moving in opposite directions and nearly parallel to the shoreline. The ranges of
conditions examined are 3°[les ]α[les ]45°, 1×103[les ]Re[les ]6×103 and 0.05[les ]Fr[les ]0.14,
where Re and Fr are the on-slope Reynolds number and the Froude number of
the vortices, respectively. The minimum distance from the shoreline reached by the
vortices and their along-shore speed are in general agreement with the predictions
when, respectively, R*i<3 (where R*i is the non-dimensional initial distance of the
vortices from the shore-line) and Re[gsim ]1500. The vortex ring model is likely to have
useful applications to the study of the dynamics of the near-shore zone.
Transition of streamwise streaks in
zero-pressure-gradient boundary layers
Authors: BRANDT LUCA , HENNINGSON DAN S.
Published: December 2002

A transition scenario initiated by streamwise low- and high-speed streaks in a flat-plate
boundary layer is studied. In many shear flows, the perturbations that show the highest
potential for transient energy amplification consist of streamwise-aligned vortices.
Due to the lift-up mechanism these optimal disturbances lead to elongated streamwise
streaks downstream, with significant spanwise modulation. In a previous investigation
(Andersson et al. 2001), the stability of these streaks in a zero-pressure-gradient
boundary layer was studied by means of Floquet theory and numerical simulations.
The sinuous instability mode was found to be the most dangerous disturbance. We
present here the first simulation of the breakdown to turbulence originating from
the sinuous instability of streamwise streaks. The main structures observed during
the transition process consist of elongated quasi-streamwise vortices located on the
flanks of the low-speed streak. Vortices of alternating sign are overlapping in the
streamwise direction in a staggered pattern. The present scenario is compared with
transition initiated by Tollmien–Schlichting waves and their secondary instability and
by-pass transition initiated by a pair of oblique waves. The relevance of this scenario
to transition induced by free-stream turbulence is also discussed.
Influence of suspended sediment
on the transport processes of nonlinear
reactive substances in turbulent streams
Authors: REVELLI R. , RIDOLFI L.
Published: December 2002

The fluid dynamic behaviour of a reactive chemical in a stream can be greatly
influenced by the presence of sorbing suspended particles. In this case, a kinetically
controlled mass transfer is established between sorbed and dissolved phases and
complex interactions emerge between fluid dynamical transport processes,
sorption–desorption kinetics and chemical reactions. These conditions often occur in rivers,
where both suspended sediment and reactive substances are frequently present. This
paper deals with the important case in which the chemical reactions are nonlinear
decay phenomena that often affect chemical or biological substances. A vertical
two-dimensional mathematical model is formulated to take into account advection,
turbulent diffusion, particle sedimentation, exchange kinetics between sorbed and
dissolved phases, and decay. The decay is modelled for the case in which two different
nonlinear decay reactions affect the dissolved and sorbed phases. The main result
of the work is to obtain analytically a one-dimensional differential model of the
vertically averaged concentration of the dissolved phase, this being conceptually
similar to the classical advection–dispersion–decay equation. However, in this case
we include the effects of (i) the kinetics with the phase sorbed by suspended particles
and (ii) the influence of the two different decay processes. For this purpose, the
multiple-scale method of homogenization is applied to the two-dimensional model.
The resultant one-dimensional differential model shows how suspended load and
decay phenomena affect the pollutant transport mechanisms to a great extent in a
non-intuitive way and that the links are nonlinear. Some quantitative results show
that these influences are, in general, not negligible.
Gravitational instability in suspension flow
Authors: CARPEN ILEANA C. , BRADY JOHN F.
Published: December 2002

The gravity-driven flow of non-neutrally buoyant suspensions is shown to be unstable
to spanwise perturbations when the shearing motion generates a density profile that
increases with height. The instability is simply due to having heavier material over
light – a Rayleigh–Taylor-like instability. The wavelength of the fastest growing
disturbance is on the order of the thickness of the suspension layer. The parameters
important to the problem are the angle of inclination of the layer relative to gravity,
the relative density difference between the particles and the fluid, the ratio of the
particle size to the thickness of the layer and the bulk volume fraction of particles.
The instability is illustrated for a range of these parameters and shown to be most
pronounced at intermediate values thereof. This instability mechanism may play an
important role in pattern formation in multiphase flows.
Consolidating democracy? The structural underpinnings of Ghana's 2000 elections
Authors: Smith Daniel A.
Published: December 2002

In 2000, Ghana's landmark elections ushered in a new era of democracy. Scholars, however, have yet to scrutinise the structural underpinnings of the country's electoral system. This article offers a detailed assessment of Ghana's bloated voters' register, patterns of voter turnout and the lingering accusation of electoral irregularities in the Volta and Ashanti Regions in the 2000 elections. Most significantly, it critically analyses the severe malapportionment of the country's 200 parliamentary seats. While the 2000 elections helped to consolidate the democratic process in Ghana, structural inequalities continue to plague the country's electoral system.
Routine outcome assessment in mental health services
Authors: SLADE MIKE
Published: December 2002

Measuring and interpreting outcome is more difficult in mental health services than in some other
areas of health care, for at least five reasons. First, the effect of the treatment may be to slow decline
or to maintain the current level, so the score on the outcome measure itself may not improve (or
may even get worse) despite best quality clinical care. Secondly, the best available evidence in the
United Kingdom indicates that clinical and social variables predict no more than 30% of the
variance in an individual's quality of life (UK700 Group, 1999). Thirdly, different types of outcome
are desynchronous (e.g. Drury et al. 1996), changing at different rates during an intervention.
Fourthly, there may not be agreement regarding what is a positive change in outcome – the patient
who has fewer episodes of mania as a result of treatment may see this as a negative outcome.
Finally, three levels of mental health service can be differentiated: treatment (specific
interventions); programme (combination of different treatment components); and system (all
programmes for a defined target group in a given area) (Burns & Priebe, 1996). The outcome data
needed to evaluate each level will be very different.
Increased serum albumin, γ globulin, immunoglobulin IgG, and IgG2 and IgG4 in autism
Authors: CROONENBERGHS J. , WAUTERS A. , DEVREESE K. , VERKERK R. , SCHARPE S. , BOSMANS E. , EGYED B. , DEBOUTTE D. , MAES M.
Published: December 2002

Background. Research on the biological pathophysiology of autism has found some evidence that immune alterations may play a role in the pathophysiology of that illness. As a consequence we expected to find that autism is accompanied by abnormalities in the pattern obtained in serum protein electrophoresis and in the serum immunoglobulin (Ig) and IgG subclass profile.

Method. We examined whether subjects with autism showed changes in total serum protein (TSP) and the serum concentrations of albumin, α1 globulin, α2 globulin, β globulin and γ globulins, IgA, IgM and IgG and the IgG subclasses IgG1, IgG2, IgG3 and IgG4, compared with normal controls.

Results. We found significantly increased concentrations of TSP in autistic subjects, which were attributable to increased serum concentrations of albumin and γ globulin. Serum IgG, IgG2 and IgG4 were also significantly raised. In autism there were significant and positive correlations between social problems and TSP and serum γ globulin and between withdrawal symptoms and TSP and serum albumin and IgG.

Conclusions. The results suggest that autism is characterized by increased TSP, a unique pattern obtained in serum protein electrophoresis, i.e. increased serum albumin and IgG, and by a specific IgG subclass profile, i.e. increased serum IgG2 and IgG4. The increased serum concentrations of IgGs in autism may point towards an underlying autoimmune disorder and/or an enhanced susceptibility to infections resulting in chronic viral infections, whereas the IgG subclass skewing may reflect different cytokine-dependent influences on autoimmune B cells and their products.
Searching for a Gulf War syndrome using cluster analysis
Authors: EVERITT B. , ISMAIL K. , DAVID A. S. , WESSELY S.
Published: December 2002

Background. Gulf veterans report medically unexplained symptoms more frequently than non-Gulf veterans did. We examined whether Gulf and non-Gulf veterans could be distinguished by their patterns of symptom reporting.

Method. A k-means cluster analysis was applied to 500 randomly sampled veterans from each of three United Kingdom military cohorts of veterans; those deployed to the Gulf conflict between 1990 and 1991; to the Bosnia peacekeeping mission between 1992 and 1997; and military personnel who were in active service but not deployed to the Gulf (Era). Sociodemographic, health variables and scores for ten symptom groups were calculated.

Results. The gap statistic indicated the five-group solution as one that provided a particularly informative description of the structure in the data. Cluster 1 consisted of low scores for all symptom groups. Cluster 2 had veterans with highest symptom scores for musculoskeletal symptoms and high scores for psychiatric symptoms. Cluster 3 had high scores for psychiatric symptoms and marginally elevated scores for the remaining nine groups symptom groups. Cluster 4 had elevated scores for musculoskeletal symptoms only and cluster 5 was distinguishable from the other clusters in having high scores in all symptom groups, especially psychiatric and musculoskeletal.

Conclusion. The findings do not support the existence of a unique syndrome affecting a subgroup of Gulf veterans but emphasize the excess of non-specific self-reported ill health in this group.
β2 adrenergic receptor 5′ haplotypes influence promoter activity
Authors: Johnatty Sharon E , Abdellatif Maha , Shimmin Lawrence , Clark Richard B , Boerwinkle Eric
Published: December 2002

Transcriptional control of the human β2 adrenergic receptor gene (ADRB2) predominantly resides within a 549 base pair region immediately 5′ to the start of translation. Within this region, four naturally occurring polymorphisms, −468 C→G, −367 T→C, −47 T→C, and −20 T→C, have been identified.

To determine the individual site and haplotype effects of these polymorphisms, we generated 16 luciferase‐based mutant constructs which were transiently transfected into HEK293 cells, and measured ADRB2 promoter‐driven luciferase activity.

Two of the 16 mutant constructs, GCCT (−468G, −367C, −47C, −20T) and CTCT, showed a highly significant 3 fold decrease in luciferase induction relative to the reference CTTT. These haplotype effects could not be accounted for by the separate and additive effects of each site.

These findings indicate that promoter polymorphisms interact to significantly alter β2 adrenergic receptor expression, and should be examined further for their association with disease‐related phenotypes.

British Journal of Pharmacology (2002) 137, 1213–1216. doi:10.1038/sj.bjp.0704935
The effects of the cyclosporin A, a P‐glycoprotein inhibitor, on the pharmacokinetics of baicalein in the rat: a microdialysis study
Authors: Tsai T H , Liu S C , Tsai P L , Ho L K , Shum A Y C , Chen C F
Published: December 2002

Baicalein is a bioactive flavonoid isolated from the root of Scutellaria baicalensis Georgi, a medicinal herb that has been used since ancient times to treat bacterial infections. As little is known concerning its pharmacokinetics, this study focussed on its pharmacokinetics as well as the possible roles of the multidrug transporter P‐glycoprotein on its distribution and disposition.

Three microdialysis probes were simultaneously inserted into the jugular vein, the hippocampus and the bile duct of male Sprague–Dawley rats for sampling in biological fluids following the administration of baicalein (10, 30 and 60 mg kg−1) through the femoral vein. The P‐glycoprotein inhibitor cyclosporin A was used to help delineate its roles.

The study design consisted of two groups of six rats in parallel: control rats which received baicalein alone and the cyclosporin A treated‐group in which the rats were injected cyclosporin A, a P‐glycoprotein inhibitor, 10 min prior to baicalein administration.

Cyclosporin A treatment resulted in a significant increase in elimination half‐life, mean residence time and area under the concentration versus time curve (AUC) of unbound baicalein in the brain. However, AUC in the bile was decreased.

The decline of baicalein in the hippocampus, blood and bile suggested that there was rapid exchange and equilibration between the peripheral compartment and the central nervous system. In addition, the results indicated that baicalein was able to penetrate the blood–brain barrier as well as undergoing hepatobiliary excretion.

Although no direct transport studies were undertaken and multiple factors may affect BBB penetration and hepatobiliary excretion, strong association of the involvement of P‐glycoprotein in these processes is indicated.

British Journal of Pharmacology (2002) 137, 1314–1320. doi:10.1038/sj.bjp.0704959
Hormonal‐dependent recruitment of Na+,K+‐ATPase to the plasmalemma is mediated by PKCβ and modulated by [Na+]i
Authors: Budu Claudia E , Efendiev Riad , Cinelli Angel M , Bertorello Alejandro M , Pedemonte Carlos H
Published: December 2002

The present study demonstrates that stimulation of hormonal receptors of proximal tubule cells with the serotonin‐agonist 8‐hydroxy‐2‐(di‐n‐propylamino) tetraline (8‐OH‐DPAT) induces an augmentation of Na+,K+‐ATPase activity that results from the recruitment of enzyme molecules to the plasmalemma.

Cells expressing the rodent wild‐type Na+,K+‐ATPase α‐subunit had the same basal Na+,K+‐ATPase activity as cells expressing the α‐subunit S11A or S18A mutants, but stimulation of Na+,K+‐ATPase activity was completely abolished in either mutant.

8‐OH‐DPAT treatment of OK cells led to PKCβ‐dependent phosphorylation of the α‐subunit Ser‐11 and Ser‐18 residues, and determination of enzyme activity with the S11A and S18A mutants indicated that both residues are essential for the agonist‐dependent stimulation of Na+,K+‐ATPase activity.

When cells were treated with both dopamine and 8‐OH‐DPAT, an activation of Na+,K+‐ATPase was observed at basal intracellular sodium concentration (∼9 mM), and this activation was gradually reduced and became a significant inhibition as the concentration of intracellular sodium gradually increased from 9 to 19 mM. Thus, besides the antagonistic effects of dopamine and 8‐OH‐DPAT, intracellular sodium modulates whether an activation or an inhibition of Na+,K+‐ATPase is produced.

British Journal of Pharmacology (2002) 137, 1380–1386. doi:10.1038/sj.bjp.0704962
Effects of levobupivacaine, ropivacaine and bupivacaine on HERG channels: stereoselective bupivacaine block
Authors: González Teresa , Arias Cristina , Caballero Ricardo , Moreno Ignacio , Delpón Eva , Tamargo Juan , Valenzuela Carmen
Published: December 2002

Levobupivacaine and ropivacaine are the pure S(−) enantiomers of N‐butyl‐ and N‐propyl‐2′,6′‐pipecoloxylidide, developed as less cardiotoxic alternatives to bupivacaine. In the present study, we have analysed the effects of levobupivacaine, ropivacaine and bupivacaine on HERG channels stably expressed in CHO cells.

The three drugs blocked HERG channels in a concentration‐, time‐ and state‐dependent manner. Block measured at the end of 5 s pulses to −10 mV induced by 20 μM bupivacaine (52.7±2.0%, n=15) and ropivacaine (55.5±2.7%, n=13) was similar (P>0.05) and both lower than that induced by levobupivacaine (67.5±4.2%, n=11) (P<0.05).

Dextrobupivacaine (20 μM) was less potent (47.2±5.2%, n=10) than levobupivacaine (P<0.05), indicating stereoselective HERG channel block.

Block induced by the three local anaesthetics exhibited a steep voltage dependence in the range of channel activation. In all cases, block measured at the maximum peak current at a test potential of 0 mV after promoting recovery from inactivation (I→O) was lower than that observed at the end of 5‐s pulses (I+O).

Levobupivacaine, ropivacaine and bupivacaine accelerated HERG inactivation kinetics, slowed the recovery from inactivation and shifted the inactivation curve towards more negative membrane potentials. The three local anaesthetics induced a rapid time‐dependent decline after using a protocol that quickly activates HERG channels.

All these results suggest that: (1) these drugs bind to the open and the inactivated states of HERG channels, (2) they stabilize HERG channels in the inactivated state, and (3) block induced by bupivacaine enantiomers is stereoselective.

British Journal of Pharmacology (2002) 137, 1269–1279. doi:10.1038/sj.bjp.0704978
Oxidative and non‐oxidative mechanisms of neuronal cell death and apoptosis by L‐3,4‐dihydroxyphenylalanine (L‐DOPA) and dopamine
Authors: Pedrosa R , Soares‐da‐Silva P
Published: December 2002

The present study was designed to evaluate the nature of intervening agents in L‐DOPA‐ and dopamine‐induced neurotoxicity in Neuro‐2A cells.

In the absence of cells and in conditions of light protection, at 37°C, L‐DOPA or dopamine (1 mM) in culture medium degraded spontaneously in a time‐dependent manner, this being prevented by ascorbic acid (200 μM) and other antioxidants, namely glutathione (1 mM), N‐acetyl‐L‐cysteine (1 mM), sodium metabisulphite (200 μM), but not N‐ter‐butyl‐α‐phenylnitrone (1 mM) and deferoxamine (100 μM).

The viability of Neuro‐2A cells declined following treatment with L‐DOPA or dopamine in a concentration‐ and time‐dependent manner. The decrease in cell viability by L‐DOPA (10±4% of control) or dopamine (15±4% of control) was markedly attenuated by antioxidants (ascorbic acid, glutathione, N‐acetyl‐L‐cysteine and sodium metabisulphite). Autoxidation of L‐DOPA or dopamine was accompanied by the formation of H2O2 in a time‐dependent manner, this being completely prevented by ascorbic acid at 24 h or markedly reduced at 48 h.

Protective effects of 100 U ml−1 catalase (40±1% of control) against L‐DOPA‐induced cell death were lower than those conferred by 200 μM ascorbic acid (70±3% of control). Catalase‐induced protection (59±5% of control) against dopamine‐induced cell death was similar to that conferred by 200 μM ascorbic acid (57±4% of control). L‐DOPA‐induced neuronal cell death was also accompanied by increases in caspase‐3 activity, this being insensitive to ascorbic acid. Dopamine‐induced increase in caspase‐3 activity occurred only when autoxidation of the amine was prevented by ascorbic acid.

It is suggested that in addition to generation of H2O2 and quinone formation, L‐DOPA‐ and dopamine‐induced cell death may result from induction of apoptosis, as evidenced by increases in caspase‐3 activity. Dopamine per se induces apoptosis by a mechanism independent of oxidative stress, as evidenced by the fact that increases in caspase‐3 activity occurred only when autoxidation of the amine was prevented.

British Journal of Pharmacology (2002) 137, 1305–1313. doi:10.1038/sj.bjp.0704982
L‐Arginyl‐3,4‐Spermidine is neuroprotective in several in vitro models of neurodegeneration and in vivo ischaemia without suppressing synaptic transmission
Authors: Morrison Barclay , Pringle Ashley K , McManus Terence , Ellard John , Bradley Mark , Signorelli Francesco , Iannotti Fausto , Sundstrom Lars E
Published: December 2002

Stroke is the third most common cause of death in the world, and there is a clear need to develop new therapeutics for the stroke victim. To address this need, we generated a combinatorial library of polyamine compounds based on sFTX‐3.3 toxin from which L‐Arginyl‐3,4‐Spermidine (L‐Arg‐3,4) emerged as a lead neuroprotective compound. In the present study, we have extended earlier results to examine the compound's neuroprotective actions in greater detail.

In an in vitro ischaemia model, L‐Arg‐3,4 significantly reduced CA1 cell death when administered prior to induction of 60 min of ischaemia as well as when administered immediately after ischaemia. Surprisingly, L‐Arg‐3,4 continued to prevent cell death significantly when administration was delayed for as long as 60 min after ischaemia.

L‐Arg‐3,4 significantly reduced cell death in excitotoxicity models mediated by glutamate, NMDA, AMPA, or kainate. Unlike glutamate receptor antagonists, 300 μM L‐Arg‐3,4 did not suppress synaptic transmission as measured by evoked responses in acute hippocampal slices.

L‐Arg‐3,4 provided significant protection, in vitro, in a superoxide mediated injury model and prevented an increase of superoxide production after AMPA or NMDA stimulation. It also decreased nitric oxide production after in vitro ischaemia and NMDA stimulation, but did so without inhibiting nitric oxide synthase directly.

Furthermore, L‐Arg‐3,4 was significantly neuroprotective in an in vivo model of global forebrain ischaemia, without any apparent neurological side‐effects.

Taken together, these results demonstrate that L‐Arg‐3,4 is protective in several models of neurodegeneration and may have potential as a new therapeutic compound for the treatment of stroke, trauma, and other neurodegenerative diseases.

British Journal of Pharmacology (2002) 137, 1255–1268. doi:10.1038/sj.bjp.0704986
Antibodies and a cysteine‐modifying reagent show correspondence of M current in neurons to KCNQ2 and KCNQ3 K+ channels
Authors: Roche John P , Westenbroek Ruth , Sorom Abraham J , Hille Bertil , Mackie Ken , Shapiro Mark S
Published: December 2002

KCNQ K+ channels are thought to underlie the M current of neurons. To probe if the KCNQ2 and KCNQ3 subtypes underlie the M current of rat superior cervical ganglia (SCG) neurons and of hippocampus, we raised specific antibodies against them and also used the cysteine‐alkylating agent N‐ethylmaleimide (NEM) as an additional probe of subunit composition.

Tested on tsA‐201 (tsA) cells transfected with cloned KCNQ1‐5 subunits, our antibodies showed high affinity and selectivity for the appropriate subtype. The antibodies immunostained SCG neurons and hippocampal sections at levels similar to those for channels expressed in tsA cells, indicating that KCNQ2 and KCNQ3 are present in SCG and hippocampal neurons. Some hippocampal regions contained only KCNQ2 or KCNQ3 subunits, suggesting the presence of M currents produced by channels other than KCNQ2/3 heteromultimers.

We found that NEM augmented M currents in SCG neurons and KCNQ2/3 currents in tsA cells via strong voltage‐independent and modest voltage‐dependent actions. Expression of individual KCNQ subunits in tsA cells revealed voltage‐independent augmentation of KCNQ2, but not KCNQ1 nor KCNQ3, currents by NEM indicating that this action on SCG M currents likely localizes to KCNQ2. Much of the voltage‐independent action is lost after the C242T mutation in KCNQ2.

The correspondence of NEM effects on expressed KCNQ2/3 and SCG M currents, along with the antibody labelling, provide further evidence that KCNQ2 and KCNQ3 subunits strongly contribute to the M current of neurons. The site of NEM action may be important for treatment of diseases caused by under‐expression of these channels.

British Journal of Pharmacology (2002) 137, 1173–1186. doi:10.1038/sj.bjp.0704989
Inhibition of striatal and retinal dopamine release via nociceptin/orphanin FQ receptors
Authors: Flau K , Redmer A , Liedtke S , Kathmann M , Schlicker E
Published: December 2002

We determined the effects of nociceptin/orphanin FQ and the NOP receptor ligands acetyl‐Arg‐Tyr‐Tyr‐Arg‐Ile‐Lys‐NH2 (Ac‐RYYRIK‐NH2) and naloxone benzoylhydrazone on transmitter release in vitro.

The electrically evoked tritium overflow from guinea‐pig and mouse striatal slices and guinea‐pig retinal discs preincubated with [3H]‐dopamine was inhibited by nociceptin/orphanin FQ (pEC50 7.9, 7.6 and 8.6; Emax 30, 50 and 55%). Ac‐RYYRIK‐NH2 0.032 μM and naloxone benzoylhydrazone 5 μM antagonized the effect of nociceptin/orphanin FQ in striatal slices of the guinea‐pig (apparent pA2 9.1 and 6.8) and the mouse (apparent pA2 9.2 and 7.5) and strongly attenuated the effect of nociceptin/orphanin FQ 0.1 μM in guinea‐pig retinal discs. Ac‐RYYRIK‐NH2 0.032 μM did not affect the evoked overflow by itself whereas naloxone benzoylhydrazone 5 μM inhibited it in each tissue.

The electrically evoked tritium overflow from mouse brain cortex slices preincubated with [3H]‐noradrenaline was inhibited by nociceptin/orphanin FQ (pEC50 7.9, Emax 85%), Ac‐RYYRIK‐NH2 (pEC50 8.3, Emax 47%) but not affected by naloxone benzoylhydrazone 5 μM. Ac‐RYYRIK‐NH2 and naloxone benzoylhydrazone showed apparent pA2 values of 8.6 and 6.9.

In conclusion, the inhibitory effect of nociceptin/orphanin FQ on dopamine release in the striatum and retina and on noradrenaline release in the cerebral cortex is mediated via NOP receptors. Ac‐RYYRIK‐NH2 behaves as an extremely potent NOP receptor antagonist in the striatum and retina and as a partial agonist in the cortex.

British Journal of Pharmacology (2002) 137, 1355–1361. doi:10.1038/sj.bjp.0704998
Endomorphin analogues containing D‐Pro2 discriminate different μ‐opioid receptor mediated antinociception in mice
Authors: Sakurada Shinobu , Watanabe Hiroyuki , Hayashi Takafumi , Yuhki Masayuki , Fujimura Tsutomu , Murayama Kimie , Sakurada Chikai , Sakurada Tsukasa
Published: December 2002

The antagonistic actions of D‐Pro2‐endomorphins on inhibition of the paw withdrawal response by endomorphins were studied in mice. D‐Pro2‐endomorphin‐1 and D‐Pro2‐endomorphin‐2, injected intrathecally (i.t.), had no significant effect on the nociceptive thermal threshold alone. When D‐Pro2‐endomorphin‐1 (0.05–0.1 pmol) was injected simultaneously with i.t. endomorphin‐1 (5.0 nmol) or endomorphin‐2 (5.0 nmol), antinociception induced by endomoprhin‐1 was reduced significantly, whereas endomorphin‐2‐induced antinociception was not affected by D‐Pro2‐endomorphin‐1. Antinociception induced by i.t. endomorphin‐2 (5.0 nmol) was reduced significantly by its analogue, D‐Pro2‐endomorphin‐2 (100 pmol), but not by D‐Pro2‐endomorphin‐1. D‐Pro2‐endomorphin‐1. D‐Pro2‐endomorphin‐1 also antagonized the antinociceptive effect of i.t. DAMGO, a μ‐opioid receptor agonist, whereas D‐Pro2‐endomorphin‐2 failed to reduce the effect of DAMGO. These results suggest that endomorphin analogues containing D‐Pro2 are able to discriminate the antinociceptive actions of μ1‐ and μ2‐opioid receptor agonists at the spinal cord level.

British Journal of Pharmacology (2002) 137, 1143–1146. doi:10.1038/sj.bjp.0705047
THE SOLAR NEUTRINO PROBLEM AND ITS OSCILLATION SOLUTION
Authors: SMY MICHAEL B.
Published: December 2002

The current status of solar neutrino measurements and their oscillation interpretation is reviewed.
POLARIZATION EFFECTS IN B → V1 V2 AND SUBSEQUENT DECAYS
Authors: KRAMER G. , SONG H. S. , YU CHAEHYUN
Published: December 2002

The covariant density matrix formalism is used to obtain the joint angular distributions of the decay B → V1V2 followed by subsequent decays V1 → a1b1 and V2 → a2b2. In particular, the case that V1 is J/ψ and V2 is an axial vector meson K1(1270) as well as a vector meson like K*(890) or ϕ(1020) is considered and also the decay mode of ϕ → ρ π besides ϕ → K+ K- is discussed.
BOUNDS ON DIRECT COUPLINGS OF SUPERHEAVY METASTABLE PARTICLES TO THE INFLATON FIELD FROM ULTRA HIGH ENERGY COSMIC RAY EVENTS
Authors: CAMPOS A. H. , LENGRUBER L. L. , ROSENFELD R. , REIS H. C. , SATO R.
Published: December 2002

Top-down models for the origin of ultra high energy cosmic rays (UHECR's) propose that these events are the decay products of relic superheavy metastable particles, usually called X particles. These particles can be produced in the reheating period following the inflationary epoch of the early Universe. We obtain constraints on some parameters such as the lifetime and direct couplings of the X-particle to the inflaton field from the requirement that they are responsible for the observed UHECR flux.
COMPUTATIONAL AEROACOUSTICS EXAMPLES SHOWING THE FAILURE OF THE ACOUSTIC ANALOGY THEORY TO IDENTIFY THE CORRECT NOISE SOURCES
Authors: TAM CHRISTOPHER K. W.
Published: December 2002

Lighthill's Acoustic Analogy has been the dominant theory of aeroacoustics, especially jet aeroacoustics for almost fifty years. As yet, except for the u8 scaling law, which was derived by dimensional analysis, jet noise prediction based on the Acoustic Analogy approach has not been particularly successful. This paper examines some of the weaknesses and ambiguities in the formulation of the Acoustic Analogy theories. It is concluded that if the analogy is carried out completely, in the sense that the full wave propagation terms are retained in the propagation part of the equations of the analogy, then the theory offers no sensible noise source terms. To demonstrate that the Acoustic Analogy can fail to identify the correct noise sources, four examples are considered. They include an initial value problem, a boundary problem, the problem of weak solution and the problem of sound generation by instability waves in jets and mixing layers. These examples show clearly how, in each case, the Acoustic Analogy theory identifies the wrong noise source. Indeed, the Acoustic Analogy could provide, if not careful, misleading interpretation of the physics of sound generation.

This paper is dedicated to Professor David G. Crighton, outstanding applied mathematician, world famous acoustician and a much respected friend.
Influence of network chain orientation on the mechanical property of epoxy resin filled with silica particles
Authors: Harada Miyuki , Morimoto Mitsuhiko , Ochi Mitsukazu
Published: December 2002

When tensile stress was applied to epoxy resin filled with silica particles, we expected that the stress concentration would occur in the epoxy matrix near the interface between the matrix and the silica particles. We investigated the plastic deformation of the network chains near the interface, which was quantitatively evaluated using a polarized microscope FTIR technique. A biphenol‐type epoxy resin, which has a mesogenic group in the backbone moiety, was used as the matrix resin. As a result, reorientation of the network chains along the direction of the tensile stress near the interface with the silica particles was observed. Especially when the silica/matrix interface has good bonding properties, the reorientation of the network chains was observed at a larger area around the silica particles. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 87: 787–794, 2003
Effect of filler–fiber interactions on compressive strength of fly ash and short‐fiber epoxy composites
Authors: Kulkarni S. M. , Kishore
Published: December 2002

Compressive properties of epoxy composites reinforced with fly ash and fibers, which have differing aspect ratios, are studied. Retention of strength and modulus are observed for a greater range of fiber volume fractions following fly ash introduction into the system. A slight decrease in density was also observed when fly ash content was higher, making these composites with materials of differing aspect ratio bearing reinforcement systems suitable in weight specific applications. The investigations showed that strength decrease is larger in fiber‐bearing samples compared with only ash‐bearing samples. This decrease was ascribed to the tendency of fibers to bunch. When the ash filler was introduced, this tendency of fibers to cluster appears to be reduced, resulting in increased strength and modulus. Further attempts are made to analyze these interactions of fibers and fillers through observations made on the surfaces of failed samples by scanning electron microscopy. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 87: 836–841, 2003