bluuebunny/crossref_metadata_2025 huggingface dataset:
Attenuation of apoptosis in enterocytes by blockade of potassium channels
Authors: Grishin Anatoly , Ford Henri , Wang Jin , Li Hui , Salvador-Recatala Vicenta , Levitan Edwin S. , Zaks-Makhina Elena
Published: July 2005

Apoptosis plays an important role in maintaining the balance between proliferation and cell loss in the intestinal epithelium. Apoptosis rates may increase in intestinal pathologies such as inflammatory bowel disease and necrotizing enterocolitis, suggesting pharmacological prevention of apoptosis as a therapy for these conditions. Here, we explore the feasibility of this approach using the rat epithelial cell line IEC-6 as a model. On the basis of the known role of K+ efflux in apoptosis in various cell types, we hypothesized that K+ efflux is essential for apoptosis in enterocytes and that pharmacological blockade of this efflux would inhibit apoptosis. By probing intracellular [K+] with the K+-sensitive fluorescent dye and measuring the efflux of 86Rb+, we found that apoptosis-inducing treatment with the proteasome inhibitor MG-132 leads to a twofold increase in K+ efflux from IEC-6 cells. Blockade of K+ efflux with tetraethylammonium, 4-aminopyridine, stromatoxin, chromanol 293B, and the recently described K+ channel inhibitor 48F10 prevents DNA fragmentation, caspase activation, release of cytochrome c from mitochondria, and loss of mitochondrial membrane potential. Thus K+ efflux occurs early in the apoptotic program and is required for the execution of later events. Apoptotic K+ efflux critically depends on activation of p38 MAPK. These results demonstrate for the first time the requirement of K+ channel-mediated K+ efflux for progression of apoptosis in enterocytes and suggest the use of K+ channel blockers to prevent apoptotic cell loss occurring in intestinal pathologies.
Events at the Host-Microbial Interface of the Gastrointestinal Tract V. Paneth cell α-defensins in intestinal host defense
Authors: Bevins Charles L.
Published: July 2005

Host defense of the small intestine is mediated, in part, by antimicrobial peptides, including α-defensins. In the small intestine, Paneth cells, specialized secretory epithelial cells located at the base of the crypt invaginations lining the intestinal wall, produce α-defensins. The α-defensins are cysteine-rich cationic peptides with antibiotic activity against a wide range of bacteria and other microbes. Studies of transgenic and knockout mice have supported a pivotal role of Paneth cell α-defensins in protection from bacterial pathogens. New data suggest that deficient expression of Paneth cell α-defensins may contribute to the pathophysiology of Crohn's disease, a chronic inflammatory bowel disease.
Transcriptional profiling of tissue plasticity: role of shifts in gene expression and technical limitations
Authors: Flück Martin , Däpp Christoph , Schmutz Silvia , Wit Ernst , Hoppeler Hans
Published: July 2005

Reprogramming of gene expression has been recognized as a main instructive modality for the adjustments of tissues to various kinds of stress. The recent application of gene expression profiling has provided a powerful tool to elucidate the molecular pathways underlying such tissue remodeling. However, the biological interpretations of expression profiling results critically depend on normalization of transcript signals to mRNA standards before statistical evaluation. A hypothesis is proposed whereby the “fluctuating nature” of gene expression represents an inherent limitation of the test system used to quantify RNA levels. Misinterpretation of gene expression data occurs when RNA quantities are normalized to a subset of mRNAs that are subject to strong regulation. The contention of contradictory biological outcomes using different RNA-normalization schemes is demonstrated in two models of skeletal muscle plasticity with data from custom-designed microarrays and biochemical and ultrastructural evidence for correspondingly altered RNA content and nucleolar activity. The prevalence of these biological constraints is underlined by a literature survey in different models of tissue plasticity with emphasis on the unique malleability of skeletal muscle. Finally, recommendations on the optimal experimental layout are given to control biological and technical variability in microarray and RT-PCR studies. It is proposed to approach normalization of transcript signals by measuring total RNA and DNA content per sample weight and by correcting for concurrently estimated endogenous standards such as major ribosomal RNAs and spiked RNA and DNA species. This allows for later conversion to diverse tissue-relevant references and should improve the physiological interpretations of phenotypic plasticity.
Modeling the blood lactate kinetics at maximal short-term exercise conditions in children, adolescents, and adults
Authors: Beneke Ralph , Hütler Matthias , Jung Marcus , Leithäuser Renate M.
Published: July 2005

Whether age-related differences in blood lactate concentrations (BLC) reflect specific BLC kinetics was analyzed in 15 prepubescent boys (age 12.0 ± 0.6 yr, height 1.54 ± 0.06 m, body mass 40.0 ± 5.2 kg), 12 adolescents (16.3 ± 0.7 yr, 1.83 ± 0.07 m, 68.2 ± 7.5 kg), and 12 adults (27.2 ± 4.5 yr, 1.83 ± 0.06 m, 81.6 ± 6.9 kg) by use of a biexponential four-parameter kinetics model under Wingate Anaerobic Test conditions. The model predicts the lactate generated in the extravasal compartment (A), invasion ( k1), and evasion ( k2) of lactate into and out of the blood compartment, the BLC maximum (BLCmax), and corresponding time (TBLCmax). BLCmax and TBLCmax were lower ( P < 0.05) in boys (BLCmax 10.2 ± 1.3 mmol/l, TBLCmax 4.1 ± 0.4 min) than in adolescents (12.7 ± 1.0 mmol/l, 5.5 ± 0.7 min) and adults (13.7 ± 1.4 mmol/l, 5.7 ± 1.1 min). No differences were found in A related to the muscle mass (AMM) and k1 between boys (AMM: 22.8 ± 2.7 mmol/l, k1: 0.865 ± 0.115 min−1), adolescents (22.7 ± 1.3 mmol/l, 0.692 ± 0.221 min−1), and adults (24.7 ± 2.8 mmol/l, 0.687 ± 0.287 min−1). The k2 was higher ( P < 0.01) in boys (2.87 10−2 ± 0.75 10−2 min−1) than in adolescents (2.03 × 10−2 ± 0.89 × 10−2 min−1) and adults (1.99 × 10−2 ± 0.93 × 10−2 min−1). Age-related differences in the BLC kinetics are unlikely to reflect differences in muscular lactate or lactate invasion but partly faster elimination out of the blood compartment.
Role of physical activity in preventing and treating obesity
Authors: Hill James O. , Wyatt Holly R.
Published: July 2005

There is an inverse relationship between physical activity and weight gain. However, additional research is needed to quantify the amount of physical activity required to prevent weight gain in different populations, improve the way we convey physical activity recommendations to the public, and help the individuals increase their physical activity. Although physical activity does not appear to contribute significantly to weight loss, it is critical for maintenance of weight loss. Available data are consistent in that 60–90 min/day of moderate-intensity physical activity is required to maintain a significant weight loss. Although there is agreement about the need for high levels of physical activity to maintain weight loss, there is a need for more research to understand why physical activity is critical for weight loss maintenance. Finally, additional research is needed to determine whether there is an optimal level of physical activity below which it is difficult for most people to achieve a balance between energy intake and expenditure at a healthy body weight. The increasing prevalence of obesity may reflect the fact that the majority of the population has fallen below such a level of physical activity.
Task failure during fatiguing contractions performed by humans
Authors: Maluf Katrina S. , Enoka Roger M.
Published: July 2005

By comparing the physiological adjustments that occur when two similar fatiguing contractions are performed to failure, it is possible to identify mechanisms that limit the duration of the more difficult task. This approach has been used to study two fatiguing contractions, referred to as the force and position tasks, which differed in the type of feedback given to the subject and the amount of support provided by the surroundings. Even though the two tasks required a similar net muscle torque during submaximal isometric contractions, the duration that the position task could be sustained was consistently much briefer than that for the force task. The position task involved a greater rate of increase in EMG activity and more marked changes in motor unit recruitment and rate coding compared with the force task. These observations are consistent with the hypothesis that the motor unit pool was recruited more rapidly during the position task. The difference in motor unit behavior appeared to be caused by variation in synaptic input, likely involving heightened sensitivity of the stretch reflex during the position task. Upon repeat performances of the two fatiguing contractions, some subjects were able to increase the time to failure for the force task but not the position task. Furthermore, the time to failure for the position task could be influenced by the postural demands associated with maintaining the position of the limb, and the difference in the two durations was enhanced when the postural activity evoked a pressor response. These observations indicate that the difference in the duration of the two fatiguing contractions was attributable to differences in the control strategy used to sustain the tasks and the magnitude of the associated postural activity.
Retraction of Poehlman et al. Journal of Applied Physiology 76: 2281–2287, 1994
Authors: Poehlman Eric T.
Published: July 2005

RE: Poehlman, Eric T., Andrew W. Gardner, Paul J. Arciero, Michael I. Goran, and Jorges Calles-Escandon. Effects of endurance training on total fat oxidation in elderly persons.
A Spectrum From Pure Post-Spike Effects to Synchrony Effects in Spike-Triggered Averages of Electromyographic Activity During Skilled Finger Movements
Authors: Schieber Marc H. , Rivlis Gil
Published: July 2005

During individuated finger movements, a high proportion of synchrony effects was found in spike-triggered averages (SpikeTAs) of rectified electromyographic activity aligned on the spikes discharged by primary motor cortex (M1) neurons. Because synchrony effects can be produced even if the trigger neuron itself provides no direct synaptic connections to motoneurons, such nonoscillatory synchrony effects often are discounted when considering control of motoneuron pools. We therefore examined the distinctions between pure postspike effects and synchrony effects. The criteria usually applied to distinguish pure and synchrony effects—onset latency and peak width—failed to separate the present SpikeTA effects objectively into distinct subpopulations. Synchrony effects generally were larger than pure effects. Many M1 neurons produced pure effects in some muscles while producing synchrony effects in others. M1 neurons producing no effects, only pure effects, only synchrony effects, or both pure and synchrony effects did not fall into different groups based on discharge characteristics during finger movements. Nor were neurons producing different types of SpikeTA effects segregated spatially in M1. These observations suggest that neurons producing pure and synchrony SpikeTA effects come from similar M1 populations. We discuss potential mechanisms that might have produced a continuous spectrum of variation from pure to synchrony effects in the present monkeys. Although synchrony effects cannot be taken as evidence of mono- or disynaptic connections from the recorded neuron to the motoneuron pool, the functional linkages indicated by synchrony effects represent a substantial fraction of M1 input to motoneuron pools during skilled, individuated finger movements.
Temperature Sensitivity of Dopaminergic Neurons of the Substantia Nigra Pars Compacta: Involvement of Transient Receptor Potential Channels
Authors: Guatteo Ezia , Chung Kenny K. H. , Bowala Tharushini K. , Bernardi Giorgio , Mercuri Nicola B. , Lipski Janusz
Published: July 2005

Changes in temperature of up to several degrees have been reported in different brain regions during various behaviors or in response to environmental stimuli. We investigated temperature sensitivity of dopaminergic neurons of the rat substantia nigra pars compacta (SNc), an area important for motor and emotional control, using a combination of electrophysiological techniques, microfluorometry, and RT-PCR in brain slices. Spontaneous neuron firing, cell membrane potential/currents, and intracellular Ca2+level ([Ca2+]i) were measured during cooling by ≤10° and warming by ≤5° from 34°C. Cooling evoked slowing of firing, cell membrane hyperpolarization, increase in cell input resistance, an outward current under voltage clamp, and a decrease of [Ca2+]i. Warming induced an increase in firing frequency, a decrease in input resistance, an inward current, and a rise in [Ca2+]i. The cooling-induced current, which reversed in polarity between −5 and −17 mV, was dependent on extracellular Na+. Cooling-induced whole cell currents and changes in [Ca2+]iwere attenuated by 79% in the presence of 2-aminoethoxydiphenylborane (2-APB; 200 μM), and the outward current was reduced by 20% with ruthenium red (100 μM). RT-PCR conducted with tissue punches containing the SNc revealed mRNA expression for TRPV3 and TRPV4 channels, known to be activated in expression systems by temperature changes within the physiological range. 2-APB, a TRPV3 modulator, increased baseline [Ca2+]i, whereas 4αPDD, a TRPV4 agonist, increased spontaneous firing in 7 of 14 neurons tested. We conclude that temperature-gated TRPV3 and TRPV4 cationic channels are expressed in nigral dopaminergic neurons and are constitutively active in brain slices at near physiological temperatures, where they affect the excitability and calcium homeostasis of these neurons.
Properties of Mouse Spinal Lamina I GABAergic Interneurons
Authors: Dougherty Kimberly J. , Sawchuk Michael A. , Hochman Shawn
Published: July 2005

Lamina I is a sensory relay region containing projection cells and local interneurons involved in thermal and nociceptive signaling. These neurons differ in morphology, sensory response modality, and firing characteristics. We examined intrinsic properties of mouse lamina I GABAergic neurons expressing enhanced green fluorescent protein (EGFP). GABAergic neuron identity was confirmed by a high correspondence between GABA immunolabeling and EGFP fluorescence. Morphologies of these EGFP+/GABA+ cells were multipolar (65%), fusiform (31%), and pyramidal (4%). In whole cell recordings, cells fired a single spike (44%), tonically (35%), or an initial burst (21%) in response to current steps, representing a subset of reported lamina I firing properties. Membrane properties of tonic and initial burst cells were indistinguishable and these neurons may represent one functional population because, in individual neurons, their firing patterns could interconvert. Single spike cells were less excitable with lower membrane resistivity and higher rheobase. Most fusiform cells (64%) fired tonically while most multipolar cells (56%) fired single spikes. In summary, lamina I inhibitory interneurons are functionally divisible into at least two major groups both of which presumably function to limit excitatory transmission.
Changes in Corticospinal Efficacy Contribute to the Locomotor Plasticity Observed After Unilateral Cutaneous Denervation of the Hindpaw in the Cat
Authors: Bretzner Frédéric , Drew Trevor
Published: July 2005

We used microwire electrodes chronically implanted into the hindlimb representation of the motor cortex as well as into the pyramidal tract to test the hypothesis that the corticospinal system contributes to the locomotor plasticity that is observed after cutaneous denervation of the cat hindpaw. A total of 23 electrodes implanted into the motor cortex in three cats trained to walk on a treadmill produced phase-dependent, short-latency, twitch responses in hindlimb flexor and extensor muscles during locomotion. After a unilateral cutaneous denervation of the hindpaw, the cats showed transient deficits in locomotion, including a dragging of the hindpaw along the treadmill belt during the swing phase. This deficit rapidly recovered over the course of a few days. The recovery of locomotion was accompanied by an increase in the magnitude of the responses evoked in different muscles by the cortical stimulation at all 23 cortical sites. Response magnitude increased rapidly within the first 1–2 wk postdenervation before attaining a plateau at ≥3 wk. In two cats, for which detailed information was obtained, response magnitude in the knee flexor, semitendinosus (St), was increased by >250% at 14/18 sites (mean increase = 1,235%). Increased responses in the St to stimulation were also observed at two of the four pyramidal tract sites after the denervation but were relatively smaller (max = 593%) than those evoked by the cortical stimulation. We suggest that the denervation produces changes in both cortical and spinal excitability that, together, produce a change in corticospinal efficacy that contributes to the recovery of locomotor function.
Chronic Suppression of Activity in Barrel Field Cortex Downregulates Sensory Responses in Contralateral Barrel Field Cortex
Authors: Li Lu , Rema V. , Ebner Ford F.
Published: July 2005

Numerous lines of evidence indicate that neural information is exchanged between the cerebral hemispheres via the corpus callosum. Unilateral ablation lesions of barrel field cortex (BFC) in adult rats induce strong suppression of background and evoked activity in the contralateral barrel cortex and significantly delay the onset of experience-dependent plasticity. The present experiments were designed to clarify the basis for these interhemispheric effects. One possibility is that degenerative events, triggered by the lesion, degrade contralateral cortical function. Another hypothesis, alone or in combination with degeneration, is that the absence of interhemispheric activity after the lesion suppresses contralateral responsiveness. The latter hypothesis was tested by placing an Alzet minipump subcutaneously and connecting it via a delivery tube to a cannula implanted over BFC. The minipump released muscimol, a GABAAreceptor agonist at a rate of 1 μl/h, onto one barrel field cortex for 7 days. Then with the pump still in place, single cells were recorded in the contralateral BFC under urethan anesthesia. The data show a ∼50% reduction in principal whisker responses (D2) compared with controls, with similar reductions in responses to the D1 and D3 surround whiskers. Despite these reductions, spontaneous firing is unaffected. Fast spiking units are more sensitive to muscimol application than regular spiking units in both the response magnitude and the center/surround ratio. Effects of muscimol are also layer specific. Layer II/III and layer IV neurons decrease their responses significantly, unlike layer V neurons that fail to show significant deficits. The results indicate that reduced activity in one hemisphere alters cortical excitability in the other hemisphere in a complex manner. Surprisingly, a prominent response decrement occurs in the short-latency (3–10 ms) component of principal whisker responses, suggesting that suppression may spread to neurons dominated by thalamocortical inputs after interhemispheric connections are inactivated. Bilateral neurological impairments have been described after unilateral stroke lesions in the clinical literature.
Bimanual Coordination During Rhythmic Movements in the Absence of Somatosensory Feedback
Authors: Spencer Rebecca M. C. , Ivry Richard B. , Cattaert Daniel , Semjen Andras
Published: July 2005

We investigated the role of somatosensory feedback during bimanual coordination by testing a bilaterally deafferented patient, a unilaterally deafferented patient, and three control participants on a repetitive bimanual circle-drawing task. Circles were drawn symmetrically or asymmetrically at varying speeds with full, partial, or no vision of the hands. Strong temporal coupling was observed between the hands at all movement rates during symmetrical drawing and at the comfortable movement rate during asymmetrical drawing in all participants. When making asymmetric movements at the comfortable and faster rates, the patients and controls exhibited similar evidence of pattern instability, including a reduction in temporal coupling and trajectory deformation. The patients differed from controls on measures of spatial coupling and variability. The amplitudes and shapes of the two circles were less similar across limbs for the patients than the controls and the circles produced by the patients tended to drift in extrinsic space across successive cycles. These results indicate that somatosensory feedback is not critical for achieving temporal coupling between the hands nor does it contribute significantly to the disruption of asymmetrical coordination at faster movement rates. However, spatial consistency and position, both within and between limbs, were disrupted in the absence of somatosensory feedback.
Dopamine Modulation of Two Delayed Rectifier Potassium Currents in a Small Neural Network
Authors: Gruhn Matthias , Guckenheimer John , Land Bruce , Harris-Warrick Ronald M.
Published: July 2005

Delayed rectifier potassium currents [ IK(V)] generate sustained, noninactivating outward currents with characteristic fast rates of activation and deactivation and play important roles in shaping spike frequency. The pyloric motor network in the stomatogastric ganglion of the spiny lobster, Panulirus interruptus, is made up of one interneuron and 13 motor neurons of five different classes. Dopamine (DA) increases the firing frequencies of the anterior burster (AB), pyloric (PY), lateral pyloric (LP), and inferior cardiac (IC) neurons and decreases the firing frequencies of the pyloric dilator (PD) and ventricular dilator (VD) neurons. In all six types of pyloric neurons, IK(V)is small with respect to other K+currents. It is made up of at least two TEA-sensitive components that show differential sensitivity to 4-aminopyridine and quinidine, and have differing thresholds of activation. One saturable component is activated at potentials above −25 mV, whereas the second component appears at more depolarized voltages and does not saturate at voltage steps up to +45 mV. The magnitude of the components varies among cell types but also shows considerable variation within a single type. A subset of PY neurons shows a marked enhancement in spike frequency with DA; DA evokes a pronounced reversible increase in IK(V)conductance of ≤30% in the PY neurons studied, and on average significantly increases both components of IK(V). The AB neuron also shows a reversible 20% increase in the steady state IK(V). DA had no effect on IK(V)in PD, LP, VD, and IC neurons. The physiological roles of these currents and their modulation by DA are discussed.
Dopamine Modulation of Phasing of Activity in a Rhythmic Motor Network: Contribution of Synaptic and Intrinsic Modulatory Actions
Authors: Johnson Bruce R. , Schneider Lauren R. , Nadim Farzan , Harris-Warrick Ronald M.
Published: July 2005

The phasing of neuronal activity in a rhythmic motor network is determined by a neuron's intrinsic firing properties and synaptic inputs; these could vary in their relative importance under different modulatory conditions. In the lobster pyloric network, the firing of eight follower pyloric (PY) neurons is shaped by their intrinsic rebound after pacemaker inhibition and by synaptic input from the lateral pyloric (LP) neuron, which inhibits all PY neurons and is electrically coupled to a subset of them. Under control conditions, LP inhibition is weak and has little influence on PY firing. We examined modulation that could theoretically enhance the LP's synaptic contribution to PY firing. We measured the effects of dopamine (DA) on LP→PY synapses, driving the LP neuron with trains of realistic waveforms constructed from prerecorded control and DA LP oscillations, which differed in shape and duration. Under control conditions, chemical inhibition underwent severe depression and disappeared; in the mixed synapses, electrical coupling dominated. Switching between control and DA LP waveforms (with or without DA present) caused only subtle changes in synaptic transmission. DA markedly enhanced synaptic inhibition, reduced synaptic depression and weakened electrical coupling, reversing the sign of the mixed synapses. Despite this, removal of the LP from the intact network still had only weak effects on PY firing. DA also enhances PY intrinsic rebound properties, which still control the onset of PY firing. Thus in a rhythmic network, the functional importance of synaptic modulation can only be understood in the context of parallel modulation of intrinsic properties.
Change in Muscle Fascicle Length Influences the Recruitment and Discharge Rate of Motor Units During Isometric Contractions
Authors: Pasquet Benjamin , Carpentier Alain , Duchateau Jacques
Published: July 2005

This study examines the effect of fascicle length change on motor-unit recruitment and discharge rate in the human tibialis anterior (TA) during isometric contractions of various intensities. The torque produced during dorsiflexion and the surface and intramuscular electromyograms (EMGs) from the TA were recorded in eight subjects. The behavior of the same motor unit ( n = 59) was compared at two ankle joint angles (+10 and −10° around the ankle neutral position). Muscle fascicle length of the TA was measured noninvasively using ultrasonography recordings. When the ankle angle was moved from 10° plantarflexion to 10° dorsiflexion, the torque produced during maximal voluntary contraction (MVC) was significantly reduced [35.2 ± 3.3 vs. 44.3 ± 4.2 (SD) Nm; P < 0.001] and the average surface EMG increased (0.47 ± 0.08 vs. 0.43 ± 0.06 mV; P < 0.05). At reduced ankle joint angle, muscle fascicle length declined by 12.7% ( P < 0.01) at rest and by 18.9% ( P < 0.001) during MVC. Motor units were activated at a lower recruitment threshold for short compared with long muscle fascicle length, either when expressed in absolute values (2.1 ± 2.5 vs. 3.6 ± 3.7 Nm; P < 0.001) or relative to their respective MVC (5.2 ± 6.1 vs. 8.8 ± 9.0%). Higher discharge rate and additional motor-unit recruitment were observed at a given absolute or relative torque when muscle fascicles were shortened. However, the data indicate that increased rate coding was mainly present at low torque level (<10% MVC), when the muscle-tendon complex was compliant, whereas recruitment of additional motor units played a dominant role at higher torque level and decreased compliance (10–35% MVC). Taken together, the results suggest that the central command is modulated by the afferent proprioceptive information during submaximal contractions performed at different muscle fascicle lengths.
Adaptive Exponential Integrate-and-Fire Model as an Effective Description of Neuronal Activity
Authors: Brette Romain , Gerstner Wulfram
Published: July 2005

We introduce a two-dimensional integrate-and-fire model that combines an exponential spike mechanism with an adaptation equation, based on recent theoretical findings. We describe a systematic method to estimate its parameters with simple electrophysiological protocols (current-clamp injection of pulses and ramps) and apply it to a detailed conductance-based model of a regular spiking neuron. Our simple model predicts correctly the timing of 96% of the spikes (±2 ms) of the detailed model in response to injection of noisy synaptic conductances. The model is especially reliable in high-conductance states, typical of cortical activity in vivo, in which intrinsic conductances were found to have a reduced role in shaping spike trains. These results are promising because this simple model has enough expressive power to reproduce qualitatively several electrophysiological classes described in vitro.
Conditions of cracking of a stringer
Authors: Bardzokas D. I. , Sfyris G. I.
Published: July 2005

In the limits of brittle failure of materials, we investigate the problem of possible cracking of an infinite stringer on the boundary of an elastic half‐infinite plate. The plate is exposed to tensioning by uniformly distributed forces, and also to contact
stresses due to application of forces on the stringer. The accurate solution of a contact problem of interaction of an infinitely continuous stringer is constructed. With the help of
this solution, we formulate the condition of cracking of a stringer and the necessary restrictions for external loading, which provide the contacts of a broken stringer with a plate without propagation of a crack inside the stringer. The problem considered here is of interest for theory and practice. We firstly formulate the modified problem of E. Melan and with the help of Fourier integral transformation, we construct its acoustic solution and
then formulate the condition of cracking of an infinite stringer. After that, reveal the necessary restrictions on external loadings, which provide the contact of the failed stringer with a plate without propagation of the crack inside the plate.
Thiazolidinediones Do Not Reduce Target Vessel Revascularization in Diabetic Patients Undergoing Percutaneous Coronary Intervention
Authors: Cho Leslie , Lewis Bruce E. , Steen Lowell H. , Leya Ferdinand S.
Published: July 2005

Background: Animal studies have suggested that thiazolidinediones (TZDs) have antirestenotic properties. However, human data are lacking. The goal of this single-center study was to assess the target vessel revascularization (TVR) rate following percutaneous coronary intervention (PCI) among diabetic patients according to TZD use. Methods: A total of 325 consecutive diabetic patients who underwent PCI between January 2000 and December 2001 were included in the analysis. Among them, 82 patients were on TZD and 243 patients were on other hypoglycemic regimens. All patients were treated with stents and platelet glycoprotein IIb/IIIa inhibitors at the time of intervention. TVR and death/myocardial infarction/TVR were assessed at 1 year. Results: TZD patients were more likely to be younger, male and have hyperlipidemia. TVR occurred in 36.6% of TZD patients compared with 23.9% of non-TZD patients (p = 0.04). One-year death, myocardial infarction and TVR occurred in 41.1% of TZD patients compared with 30.8% of non-TZD patients (p = 0.04). Conclusion: In this retrospective analysis, TZD therapy did not decrease the need for repeat revascularization following PCI. Prospective randomized studies are warranted.
Detoxifying Capacity and Kinetics of Prometheus® – A New Extracorporeal System for the Treatment of Liver Failure
Authors: Evenepoel Pieter , Laleman Wim , Wilmer Alexander , Claes Kathleen , Maes Bart , Kuypers Dirk , Bammens Bert , Nevens Frederik , Vanrenterghem Yves
Published: July 2005

Background/Aims: Extracorporeal liver support therapies have been used for several decades as a bridging therapy prior to liver transplantation or as an addendum to standard medical therapy. The Prometheus® system represents a cell-free, extracorporeal, liver assist method for the removal of both albumin-bound and water-soluble endogenous toxins. The aim of the present study was to evaluate the removal capacity and selectivity of the different inbuilt dialyzers and adsorption columns during a single 6-hour treatment. Methods: Nine patients with acute on chronic liver failure were included (6 females, age 49 ± 4 years). Levels of endogenous toxins (urea nitrogen [UN, mg/dl], creatinine [Cr, mg/dl], total bilirubin [tB, mg/dl], and bile acids [BA, µmol/l]) and albumin [Alb, g/l] were monitored in blood sampled at different sites (arterial line, venous line and between the absorbers and the high-flux dialyzer) and at various time points (time 0, 30, 60, 120, 240, and 360 min). Results: A significant decrease of the serum level of all toxins was observed (UN 108.7 ± 23.2 vs. 38.1 ± 14.9, Cr 2.4 ± 0.7 vs. 1.2 ± 0.3, tB 31.1 ± 4.1 vs. 17.0 ± 1.6, BA 155.7 ± 32.5 vs. 66.0 ± 15.4; mean ± SEM, time 0 vs. time 360, signed rank rest, all p < 0.005). The reduction rate of UN, Cr, tB and BA amounted to 68.1 ± 5.1, 45.9 ± 6.2, 41.2 ± 5.1, and 58.2 ± 5.0%, respectively. Blood clearances [Cl, ml/min] of all, but especially of the protein-bound toxins declined over time (Cl UN 171.5 ± 4.3 vs. 142.9 ± 16.8; Cl Cr 135.7 ± 10.0 vs. 111.8 ± 9.1; Cl tB 29.3 ± 5.1 vs. 13.7 ± 3.7; Cl BA 84.9 ± 4.8 vs. 45.1 ± 13.3; time 30 vs. time 360; linear mixed models, all p < 0.005). Serum albumin levels decreased by 2.9 ± 0.9 g/l (signed rank test, p = 0.055). Not unexpectedly, tB was almost uniquely cleared by the adsorbers (UN 0.2 ± 1.1, Cr 6.9 ± 5.7, tB 92.3 ± 4.2, BA 62.9 ± 3.9% of total Cl). Conclusion: Both albumin-bound and water-soluble toxins are adequately removed by the Prometheus® system. Our data suggest that the rate and efficacy of removal of albumin-bound toxins is related to both the strength of the albumin binding and the saturation of the adsorption columns. Limited losses of albumin occur during treatment with the Prometheus system.
Meta-Analysis of Trials Comparing Oral Anticoagulation and Aspirin versus Dual Antiplatelet Therapy after Coronary Stenting
Authors: Rubboli Andrea , Milandri Milena , Castelvetri Cristina , Cosmi Benilde
Published: July 2005

The combination of oral anticoagulation (OAC) and aspirin was the antithrombotic treatment initially adopted after coronary stenting (PCI-S). Although dual antiplatelet therapy with aspirin and a thienopyridine subsequently proved safer and more effective, OAC and aspirin combination is still used in patients with an indication for long-term OAC undergoing PCI-S. The absolute (AR) and relative (RR) risk of cardiac events and hemorrhagic/vascular complications of OAC and aspirin versus antiplatelet therapy were evaluated in a meta-analysis of four historical clinical trials. In 2,436 patients, the RR of a 30-day primary composite endpoint of death, myocardial infarction and the need for revascularization was significantly reduced by antiplatelet therapy (RR 0.41; 95% CI 0.25–0.69), whereas the RR of stent thrombosis (RR 0.26; 95% CI 0.06–1.14) and major bleeding (RR 0.36; 95% CI 0.14–1.02) was not statistically different. The 30-day AR of death, myocardial infarction, need for revascularization, major bleedings and vascular complications with OAC and aspirin were 0.65, 3.8, 4.2, 6.4 and 6.6%, respectively. In conclusion, due to the low AR of adverse events, the combination of OAC and aspirin appears an acceptable treatment after PCI-S in patients in whom long-term OAC is deemed mandatory.
Factors Affecting Deficit Awareness in Persons with Dementia
Authors: Snow A. Lynn , Graham David P. , Molinari Victor A. , Orengo Claudia A. , Doody Rachelle S. , Norris Margaret P. , Kunik Mark E.
Published: July 2005

Objective: This study examined factors affecting deficit awareness (DA) and the effects of diagnostic status (dementia and depression), measurement method and DA dimension on these relationships. Methods: One hundred and twenty-one participants (66 persons with dementia and 55 persons without dementia, matched for depression diagnosis) were enrolled, each with a family informant. Participant DA (clinician and informant rated), cognitive impairment, physical illness, functional disability and caregiver burden were assessed. Results: Factors affecting DA included presence of dementia, presence of depression, cognitive impairment, caregiver burden, and functional disability. The relationship between these factors and DA varied by DA dimension. Conclusions: DA measurement method was an important moderating variable; clinicians may be better at evaluating cognitive DA whereas informants may be better at evaluating functional and emotional/behavioral DA.
Differential in vivo Inhibition of [3H]Nemonapride Binding by Atypical Antipsychotics in Rat Striatum, Olfactory Lobes, and Frontal Cortex
Authors: Assié M.-B. , Consul-Denjean N. , Koek W. , Newman-Tancredi A.
Published: July 2005

Dopamine D2 receptor blockade is thought to be mandatory for antipsychotic action because most of the currently used antipsychotics have high affinity at these receptors. Here, we examined the in vivo binding characteristics of the D2-like receptor antagonist [3H]nemonapride in rat brain areas including the striatum, olfactory lobes and frontal cortex and its inhibition by a series of D2 antagonist antipsychotics. In vivo affinity of [3H]nemonapride was similar (apparent Kd value: 0.05 µmol/kg) in all brain regions examined. The estimated number of binding sites was higher in the striatum (66 fmol/mg wet weight) than in the olfactory lobes (28 fmol/mg wet weight) and the frontal cortex (21 fmol/mg wet weight). In the striatum, [3H]nemonapride binding was inhibited in a dose-dependent manner with the following order of potency (ED50, mg/kg): nemonapride (0.04), raclopride (0.13), spiperone and risperidone (0.14), haloperidol (0.21), clozapine (7.2) and thioridazine (9.4); in the olfactory lobes: nemonapride (0.03), raclopride and spiperone (0.09), haloperidol (0.10), risperidone (0.15), thioridazine and clozapine (11); in the frontal cortex, only the high affinity dopamine D2 antagonist compounds nemonapride (0.05), haloperidol (0.09), and raclopride (0.12) significantly decreased the binding of [3H]nemonapride. The present data suggest that conventional and atypical antipsychotics may be distinguished by their differential occupancy of striatal versus frontocortical D2-like receptors in vivo.
A Phase II Trial of Raltitrexed (Tomudex®) in Advanced Pancreatic and Biliary Carcinoma
Authors: François Eric , Hebbar M. , Bennouna J. , Mayeur D. , Perrier H. , Dorval E. , Martin C. , Bourgeois H. , Barthélemy P. , Douillard J.Y.
Published: July 2005

Purpose: To evaluate the impact of raltitrexed (Tomudex®) on the quality of life in a multicenter, phase II study in advanced pancreatic and biliary carcinomas. Patients and Methods: Forty-six patients with advanced, histologically proven pancreatic (n = 37, 80.4%) or biliary (n = 9, 19.6%) carcinoma received 3 mg/m2 raltitrexed intravenously once every 3 weeks. For the quality of life assessments, EORTC QLQ-C30 was used, and the evaluation of the clinical benefit was performed according to the 4 criteria of the clinical benefit response. All patients were assessed for safety, and 41 patients were evaluable for objective response. Results: Patients (63% male/37% female) had a mean age of 61.2 years, 71.7% had a PS of 0–1, 78.3% had metastatic disease, and 63% had at least 2 tumoral sites. A total of 176 cycles were administered with a mean of 4 cycles per patient (range 1–12). Three out of 43 patients evaluable for EORTC QLQ-C30 (7.0%; CI95% 1.4–19.0%) had a quality of life improvement. Thirty-two patients fulfilled the 4 criteria required to evaluate the clinical benefit response; 5 were responders (15.6%; CI95% 5.3–32.8%); 1 patient was a good responder based on both the EORTC questionnaire and the clinical benefit response. Forty-one patients were assessable for response, 3 responded to treatment (response rate: 6.5 %; CI95% 1.3–17.9%). Median survival was 4.6 months (CI95% 2.9–8.2 months), the 1-year survival rate was 21.8%. The most common grade 3–4 toxicities were neutropenia (8%), leukopenia (8%), thrombopenia (6%), anemia (6%), liver enzyme elevations (11%), asthenia (9%), vomiting (9%), abdominal pain (7%), and phlebitis (6%). One treatment-related death occurred (neutropenic sepsis). Conclusion: Raltitrexed appeared to be generally well tolerated and showed a clinical benefit response and/or quality of life improvement in a limited number of patients.
Epithelial Syndecan-1 Expression Is Associated with Stage and Grade in Colorectal Cancer
Authors: Lundin M. , Nordling S. , Lundin J. , Isola J. , Wiksten J.-P. , Haglund C.
Published: July 2005

Objectives: Loss of epithelial heparan sulfate proteoglycan syndecan-1 has been associated with a more aggressive behavior in various cancer forms, but the prognostic significance of syndecan-1 expression in colorectal cancer is unclear. The aim of this study was to evaluate the prognostic value of immunohistochemical syndecan-1 expression in a series of 237 patients with colorectal cancer. Methods: Paraffin-embedded formalin-fixed specimens were stained with a syndecan-1-specific monoclonal antibody, and both the epithelial and stromal expression were analyzed. Results: Epithelial expression of syndecan-1 was seen in 222 tumors (94%), and it was associated with low stage of disease (p = 0.002) and low histological differentiation grade (p = 0.048). The cumulative 5-year survival of patients with weak and strong syndecan-1 expression was 49 and 54 %, respectively (p = 0.234). Syndecan-1 stromal immunoreactivity was observed in 138 tumors (58%), but lacked prognostic significance. Staining pattern and distribution can be viewed from digitized representative microscope slides (virtual slides) at http://www.webmicroscope.net/supplements/syndecan. Conclusions: The results are in line with previous reports in that low epithelial syndecan-1 expression was associated with a higher histological grade and a more advanced clinical stage of the patients. This study shows that syndecan-1 is expressed also in stromal tissue of colorectal cancer, but it does not support the proposed role of stromal syndecan-1 expression as a marker of poor clinical outcome.
Alterations of Rb Pathway Components Are Frequent Events in Patients with Oral Epithelial Dysplasia and Predict Clinical Outcome in Patients with Squamous Cell Carcinoma
Authors: Soni Shilpi , Kaur Jatinder , Kumar Anupam , Chakravarti Nitin , Mathur Meera , Bahadur Sudhir , Shukla Nootan Kumar , Deo Suryanaryana V.S. , Ralhan Ranju
Published: July 2005

Objective: This study was designed to test the hypothesis that alterations in expression of G1/S modulators cyclin D1, p16 and pRb occur in patients with oral epithelial dysplasia, considered to be at increased risk for malignant transformation. In addition, the analysis of expression of all three markers in the same set of oral cancer patients would provide a unique opportunity to determine whether these alterations have cooperative or synergistic effects on oral cancer development and prognosis. Patients and Methods: A prospective study was undertaken to carry out immunohistochemical analysis of cyclin D1, p16 and pRb proteins in serial paraffin-embedded tissue sections of 220 oral squamous cell carcinomas (OSCCs), 90 potentially malignant lesions (52 oral hyperplastic lesions, 38 dysplasias) and 81 matched histologically normal oral tissues and correlated them with clinicopathological parameters. Ninety-eight OSCC patients were followed up for a maximum period of 94 months with overall median survival of 21 months. Results: Seventy-five of 90 (83%) potentially malignant lesions and 198 of 220 (90%) OSCCs showed altered expression of at least one of the proteins in the pRb pathway, while 10 of 90 (11%) patients with potentially malignant lesions and 40 (18%) of 220 OSCC patients showed all three alterations. Loss of p16 was the earliest event in oral tumorigenesis. In a multivariate model, loss of pRb was associated with transition from hyperplasia to dysplasia (OR = 3.727, p = 0.005). The transition of potentially malignant lesions to malignant stage was associated with pRb–/cyclin D1+ phenotype (OR = 2.294, p = 0.001) and p53+ phenotype (OR = 2.230, p = 0.002). Loss of pRb and accumulation of p53 (pRb–/p53+) phenotype was associated with histologic progression of the tumors and acquisition of invasive potential. Multivariate analysis using Cox’s proportional hazards model revealed that pRb–/p53+ phenotype was the most significant adverse prognosticator for disease-free survival (hazards ratio, (HR) = 2.642, p = 0.004). Conclusions: Deregulation of the p16/pRb/cyclin D1 pathway is an early event in acquisition of dysplasia, but deregulation of both pRb and p53 pathways is associated with malignant transformation and adverse prognosis in oral tumorigenesis.
A Phase II Study of Epirubicin, Cisplatin and Capecitabine Combination Chemotherapy in Patients with Metastatic or Advanced Gastric Cancer
Authors: Cho Eun Kyung , Lee Woon Ki , Im Seok-Ah , Lee Soon Nam , Park Se Hoon , Bang Soo-Mee , Park Dong Kyun , Park Yeon Ho , Shin Dong Bok , Lee Jae Hoon
Published: July 2005

Objectives: The purpose of this study was to evaluate the antitumor activity and safety of an epirubicin, cisplatin, and capecitabine (ECX) combination in patients with metastatic or advanced gastric cancer. Patients and Methods: Patients with metastatic or advanced measurable gastric adenocarcinoma received ECX combination chemotherapy. Epirubicin 50 mg/m2 and cisplatin 60 mg/m2 were administered on day 1 by intravenous injection. Capecitabine 1,000 mg/m2 twice daily was administered orally on day 1–14. The cycle was repeated every 3 weeks. Results: Fifty-four patients were enrolled in this study. Fifty patients were assessable for responses and 53 for toxicity. A total of 250 cycles were administered. The overall best response rate by intent-to-treat analysis was 59% including 52% partial responses and 7% complete responses. Median response duration and time to progression was 5.8 and 6 months, respectively. Median survival for all patients was 9.6 months (95% CI, 8.7–10.5 months). The most common grade 3/4 hematological adverse event was neutropenia in 31% (76 cycles) including febrile neutropenia in 4.8% (11 cycles). Non-hematological toxicity was generally mild and reversible. Grade 3/4 nausea, vomiting and stomatitis occurred in 8, 9, and 8% of the patients, respectively. Hand-foot skin reactions developed in 51% of patients, but most were self-limited. Grade 3 occurred in only 4%. One patient died of neutropenic sepsis. Conclusions: ECX combination regimen showed high anti-tumor activity with a tolerable toxicity pattern as a front-line chemotherapy for patients with metastatic or advanced gastric cancer.
Serum Lipid Profile in Colorectal Cancer Patients with and without Synchronous Distant Metastases
Authors: Notarnicola Maria , Altomare Donato F. , Correale Mario , Ruggieri Eustachio , D’Attoma Benedetta , Mastrosimini Anna , Guerra Vito , Caruso Maria G.
Published: July 2005

Objective: In this study, the serum lipid profile, including total cholesterol (TC), triglycerides (TG), high-density (HDL-C) and low-density lipoprotein cholesterol (LDL-C), has been investigated in colorectal cancer patients (CRC) with and without synchronous distant metastases. The aim of this study was to verify whether the presence of metastases was associated to serum lipid abnormalities, and whether lipoprotein abnormalities were linked to the nutritional status. Methods: The fasting serum lipid profile was examined in 84 CRC patients using colorimetric methods. To determine the nutritional status, the body mass index (BMI) was calculated and serum albumin was measured. Results: Patients with distant metastases showed significantly higher levels of TC, LDL-C and the LDL-C/HDL-C ratio than patients without metastases (p< 0.05). The presence of metastases was positively associated with TC, LDL-C and the LDL-C/HDL-C ratio, being independent of sex, age and BMI. Conclusions: Elevated serum lipid levels may facilitate the development of distant metastasis in CRC patients.