Evaluation of PENFAST--a fast Monte Carlo code for dose calculations in photon and electron radiotherapy treatment planning.

The aim of the present study is to demonstrate the potential of accelerated dose calculations, using the fast Monte Carlo (MC) code referred to as PENFAST, rather than the conventional MC code PENELOPE, without losing accuracy in the computed dose. For this purpose, experimental measurements of dose distributions in homogeneous and inhomogeneous phantoms were compared with simulated results using both PENELOPE and PENFAST. The simulations and experiments were performed using a Saturne 43 linac operated at 12 MV (photons), and at 18 MeV (electrons). Pre-calculated phase space files (PSFs) were used as input data to both the PENELOPE and PENFAST dose simulations. Since depth-dose and dose profile comparisons between simulations and measurements in water were found to be in good agreement (within +/-1% to 1 mm), the PSF calculation is considered to have been validated. In addition, measured dose distributions were compared to simulated results in a set of clinically relevant, inhomogeneous phantoms, consisting of lung and bone heterogeneities in a water tank. In general, the PENFAST results agree to within a 1% to 1 mm difference with those produced by PENELOPE, and to within a 2% to 2 mm difference with measured values. Our study thus provides a pre-clinical validation of the PENFAST code. It also demonstrates that PENFAST provides accurate results for both photon and electron beams, equivalent to those obtained with PENELOPE. CPU time comparisons between both MC codes show that PENFAST is generally about 9-21 times faster than PENELOPE.

Multichannel dosemeter and Al2O3:C optically stimulated luminescence fibre sensors for use in radiation therapy: evaluation with electron beams.

This article proposes an innovative multichannel optically stimulated luminescence (OSL) dosemeter for on-line in vivo dose verification in radiation therapy. OSL fibre sensors incorporating small Al(2)O(3):C fibre crystals (TLD(500)) have been tested with an X-ray generator. A reproducible readout procedure should reduce the fading-induced uncertainty ( approximately - 1% per decade). OSL readouts are temperature-dependent [ approximately 0.3% K(-1) when OSL stimulation is performed at the same temperature as irradiation; approximately 0.16% K(-1) after thermalisation (20 degrees C)]. Sensor calibration and depth-dose measurements with electron beams have been performed with a Saturne 43 linear accelerator in reference conditions at CEA-LNHB (ionising radiation reference laboratory in France). Predosed OSL sensors show a good repeatability in multichannel operation and independence versus electron energy in the range (9, 18 MeV). The difference between absorbed doses measured by OSL and an ionisation chamber were within +/-0.9% (for a dose of about 1 Gy) despite a sublinear calibration curve.

Monte Carlo simulation of a medical linear accelerator for radiotherapy use.

A Monte Carlo code MCNPX (Monte Carlo N-particle) was used to model a 25 MV photon beam from a PRIMUS (KD2-Siemens) medical linear electron accelerator at the Centre Antoine Lacassagne in Nice. The entire geometry including the accelerator head and the water phantom was simulated to calculate the dose profile and the relative depth-dose distribution. The measurements were done using an ionisation chamber in water for different square field ranges. The first results show that the mean electron beam energy is not 19 MeV as mentioned by Siemens. The adjustment between the Monte Carlo calculated and measured data is obtained when the mean electron beam energy is approximately 15 MeV. These encouraging results will permit to check calculation data given by the treatment planning system, especially for small fields in high gradient heterogeneous zones, typical for intensity modulated radiation therapy technique.

Long-lasting recovery of locomotor function in chronic spinal rat following chronic combined pharmacological stimulation of serotonergic receptors with 8-OHDPAT and quipazine.

In chronic spinal rats, long-term stimulation of 5-HT receptors with quipazine or 8-OHDPAT by means of daily injection, promotes robust locomotor recovery. The question of a possible potentiation between treatments when applied together was addressed. Daily injections of both 8-OHDPAT and quipazine, were performed for a month in spinal animals. Animals were placed on a treadmill and the bipedal hindlimb locomotion was tested. Motor performances (behavioural test) and locomotor parameters (EMG and kinematic) were analysed weekly during the treatment. Furthermore, the locomotor performances were evaluated during two supplemental months following the end of the treatment. Our results suggest that association of both agonists induced long-lasting positive effects on locomotor function. Motor performances were significantly better after combined injection of both drugs than when the agonists were used separately. But, the most significant and new result is that the locomotor scores did not decrease during the weeks that followed the end of the treatment. These results suggests a long-lasting and 5-HT-dependent reorganisation of spinal networks.

5-HT1A receptors are involved in short- and long-term processes responsible for 5-HT-induced locomotor function recovery in chronic spinal rat.

After thoracic spinal cord transection, a paraplegic syndrome occurs. Previous data showed that an acute administration of a 5-HT2 agonist (quipazine) could promote motor function recovery in spinal rats. However, continuous subdural perfusion of quipazine via an osmotic pump over 1 month proved to be more effective. The present study was designed to investigate the possible involvement of 5-HT1A receptors in such recovery. Motor performances and locomotor parameters were analysed in spinal animals receiving daily, for 1 month, a dose of the 5-HT1A agonist 8-OHDPAT. The results were compared to those obtained in spinal rats receiving either a placebo or quipazine in the same conditions. Using daily injections instead of continuous perfusion of either receptor agonist to spinal animals allowed characterization of short- and long-term consequences of pharmacological stimulation of 5-HT1A and 5-HT2 receptors on motor function recovery. Our data demonstrate that daily injections of a 5-HT1A agonist induce long-term, cumulative, positive effects on motor function recovery, as assessed by the improvement in the walking parameters observed before the 'day-test' injection. This might involve use-dependent processes depending on a chronic and/or repetitive stimulation of the spinal network for locomotion in relation to 5-HT receptor activation. A further improvement in the motor parameters, transiently observed following the injection, suggests a more direct action of 5-HT1A and 5-HT2 receptor activation on spinal neurons involved in motor pattern generation.

Locomotor recovery in the chronic spinal rat: effects of long-term treatment with a 5-HT2 agonist.

A complete transection of the spinal cord at a low thoracic level induces a paraplegic syndrome that is accompanied by a loss of spinal cord serotonin content. Former experimental data suggest that the central pattern generator for locomotion, located in the lumbar segments of the spinal cord, might be able to generate rhythmic motor outputs (similar to automatic walking under certain circumstances) involving exteroceptive stimulations and activation of serotonergic receptors. In the present study, we investigated the effects of a chronic treatment using a serotonergic agonist, delivered continuously to the sublesionned spinal cord, and its effect on motor function recovery. The data obtained from behavioural, kinematic and electromyographic measurements suggest that the chronic stimulation of 5-HT2 type receptors allows motor function recovery. Behavioural measurements show a clear improvement in motor performances when compared to spinal animals (confirmed by kinematic observations): alternating steps and foot placement is recovered in these animals. However, electromyographic data demonstrate that the pattern of activation of the muscles is only restored partially.

Calculation of perturbation correction factors for some reference dosimeters in high-energy photon beams with the Monte Carlo code PENELOPE.

The BNM-LNHB (formerly BNM-LPRI, the French national standard laboratory for ionizing radiation) is equipped with a SATURNE 43 linear accelerator (GE Medical Systems) dedicated to establishing national references of absorbed dose to water for high-energy photon and electron beams. These standards are derived from a dose measurement with a graphite calorimeter and a transfer procedure to water using Fricke dosimeters. This method has already been used to obtain the reference of absorbed dose to water for cobalt-60 beams. The correction factors rising from the perturbations generated by the dosimeters were determined by Monte Carlo calculations. To meet these applications, the Monte Carlo code PENELOPE was used and user codes were specially developed. The first step consisted of simulating the electron and photon showers produced by primary electrons within the accelerator head to determine the characteristics of the resulting photon beams and absorbed dose distributions in a water phantom. These preliminary computations were described in a previous paper. The second step, described in this paper, deals with the calculation of the perturbation correction factors of the graphite calorimeter and of Fricke dosimeters. To point out possible systematic biases, these correction factors were calculated with another Monte Carlo code, EGS4, widely used for years in the field of dose metrology applications. Comparison of the results showed no significant bias. When they were possible, experimental verifications confirmed the calculated values.

[Spontaneous multivessel coronary dissection as a cause of acute myocardial infarct--case report]]. / Dissecção coronária multivasos espontânea como causa de enfarte agudo do miocárdio--a propósito de um caso.

The authors describe a case reported in a young female with antecedents of aortic pathology and renovascular hypertension submitted to renal artery surgery admitted to emergency with an extensive acute myocardial infarction, treated with thrombolysis. After coronariography we identify, as etiological factor, a spontaneous coronary dissection involving the descending anterior coronary artery and circumflex coronary artery with no affect on the left main coronary artery. About this case, the authors make a brief review of the literature emphasizing the therapeutic options.

Serotonin-induced activation of the network for locomotion in adult spinal rats.

The biogenic amine serotonin has been described in the literature as a powerful modulator of the spinal central pattern generator for locomotion. In the present study, we tested whether administration of serotonin or its agonist quipazine could restore motor activity in a model of paraplegia. One to three weeks after a complete transection of the spinal cord at a low thoracic level, rats were given either intrathecal injections of serotonin (5 mM, 15 microL) or intraperitoneal injections of quipazine (400-600 microg/kg). Both treatments allowed recovery of locomotor activity on a treadmill in response to tail pinching. As compared with the activity elicited before treatment, the locomotor activity produced by spinal animals was characterised by longer locomotor sequences with a larger number of successive steps, better body support, better interlimb coordination, and a higher amplitude of electromyographic bursts. These results suggest that serotonergic drugs could be used for the recovery of motor functions after lesions of the spinal cord.

Modulation of the spinal network for locomotion by substance P in the neonatal rat.

The tachykinin substance P (SP) is present in the ventral and medial area of the lumbar spinal cord. Its localisation suggests that it could modulate the spinal network for locomotion. We have investigated its effects on motor outputs by applying SP, in vitro, to the lumbosacral segments of an isolated spinal cord of new-born rats. SP was applied to the lumbosacral spinal cord either on a quiescent preparation or during episodes of fictive locomotion induced by N-methyl-D,L-aspartate. When applied on quiescent preparations, SP induced a slow rhythmic activity (period >30 s). During fictive locomotion, SP increased both the locomotor frequency and the duration of the bursts of cyclic activity. Furthermore, SP stabilised the locomotor rhythm. These results demonstrate that SP is able to modulate both the "clock" and the pattern generator for locomotion.

Insight into cystic fibrosis by structural modelling of CFTR first nucleotide binding fold (NBF1).

Cystic fibrosis is a human monogenic genetic disease caused by mutations in the cystic fibrosis (CF) gene, which encodes a membrane protein which functions as a channel: the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most frequent mutation, a deletion of phenylalanine F508 (delta F508), is located in the first nucleotide binding domain of CFTR: NBF1. This mutation leads to a folding defect in NBF1, responsible for an incomplete maturation of CFTR. The absence of CFTR at the surface of epithelial cells causes the disease. Determination of the three-dimensional (3D) structure of NBF1 is a key step to understanding the alterations induced by the mutation. In the absence of any experimental data, we have chosen to build a 3D model for NBF1. This model was built by homology modelling starting from F1-ATPase, the only protein of known 3D structure in the ATP binding cassette (ABC) family. This new model defines the central and critical position of F508, predicted in the hydrophobic core of NBF1. F508 indeed could be involved in hydrophobic interactions to ensure a correct folding pathway. Moreover, this model enables the localization of the LSGGQ sequence (a highly conserved sequence in the ABC family) in a loop, at the surface of the protein. This reinforces the hypothesis of its role for mediation of domain-domain interactions of functional significance for the channel regulation. Finally, the model also allows redefinition of the ends of NBF1 within the CFTR sequence. These extremities are defined by the secondary structure elements that are involved in the NBF1 fold. They lead to reconsideration of the C-terminal limit which was initially defined by the end of exon 12.

[Can transplantation of neurons facilitate motor recovery in paraplegics? Study of an animal model]. / Les transplantations de neurones peuvent-elles faciliter la récupération motrice chez les paraplégiques? Etude d'un modèle animal.

This review strives forward at least two goals. First, to take from the literature the arguments demonstrating that hindlimbs locomotion is controlled by a spinal network of neurons (the so-called Central Pattern Generator for locomotion--CPG) known to be able to generate locomotor activity independently of the control of supraspinal nervous structures, as it is after thoracic lesions of the spinal cord. The principles of work of the CPG and its intrinsic possibilities to adapt its working are reviewed. Special reference is made to the various ways used during experiments to activate the CPG in spinal animals or clinical practice in paraplegic men: training to walk, electrical stimulations, pharmacological stimulations. Second, to show, from our own results, obtained from the study of an animal model of paraplegia, the adult spinal rat, how it could be possible to take advantage of the autonomy of the CPG, with special reference to its sensibility to monoamines, to obtain locomotor recovery in hindlimbs after section of the thoracic spinal cord, by means of transplantation of noradrenergic and/or serotonergic embryonic neurons in the lumbo-sacral spinal cord. Section of the spinal cord at a thoracic level results in an important locomotor deficit in hindlimbs, likely linked to degeneration of monoaminergic terminals in the lumbar enlargement. In the adult spinal rat, sub-lesional injection of a suspension of embryonic nervous cells, taken from either locus coeruleus or raphe sites, leads to reinnervation of the lumbar enlargement with monoaminergic terminals. Despite the fact that connections with supraspinal structures are not reestablished, transplanted animals recover progressively a posture convenient for locomotion. The hindlimbs, which are in an extended position a few days after the lesion, become progressively flexed and able to support the body weight. This evolution does not appear in spinal but non transplanted animals. But, the main point is that transplanted animals develop, within the few weeks that follow transplantation, a good-quality locomotor activity in hindlimbs which had no equivalent in spinal but non transplanted animals. The reality of a lumbar CPG for locomotion and the efficacy of pharmacological treatments and training to walk, to elicit recovery of stepping, are discussed in man, in connection with the relevance to use transplantation of monoaminergic nervous cells in the spinal cord of paraplegics.

Central modulation of stretch receptor neurons during fictive locomotion in lamprey.

1. In lamprey, stretch receptor neurons (SRNs), also referred to as edge cells, are located along the lateral margin of the spinal cord. They sense the lateral movements occurring in each swim cycle during locomotion. The isolated lamprey spinal cord in vitro was used to investigate the activity of SRNs during fictive locomotion induced by bath-applied N-methyl-D-aspartate (NMDA). Intracellular recordings with potassium acetate filled electrodes showed that 63% of SRNs had a clear locomotor-related modulation of their membrane potential. 2. Of the modulated SRNs, two-thirds had periods of alternating excitation and inhibition occurring during the ipsilateral and the contralateral ventral root bursts, respectively. The phasic hyperpolarization could be reversed into a depolarizing phase after the injection of chloride ions into the cells; this revealed a chloride-dependent synaptic drive. The remaining modulated SRNs were inhibited phasically during ipsilateral motor activity. 3. Experiments with barriers partitioning the recording chamber with the spinal cord into three pools, allowed an inactivation of the locomotor networks within one pool by washing out NMDA from the pool in which the SRN was recorded. This resulted in a marked reduction, but not an abolishment, of the amplitude of the membrane potential oscillations. Both the excitatory and the inhibitory phases were reduced, resulting from removal of input from inhibitory and excitatory interneurons projecting from the adjacent pools. If the glycine receptor antagonist strychnine (1 microM) was applied in one pool, the phasic hyperpolarizing phase disappeared without affecting the excitatory phase. 4. Bath application of the gamma-aminobutyric acid (GABA)A receptor antagonist, bicuculline (50-100 microM) blocked the spontaneous large unitary inhibitory postsynaptic potentials, which occurred without a clear phasic pattern. Bicuculline had no significant effect on the peak to peak amplitude of the locomotor-related membrane potential oscillations. The inhibition in SRNs therefore has a dual origin: glycinergic interneurons provide phasic inhibition, while the GABA system can exert a tonic inhibition via GABAA receptors. 5. These data show that, in addition to the stretch-evoked excitation, which SRNs receive during each locomotor cycle, most of them also receive excitation from the central pattern generator network during the ipsilateral contraction, which may ensure a maintained high level of sensitivity to stretch during the shortening phase of the locomotor cycle. This arrangement is analogous to the efferent control of muscle spindles exerted by gamma-motoneurons in mammals, which as a rule are coactivated with alpha-motoneurons to the same muscle (alpha-gamma linkage).

Voltage-dependent block of NMDA responses by 5-HT agonists in ventral spinal cord neurones.

1. Modulation by 5-hydroxytryptamine receptor agonists of the NMDA responses of ventral spinal cord neurones was studied by use of the whole-cell patch-clamp technique. 2. In a Mg-free solution containing tetrodotoxin and glycine, 5-hydroxytryptamine (5-HT, 10-100 microM) reduced the NMDA response, the block increasing with hyperpolarization. Kainate responses were little affected. 3. Some classical agonists of 5-HT receptors induced similar blocking effects. At 10 microM, both a selective agonist of 5-HT2 receptors, (+/-)-2,5-dimethoxy-4 iodo amphetamine (DOI), and a selective agonist of some 5-HT1 receptors, (+/-)-8-hydroxy-2(n-dipropyl amino) tetralin (8-OH-DPAT), induced pronounced blocking effects, of 48% and 33% respectively at -100 mV, whereas another 5-HT1 agonist, 5-carboxamidotryptamine (5-CT) was ineffective. At 100 microM, 5-methoxytryptamine (5-MeOT) induced a complete block of the NMDA responses recorded at -100 mV. The order of potency was: 5-MeOT congruent to DOI > 8-OH-DPAT > 5-HT > 5-CT. 4. Neither spiperone nor ketanserin (1 microM) prevented the blocking effect of 5-HT or DOI. 5. Prolonged preincubations with 5-HT did not block the response if NMDA was applied without 5-HT. When 5-HT agonists were applied both by preincubation and with NMDA, the degree of block increased during the NMDA application. 6. Lowering the NMDA concentration (from 100 to 20 microM) slightly decreased the blocking effect of 5-MeOT. 7. External Mg2+ ions (1 mM) also reduced the blocking effects of 5-HT and 5-MeOT. 8. The blocking effects described appear to be independent of classical 5-HT receptors. Their voltage-dependence suggests a mechanism of open channel block consistent with all the results obtained.

Elicitors and suppressors of hydroxyproline-rich glycoprotein accumulation are solubilized from plant cell walls by endopolygalacturonase.

Treatment of bean cell walls with a pure endopolygalacturonase of the bean pathogen Colletotrichum lindemuthianum race beta released oligogalacturonides and pectic fragments which were separated according to their charge and size. Among galacturonic-acid-containing components, elicitors and suppressors of the plant cell wall hydroxyproline-rich glycoprotein (HRGP) were recovered. Two active small oligogalacturonides with degrees of polymerization of 2 and 3 were characterized by high-performance anion-exchange-chromatography pulsed amperometric detection and fast-atom-bombardment mass spectrometry; they elicited 40-70% hydroxyproline increase within 48 hours at 450 nmol/bean cutting. In contrast, pectic fragments of higher molecular mass, predominantly composed of galacturonic acid and containing sugars typical of the rhamnogalacturonan II domain of pectic polysaccharides, had the ability to substantially suppress hydroxyproline deposition. Maximum suppressor activity, 30-40% below the activity of the control, occurred in 48 hours. In view of the low one-cycle turnover of these proteins in the cell wall and of their structural role, these changes might significantly affect cell wall properties. Elicitation and/or suppression of hydroxyproline were correlated to modifications of HRGP-extensin gene expression. Northern-blot analysis of RNA showed that changes in the transcript intensity became clearly visible within the first 12 hours after the start of either treatment. The results show that pectic components of the plant extracellular matrix have the potential to regulate wall matrix biogenesis. Implications of this finding in plant defense and development are discussed.

Neurotensin-induced modulation of spinal neurons and fictive locomotion in the lamprey.

1. Neurotensin containing interneurons are present in the spinal cord of both mammalian and nonmammalian vertebrates, but as yet little is known about their functional role. In this study we examine the effect of neurotensin on spinal cells and on the central pattern generator for locomotion in the lamprey spinal cord. 2. Bath application of neurotensin (10(-8) to 10(-6) M) slowed down the fictive locomotor activity induced by the glutamate agonist N-methyl-D-aspartate in the isolated spinal cord. The duration of the bursts of activity in the ventral roots increased in proportion to the increase of the locomotor cycle duration. 3. Intracellular recordings from grey matter neurons and intraspinal stretch receptors neurons showed that neurotensin induced a depolarization [4.4 +/- 0.5 (SE) mV, n = 19]. This depolarization could still be obtained after a blockade of voltage-sensitive sodium channels with tetrodotoxin (1.5 +/- 0.5 mV; n = 6), and after removal of calcium (2.8 +/- 0.4 mV; n = 5). Moreover no consistent change occurred in the fast and slow phase of the afterhyperpolarization (AHP) both of which are carried by potassium currents.

[Kinesitherapy for mucoviscidosis]. / Kinésithérapie dans la mucoviscidose.

Kinesitherapy is an important element in the therapeutic strategy for cystic fibrosis. The main objective is to clear the upper airways. The most effective and most widely used method is to accelerate expiratory air flow. Kinesitherapy should take into account the effect of bronchorrhoea on respiratory mechanics, re-train the ventilatory process, improve thoracomuscular mechanics, attempt to reduce dyspnoea and maintain functional capacity. Managed carefully from childhood to adulthood patients should not require ventilatory assistance. Patients and/or parents, in cooperation with the medical and para-medical team should become fully responsible for correct follow-up and effective treatment.

[The mechanism producing nausea during ventriculography performed with ioxaglate: the implications of a randomized study]. / Mecanismo de producción de las náuseas durante la ventriculografía realizada con ioxaglato: implicaciones de un estudio randomizado.

INTRODUCTION: The mechanism of ioxaglate-induced nausea has not been fully elucidated. Recent studies have demonstrated that serotonin is one of the principal neurotransmitters of emesis in humans. On the other hand, the greater capacity of ioxaglate to stimulate vomiting has been ascribed to its great ability to inhibit cholinesterase. METHODS: To determine if oral metoclopramide (a serotonin receptor-blocker) is effective in the prophylaxis of ioxaglate-induced nausea during left ventriculography, 637 of 711 consecutive eligible patients were included in a prospective study. Patients were randomized to receive, 60-90 minutes before the procedure, either diazepam 10 mg p.o. (control group [n = 315]) or diazepam 10 mg p.o. plus metoclopramide 10 mg p.o. (metoclopramide group [n = 322]). RESULTS: The two randomized groups were similar in relation to baseline clinical and hemodynamic characteristics. Nausea was documented in 103 patients (16.1%) with similar incidence in the two groups (control group: 16.8%, metoclopramide group: 15.5%; p = NS). Nausea duration was also similar (56 +/- 63 s vs 52 +/- 63 s; p = NS). When patients with and without nausea were compared, the following variables showed a significant difference between the two groups: male gender (86% vs 76%; p < 0.05), age (53 +/- 10 yrs vs 56 +/- 9 yrs; p < 0.05) and body surface area (1.84 +/- 0.2 m2 vs 1.78 +/- 0.1 m2; p < 0.01). Stepwise multiple regression analysis identified low age (p = 0.02) and male gender (p = 0.06) as independent predictors of nausea. The incidence of nausea was 24% in males < or = 45 yrs vs 9% in females > 45 yrs (p < 0.05). CONCLUSIONS: Prophylaxis with oral metoclopramide did not reduce the incidence of ioxaglate-induced nausea during left ventriculography. This data do not support a role of serotonin in the production of nausea by ioxaglate. Low age an male gender are independent predictors of nausea apparition during left ventriculography. A cholinergic mechanism is probably involved in the capacity of ioxaglate to stimulate vomiting.