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Invasion of bone by a metastatic lesion is the most common cause of pain in cancer patients. Pain management in these patients is an important and difficult task. The pain is not always properly controlled by high doses of specific medication, radiation therapy or chemotherapy. When these therapies do not provide adequate pain relief, percutaneous vertebroplasty, cementoplasty, radiofrequency ablation and internal radiotherapy appear to be elegant and efficient complementary alternative pain control methods.

A computerized model of lung has been elaborated with the aim of simulating lung lesions in CT scans. The secondary lobule was used as structuring lung element. Several lung slices that cover the entire organ are included in the model. Broncho-vascular trees have been modeled, each final leaf pointing to one lobule of the predefined slices. Lobar, segmental and sub-segmental areas are defined from the arterial tree. Information on lobule location regarding scissure and pleura have also been included in the model. The first lesion studied is the pulmonary nodule. A software tool was developed which allows the radiologist to spread nodules on lung model in a defined way until the simulated images mimic the CT. Several nodule shapes, mathematically simulated, are available and systematic and non-systematic nodule distributions have been modeled. Several predefined nodule sizes (mean and dispersion) have been carefully defined. Nodule superimposition is avoided by the distribution algorithm unless explicitly authorized. Manual nodule shifting is available, but restricted to the area defined by the distribution to which the nodule belongs. When a CT has been completely analyzed, the different actions performed to obtain the final result are stored in a file which will be connected to a database in which data concerning the patient and final diagnoses will be stored. This lung model will be used to simulate ground glass and consolidation. The software tool described here is a useful help for radiologist education and training and it can lead to better understanding of the complex information present in HRCT images and to appropriate diagnoses.

Although gamma cameras have emerged in the sixties, their spatial resolution is still not sufficient to detect small tracer concentration abnormalities. Examinations like mammo- scintigraphy requires high spatial resolution and then the possibility to position the detector as close to the explored organ as possible. Diagnostic accuracy in nuclear medicine imaging can know a notable advancement with the emergence of the new position sensitive photomultiplier tube (PSPMT). This component allows to develop a compact gamma detector which fulfils these requirements. This study investigates the feasibility and the characteristics of a medium field of view high spatial resolution gamma ray detector based on an array of R8520 PSPMT coupled to a pixelated NaI(Tl) crystal array. As first results, a photocathode uniformity variation of 1 to 3 was observed on the whole field of view. Energy resolution obtained is better than 10% FWHM at 140 keV in PSPMT centers. Concerning spatial linearity, it depends on the uniformity of the PSPMT used. Consequently, it will be necessary to develop linearity and energy correction methods. diameter. These results are better than those obtained with classical Anger gamma cameras (3). Due to its small size, it is well adapted to small organs exploration like thyroid and small animals (4). This research led to a technology transfer to ARIES company. The necessity of high spatial resolution mammoscintigraphy (5)-(6)-(7)-(8) for early and reliable detection of the breast cancer leads us to develop a new high performances gamma detector with a larger detection area. A new compact position sensitive photomultiplier tube, R8520-00-C12 (9), has been developed by HAMAMATSU. The interest of this new generation is its very low height (27 mm) which allows to build a very compact and relatively light gamma detector. Their square shape (25.7 mm x 25.7 mm) and their small dead edge (1.85 mm) authorize their juxtaposition in order to obtain a large detection area defined according to the diagnostic application. In this paper we investigate the feasibility and the characteristics of a medium field of view (MOV) high resolution gamma detector based on these PSPMTs and we present the first results concerning uniformity response, energy resolution and spatial linearity.

The recent developments in gamma cameras have lead to significant improvement of intrinsic spatial resolution in radioisotopic imaging. Moreover, the use of smaller photodetectors (PSPMT, photodiodes) enables to build more compact devices which allows to place the detector very near from the organ under study and thus to enhance the global spatial resolution. However, these improvements need the use of smaller image pixel sizes which worsens signal to noise ratio in every pixel. Moreover, a lot of examinations, such as scintimammography will be all the more useful since small nodules can be detected. In this work, we present a method combining a denoising wavelet filtering method with watershed determination, both leading to hot nodule enhancement. This method was applied to Monte Carlo simulations of a 64 mm high volume containing hot nodules of various sizes with a tumor to background ratio equal to 5. Although nodules were not visible in raw images corresponding to 10 min acquisition, the described process allowed to detect 87% of 6 mm nodules and more than 97% of nodules whose diameter was greater or equal to 7 mm. Furthermore, the whole process runs very fast

G protein-coupled receptors constitute one of the largest gene families in mammals. About a hundred orphan receptors still exist, for which the ligands and functions are unknown. We have recently identified the natural ligands of two orphan receptors expressed in dendritic cells and monocytes/macrophages. Chemerin, product of the gene Tig-2, was characterized as the ligand of the chemR23 receptor. The protein is synthesized as an inactive precursor, prochemerin, which requires the proteolytic removal of the last 6 or 7 amino acids, in order to generate a high affinity ligand of chemR23. Two neutrophil proteases, elastase and cathepsin G, are able to mediate this conversion. Besides, a peptide derived from the intracellular protein heme-binding protein (HBP) has been characterized as the first specific ligand of the FPRL2 receptor. The role of these two new systems in the control of physiological and pathological inflammatory reactions is presently being studied.

Generally, medical Gamma Camera are based on the Anger principle. These cameras use a scintillator block coupled to a bulky array of photomultiplier tube (PMT). To simplify this, we designed a new integrated CMOS image sensor in order to replace bulky PMT photodetetors. We studied several photodiodes sensors including current mirror amplifiers. These photodiodes have been fabricated using a CMOS 0.6 micrometers process from Austria Mikro Systeme (AMS). Each sensor pixel in the array occupies respectively, 1mm x 1mm area, 0.5mm x 0.5mm area and 0.2mm 0.2mm area with fill factor 98 % and total chip area is 2 square millimeters. The sensor pixels show a logarithmic response in illumination and are capable of detecting very low green light emitting diode (less than 0.5 lux) . These results allow to use our sensor in new Gamma Camera solid-state concept.

[1] Models for Martian magma oceans of varying depths predict that decompression mantle melting, perhaps forming Mars' earliest crust, could occur during gravitationally driven solid-state overturn of cumulates following magma ocean solidification. When hot cumulates rise from depth during solid-state overturn, some regions melt adiabatically, producing basaltic to andesitic magmas. The resulting crust would be formed at between 30 and 50 Myr after planetary accretion, when magma ocean solidification and subsequent overturn are complete. Models of magma oceans deeper than ∼1550 km consistently produce two separate magmatic source regions during overturn that create compositionally distinct magmas, consistent with both major and trace element data for SNC meteorites and the Martian crust. In a partial magma ocean between ∼1550 and ∼1250 km (∼15 GPa) the only early magma produced is from a shallow pyroxene + olivine source; but if the magma ocean were less than ∼1150 km (∼14 GPa) deep, the underlying (undifferentiated or minimally differentiated) mantle rises sufficiently during overturn that it melts adiabatically and produces an early magma. Magma ocean models therefore produce specific predictions for the volumes and compositions of the most ancient crust produced by a range of initial magma ocean depths. The predicted crustal compositions and volumes for a whole mantle magma ocean are consistent with observations of Mars today.

Needs of improved medical diagnostics, specially for early and reliable breast cancer detection, lead us to consider developments in scintillation crystals and position sensitive photomultiplier tubes (PSPMT) in order to develop a high resolution medium field g-ray imaging device. However, gamma rays detector need to find a compromise between many conflicting requirements. In order to optimize different parameters involved in the detection process, we have developed a Monte Carlo simulation software. Its aims were to optimize a gamma ray imaging system based on pixellated scintillation crystal coupled to a PSPMT array. Several crystal properties were taken into account as well as the measured intrinsic response of PSPMTs. Images obtained by simulations are compared with experimental results. Agreement between simulation and experimental results validate our simulation model.

Although gamma cameras have emerged in the sixties, their spatial resolution is still not sufficient to detect small tracer concentration abnormalities. Examinations like scintimammography requires high spatial resolution and then the possibility to position the detector as close to the explored organ as possible . The emergence of the new position sensitive photomultipliers tubes(PSPMT), from HAMAMATSU, permitted us to develop a compact gamma ray imaging probe which fulfils these requirements. The major interest of the new R8520-00-C12 PSPMT generation is their very low height (27mm) which allows to build a very compact and relatively light gamma ray detector. Their square shape (25.7x25.7mm2) and their very thin dead edges (1.85mm) authorize their juxtaposition in order to obtain a large detection area. In this study we investigate the characteristics of a prototype using a square 2x2 array of HAMAMATSU R8520 position sensitive photomultiplier tubes coupled to a pixelated NaI(Tl) crystal array containing 24x24 pixels each made of 2 x 2 x 5 mm3 crystals with 2.2 mm centre to centre spacing. We present the first results regarding intrinsic spatial resolution, energy resolution and homogeneity . Illuminating the detector, without scintillating crystal, with a light source simulating a scintillation at 140kev, we obtain an intrinsic spatial resolution better than 1mm on the whole field of view also including dead areas between PSPMTs. By coupling this detector to the crystal scintillator previously described, an energy resolution better than 10% FWHM at 140kev is obtained in PSPMT centers. These performances and the inherent scalability of detectors built using arrays of square tubes, make it an attractive choice for use in dedicated nuclear medicine instruments, including small animal imaging.

In order to further improve its prevention program entitled "Maternity childhood follow-up", the Paris region health insurance program for independent workers carried out a survey among female participants. The survey was designed to assess women's smoking behavior and evaluate reception of information concerning smoking-related risks and support available to stop smoking. The women's suggestions were also collected.A questionnaire was sent by the physicians in charge of the Ile de France region to the 3525 women who had reported a pregnancy.1099 answers were received (31%) The mean age of responders was 34.3 4.7 years. Their educational level was high (76% had a university degree). Before pregnancy, 37% were smokers. At the first trimester of pregnancy, 17% were smokers, 15% at the second trimester and 14% at the third trimester. Two years after childbirth, 20.5% were smokers. The proportion of women who stopped smoking was higher for those with a low Fagerström score. 29% of women said they did not receive any information about the harmful consequences of smoking. To cease smoking during pregnancy, 70% are helped by family and friends, 20% by health professionals; 3.5% took nicotine substitutes.This survey emphasises the need for improving information to pregnant women for alerting them to the dangers of smoking and for training the relevant health professionals.

[1] The possible role of solid-state convective cooling is important in understanding planetary thermal evolution. A stable compositional stratification in planetary mantles, which can arise from partial melting due to adiabatic decompression or from early magmatic differentiation, may suppress or delay convective instability, restrict the depth scale of convective motions, and reduce the convective heat flux out of the mantle. Two-dimensional numerical experiments on convection in a stably stratified viscous fluid with a strongly temperature-dependent viscosity cooled from above are carried out to understand how convecting, well-mixed layers form and thicken in time because of cooling at the planetary surface. Simple scaling laws and parameterizations are developed that allow the results of our numerical experiments to be extrapolated to viscosity variations as large as would be expected for thermally activated creep in planetary mantles. Strongly temperature-dependent viscosity reduces the available thermal buoyancy in the cold top boundary layer and therefore increases the impact of compositional stratification. Scaling laws for the mixed layer thickening rate indicate that thickening occurs mainly by buoyant, rather than viscous, entrainment of the underlying still stratified fluid. Compositional stratification may be important in the thermal evolution of the oceanic upper mantle, formation of cratonic continental lithosphere, and in planetary evolution, more generally. In several geologically realistic settings, a restricted depth of stratification or mantle viscosities on the order of 1018 Pa s or less are required for convective instability.

[1] Grain size, one of the most important microstructural properties of materials, evolves during creep deformation to minimize the free energy of polycrystalline aggregates. We apply a model of grain size evolution to the study of convective instability of cooling boundary layers. The grain size evolution model is coupled to a composite rheology where the deformation rate is the sum of that due to dislocation creep and grain size sensitive diffusion creep. The onset of convection is sensitive to grain growth rates and the initial grain size. The formation of convective instabilities is enhanced by stresses induced by plate motions; therefore small-scale convection is more likely to occur beneath fast-moving plates. In finite amplitude convection, grain size evolution leads to high viscosity in regions where convective stresses are low and can induce viscosity contrasts exceeding one order of magnitude. Such viscosity contrasts are sufficient to influence the dynamics of convection, often leading to domains which remain isolated from the well-mixed convecting fluid. A composite viscosity including diffusion creep, which has a lower activation energy than dislocation creep, reduces the effective temperature dependence of viscosity.

Radioisotopic investigations are very useful for functional diagnosis. However, visual analysis of images is lowered by blurring due to impulse response size and by their granular aspect due to low statistics. Acquired images result in the convolution between original object and detector spatial impulse response. Classical deconvolution methods used for radioisotopic image restoration fail due to bad signal to noise ratio. A new deconvolution process including two steps is designed. The first stage reduces acquired images statistical noise by applying a second order Butterworth low-pass filter. As the detector response shape may also be viewed as a 2D heat diffusion process, the deconvolution is done by running the diffusion equation into minus time. Tests were performed on physical phantom and on clinical thyroid scintigraphies acquired with IRIS (ARIES) high resolution gamma imaging probe. On physical phantom, cold spherical nodules as small as 4 mm in diameter are clearly enhanced on restored images, and diagnosis is improved.

Radioisotopic Investigations are very useful for functional diagnosis, but available gamma cameras have poor spatial resolution. Development of new PSPMT based high-resolution detectors brings new interests to this medical imaging technique. However, the Poissonian nature of emitted photon flux and low count images due to low doses administered to the patients and to collimation, lead to images with granular aspect. This noisy appearance is particularly inconvenient when looking for cold nodules as in thyroid examinations. Low-pass filters, which reduce noise, are not well suited for detecting small cold nodules. An adapted translation invariant wavelet filter is designed which takes into account the poissonian feature of noise and preserves small sized structures. The filter was tested by Monte Carlo simulations, phantom and clinical thyroid scintigraphies. Cold spherical nodules as small as 4 mm in diameter are easily detected on filtered images acquired with IRIS (ARIES) high-resolution gamma ray imaging probe. Presentation of filtered images at different scales offering enhanced visual quality and lowered noise, simultaneously with original image, allows more comfortable analysis and improves scintigraphic diagnosis ability.

Precise tumor localization with a gamma probe based on a CsI(Tl) crystal coupled to a photodiode needs to improve the energy resolution of the device. In indirect gamma detection, quality of energy resolution depends on quality of light collection. For this purpose, we developed a simulation based on the Monte Carlo method, which describes the path of visible photons produced in a scintillator crystal by a photoelectric gamma interaction at 140 keV. A set of simulations was performed in order to study the influence of crystal geometry (shape and dimensions) and side surface conditions on light collection. Amount of detected signal versus gamma photon interaction positions in the crystal was also studied. In conclusion, for a photodiode with 10 mm /spl times/ 10 min sensitive area, the best compromise between amount of collected light and uniformity of response versus interaction position was obtained for a 5 mm /spl times/ 5 mm parallelepipedic crystal having ground faces covered with white reflectors.

We summarize petrological and seismic constraints on the temperature of arc lower crust and shallow mantle, and show that published thermal models are inconsistent with these constraints. We then present thermal models incorporating temperature-dependent viscosity, using widely accepted values for activation energy and asthenospheric viscosity. These produce thin thermal boundary layers in the wedge corner, and an overall thermal structure that is consistent with other temperature constraints. Some of these models predict partial melting of subducted sediment and/or basalt, even though we did not incorporate the effect of shear heating We obtain these results for subduction of 50 Myr old oceanic crust at 60 km/Myr, and even for subduction of 80 Myr old crust at 80 km/Myr, suggesting that melting of subducted crust may not be not restricted to slow subduction of young oceanic crust.

A high resolution radioisotopic detector allows detection of small structures, but its sensitivity is poor. Increased parallel collimator sensitivity is obtained by enlarging the hole diameter. However, a hole diameter greater than the detector intrinsic spatial resolution leads to artifacts on acquired images. Linear collimator motions can remove these artifacts. However a practical realization of such motions is difficult to perform. To this end, a circular translation motion is studied in this work. Motion effectiveness was evaluated by an homogeneity index based on hexagon center loci. Several rotation radii optimizing this homogeneity were found. Moving collimator transparency was deterministically simulated. The smallest suitable motion radius is 0.32 times the structure diameter, which leads to a very small field of view decrease. A device performing such collimator motions was realized for a high resolution gamma imaging probe based on a position sensitive photomultiplier tube. The measured spatial impulse response was the same on the whole field of view for a given source to detector distance. The image restoration process allows one to recover the spatial resolution. In conclusion, moving a medium sensitivity collimator allows one to obtain both good sensitivity and high resolution in radioisotopic imaging.

The design of gamma ray imaging probes based on silicon photodiodes and on a CsI(Tl) monocrystal is delicate and complex. Electronic and statistical noise deteriorate energy and spatial resolution. A Monte Carlo simulation is used to set the probe's parameters in order to obtain the best compromise between spatial uniformity energy uniformity, spatial linearity and energy collection. The output distribution of light depends on the physical properties of crystal edges, crystal thickness and refractive index of the coupling grease. A 75/spl times/75 mm/sup 2/ squared CsI(Tl) crystal coupled to a 5 by 5 array of photodiodes (15/spl times/15 mm/sup 2/) has been simulated. Energy and spatial characteristics of the probe were determined for crystal thickness varying from 2 mm and 20 mm and refractive index of coupling grease varying from 1.5 and 2.5. The influence of the aspect of the surfaces has also been studied. The best results were obtained with a crystal thickness of 8 mm, a grease refractive index of 1.9, and a crystal with polished edges and diffusing entrance face. These parameters minimize the statistic fluctuations of the light distribution on the array of photodiode leading to the best compromise between spatial linearity and energy collection.

This enquiry was carried out to evaluate the measures of secondary prevention at 6 months and over of myocardial infarction in the ile de France region with respect to the recommendations of scientific societies and results of large scale therapeutic trials. A questionnaire was completed for the 1,215 patients selected from data obtained from the hospital discharge summary, interrogation and examination of the patient, and a telephone conversation with the attending physician. The data covered cardiovascular risk factors, the main clinical parameters, the results of biological tests and investigations carried out for risk stratification, plus different elements of therapeutic management. Compared with previous studies of the same type, this enquiry showed a favourable tendency towards the prescription of antithrombotic drugs and betablockers (98.3% and 82.4% of patients, respectively), and to patients with reputedly normal blood pressure values (84.7%). A positive result concerning the reduction in the number of smokers (17.4%) and the increase in lipid lowering prescriptions should be tempered by the fact that advice about stopping smoking was rarely given and that the quantitative target of LDL cholesterol was often ignored. Finally, the prescriptions of ACE inhibitors, physical exercise and cardiac rehabilitation remained well below the recommendations or recent scientific data.

International audience

Bark storage proteins (BSP) store nitrogen (N) translocated from senescing leaves in autumn, and supply reduced N for spring growth. Expression of bsp and BSP accumulation are associated with short day photoperiod. To determine if photoperiod-associated bsp expression varies among poplars native to different latitudes, Populus deltoides Bartr. clones originating from six latitudes were grown under natural conditions at a common location. Relative amounts of BSP mRNA in these clones were measured at 2-week intervals from August 7 to October 16. The date of maximum BSP mRNA accumulation was correlated with latitude of origin, and maximum accumulation of BSP mRNA occurred earlier in clones native to northern latitudes than in clones native to southern latitudes. This pattern of variation is consistent with photoperiodic responses of plants native to temperate climates. Genotypic variations in BSP accumulation, bark protein concentration and bark N concentration were compared among clones of six hybrid poplar (Populus trichocarpa Torr. and Gray × P. deltoides) full-sib families (three F 2 families, two F 1 families and one BC 1 family) after 6 weeks in a short day photoperiod and at midwinter. Significant differences in BSP accumulation occurred among clones within four of the six full-sib families after 6 weeks in a short day photoperiod and also at midwinter for outdoor-grown plants. Bark protein and bark N concentrations also varied significantly among clones within certain families. In general, the greatest variation was found in F 2 and BC 1 families. Within several families, relative BSP amounts were positively correlated with bark protein concentration and total bark N concentration. These results indicate a role of photoperiod in regulating bsp expression and demonstrate a genetic component underlying seasonal BSP accumulation. The results could have significance in selecting for clones with improved N storage capacity and N-use efficiency.

The FDA has a surveillance system for monitoring adverse events related to medical devices. Infection reports submitted to the FDA by breast implant manufacturers between 1977 and 1997 are characterized. Two cases of death caused by toxic shock syndrome after mammoplasty reported to the FDA are presented. Overall, 1,971 reports with a principal adverse event of infection were reported in this time frame. There was a large increase in the number of reports on infections related to breast implants between 1992 and 1995 due to the publicity and litigation surrounding breast implants. When an organism was identified in the report, the most common organism reported was Staphylococcus sp. Information on the time between the implantation and the onset of the infection or the explantation of the implant was not always reported. However, in reports that did contain this information, there were differences between the length of time to infection onset reported for saline breast implants (earlier) compared to silicone gel breast implants (later). More than half of the reports (56.6%) asserted only that there was an infection and that breast implants were explanted as a result; the remaining reports asserted that infection and other signs, symptoms, or diagnoses had afflicted the patient.

Cannabinoid receptors (CB1-R) are the target of a novel class of neuromodulators, the endocannabinoids. Yet, their signalling mechanisms in adult brain are poorly understood. We report that, in rat and mouse hippocampal slices, anandamide and 2-arachidonoylglycerol, synthetic cannabinoids, and delta(9)-tetrahydrocannabinol activated p38 mitogen-activated protein kinases (MAPK), but not c-Jun N-terminal kinase (JNK). In contrast, lysophosphatidic acid (LPA), a lipid messenger acting on different receptors, increased both p38-MAPK and JNK phosphorylation. The effects of cannabinoids on p38-MAPK were mediated through activation of CB1-R because they were blocked in the presence of SR 141716 A and absent in CB1-R knockout mice, two conditions that did not alter the effects of LPA. The activation of p38-MAPK by cannabinoids was insensitive to inhibitors of SRC: These results provide new insights into the cellular mechanisms by which cannabinoids exert their effects in hippocampus.

1. Neuropeptides FF (NPFF) and AF (NPAF) are involved in pain modulation and opioid tolerance. These peptides were known to act through uncharacterized G protein-coupled receptors (GPCR). We describe here, using an aequorin-based assay as screening tool, that an orphan GPCR, previously designated HLWAR77, is a functional high affinity receptor for NPFF and related peptides. This receptor is further designated as NPFFR. 2. Binding experiments were performed with a new radioiodinated probe, [(125)I]-EYF, derived from the EFW-NPSF sequence of the rat NPFF precursor. Chinese hamster ovary (CHO) cell membranes expressing NPFFR bound [(125)I]-EYF with a K(d) of 0.06 nM. Various NPFF analogues and related peptides inhibited [(125)I]-EYF specific binding with the following rank order (K(i)): human NPAF (0.22 nM), SQA-NPFF (0.29 nM), NPFF (0.30 nM), 1DMe (0.31 nM), EYW-NPSF (0.32 nM), QFW-NPSF (0.35 nM), 3D (1.12 nM), Met-enk-RF-NH(2) (3.25 nM), FMRF-NH(2) (10.5 nM) and NPSF (12.1 nM). 3. The stimulatory activity of the same set of peptides was measured by a functional assay based on the co-expression of NPFFR, G(alpha 16) and apoaequorin. The rank order of potency was consistent with the results of the binding assay. 4. Membranes from NPFFR expressing CHO cells bound GTP gamma[(35)S] in the presence of SQA-NPFF. This functional response was prevented by pertussis toxin treatment, demonstrating the involvement of G(i) family members. 5. SQA-NPFF inhibited forskolin induced cyclic AMP accumulation in recombinant CHO cells in a dose dependent manner. This response was abolished as well by pertussis toxin pre-treatment. 6. RT -- PCR analysis of human tissues mRNA revealed that expression of NPFFR was mainly detected in placenta, thymus and at lower levels in pituitary gland, spleen and testis.

Neuropeptide FF (NPFF) is a part of a neurotransmitter system acting as a modulator of endogenous opioid functions. At this time, no non-peptide or peptide NPFF-antagonists have been discovered. Here, we demonstrate that Neuropeptide Y (NPY) ligands, in fact possess significant ability to interact with the human NPFF(2) receptors. NPY Y(1) antagonist BIBP3226 and mixed Y(1) antagonist/Y(4) agonist GR231118 are able to displace with low affinity, 50 -- 100 nM, the specific binding on NPFF receptors expressed in CHO cells as well as in rat dorsal spinal cord, an affinity however superior to those determined against Y(2), Y(4) or Y(5) receptors. Furthermore, BIBP3226 which is unable to inhibit the forskolin-stimulated cyclic AMP production mediated by NPFF(2) receptors, antagonizes the effect of NPFF, revealing the first antagonist of NPFF receptors. These properties of NPY ligands on Neuropeptide FF receptors must be considered when evaluating pharmacological activities of these drugs.

CCR5 is a G-protein-coupled receptor activated by the chemokines RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory protein 1alpha and 1beta, and monocyte chemotactic protein 2 and is the main co-receptor for the macrophage-tropic human immunodeficiency virus strains. We have identified a sequence motif (TXP) in the second transmembrane helix of chemokine receptors and investigated its role by theoretical and experimental approaches. Molecular dynamics simulations of model alpha-helices in a nonpolar environment were used to show that a TXP motif strongly bends these helices, due to the coordinated action of the proline, which kinks the helix, and of the threonine, which further accentuates this structural deformation. Site-directed mutagenesis of the corresponding Pro and Thr residues in CCR5 allowed us to probe the consequences of these structural findings in the context of the whole receptor. The P84A mutation leads to a decreased binding affinity for chemokines and nearly abolishes the functional response of the receptor. In contrast, mutation of Thr-82(2.56) into Val, Ala, Cys, or Ser does not affect chemokine binding. However, the functional response was found to depend strongly on the nature of the substituted side chain. The rank order of impairment of receptor activation is P84AT82VT82AT82CT82S. This ranking of impairment parallels the bending of the alpha-helix observed in the molecular simulation study.

International audience; DYNAMO is a small Mars orbiter planned to be launched in 2005 or 2007, in the frame of the NASA/ CNES Mars exploration program. It is aimed at improving gravity and magnetic field resolution, in order to better understand the magnetic, geologic and thermal history of Mars, and at characterizing current atmospheric escape, which is still poorly constrained. These objectives are achieved by using a low periapsis orbit, similar to the one used by the Mars Global Surveyor spacecraft during its aerobraking phases. The proposed periapsis altitude for DYNAMO of 120–130 km, coupled with the global distribution of periapses to be obtained during one Martian year of operation, through about 5000 low passes, will produce a magnetic/gravity field data set with approximately five times the spatial resolution of MGS. Additional data on the internal structure will be obtained by mapping the electric conductivity. Low periapsis provides a unique opportunity to investigate the chemical and dynamical properties of the deep ionosphere, thermosphere, and the interaction between the atmosphere and the solar wind, therefore atmospheric escape, which may have played a crucial role in removing atmosphere and water from the planet.

The involvement of cannabinoid CB1 receptors in morphine and cocaine motivational effects was investigated using CB1 knockout mice. For this purpose, we evaluated the rewarding effects in the place conditioning paradigm and the sensitization to the locomotor responses induced by these drugs. The hyperlocomotion induced by acute morphine administration (15 mg/kg, s.c.) was preserved, but the sensitization to this locomotor response induced by chronic morphine treatment was abolished in CB1 mutant mice. Morphine (5 mg/kg, s.c.) induced conditioned place preference in wild-type mice but failed to produce any response in knockout mice, indicating the inability of morphine to induce rewarding effects in the absence of CB1 cannabinoid receptors. When the aversive effects of morphine withdrawal were investigated using the place aversion paradigm, no differences between genotypes were observed. Acute cocaine (10 mg/kg, i.p.) induced hyperlocomotor responses in wild-type and knockout mice and a chronic cocaine treatment produced a similar sensitization to this response in both genotypes. In the conditioning place preference paradigm, cocaine (20 mg/kg, i.p.) produced rewarding responses in both wild-type and knockout mice. These results demonstrate that CB1 receptors are essential for adaptive responses produced by chronic morphine but not by chronic cocaine treatment.

The new high performance radioisotopic imager IRIS we recently developed has an intrinsic spatial resolution of about 1.7 mm. To obtain a good sensitivity, it is necessary to use a collimator with holes greater than this spatial resolution. However, this induces artifacts in images. In this paper, we describe a new concept: a moving collimator. Deterministic and Monte Carlo simulations demonstrate that it is possible to obtain simultaneously global high spatial resolution and good sensitivity in radioisotopic imaging.

Scintimammography is a promising technique for breast cancer detection. Scintimammography uses radiotracer containing 99m Tc that emits 140 keV gamma photons. We developed a small field of view gamma ray imaging probe called IRIS. A possible application of this probe is scintimammography. IRIS is composed by a single NaI(T1) scintillator coupled to a 5 inch round PSPMT. In order to optimize compromise between resolution and detection efficiency, we developed a Monte Carlo code modeling light transport in NaI crystals. The thickness of the scintillator (4 mm) was optimized for 99m Tc imaging. We also designed a high-resolution collimator with a 35 mm thickness and 1.7 mm hole diameter. Detection efficiency of the crystal is 65 % at 140 keV. IRIS shows a 2.5 mm global spatial resolution in contact. Energy and spatial corrections allow a ± 5 % uniformity and an energy resolution better than 10 % at 140 keV. IRIS has a 10 cm field of view and a 13 cm external diameter at the entrance face. The small size of the detector head allows placing the detector close to the breast, improving global spatial resolution. The high-resolution gamma ray imaging probe IRIS shows physical characteristics well suited for 99m Tc breast imaging.

CB1 cannabinoid receptors are widely distributed in the central nervous system where they mediate most of the cannabinoid-induced responses. Here we have evaluated the interactions between the CB1 cannabinoid receptors and the endogenous opioid system by assaying a number of well-characterized opioid responses, e.g. antinociception and stress-mediated effects, on mutant mice in which the CB1 receptor gene was invalidated. The spontaneous responses to various nociceptive stimuli (thermal, mechanical and visceral pain) were not changed in mutant CB1 mice. Furthermore, the absence of the CB1 cannabinoid receptor did not modify the antinociceptive effects induced by different opioid agonists: morphine (preferential mu opioid agonist), D-Pen2-D-Pen5-enkephalin (DPDPE) and deltorphin II (selective delta opioid agonists), and U-50,488H (selective kappa opioid agonist) in the hot-plate and tail-immersion tests. In contrast, the stress-induced opioid mediated responses were modified in CB1 mutants. Indeed, these mutants did not exhibit antinociception following a forced swim in water at 34 degrees C and presented a decrease in the immobility induced by the previous exposure to electric footshock. However, the antinociception induced by a forced swim in water at 10 degrees C was preserved in CB1 mutants. These results indicate that CB1 receptors are not involved in the antinociceptive responses to exogenous opioids, but that a physiological interaction between the opioid and cannabinoid systems is necessary to allow the development of opioid-mediated responses to stress.

Antisera raised against two distinct peptide regions of the Drosophila neurokinin-like receptor NKD were used to immunolocalize tachykinin-receptor-like proteins in the central nervous system of two insect species: the African migratory locust, Locusta migratoria, and the gray fleshfly, Neobellieria bullata. The resulting immunopositive staining patterns were identical for both antisera. Moreover, a very similar distribution of the immunoreactive material was observed in fleshflies and locusts. Immunoreactivity was found in nerve terminals of the retrocerebral complex, suggesting a presynaptic localization of the receptor in this part of the brain. Cell bodies were stained in the subesophageal ganglion: an anterior group of four larger cells and a posterior group of about 20 cells. These cells have axons projecting into the contralateral nervus corporis allati (NCA) II, bypassing the corpus allatum and projecting through the NCA I into the storage part of the corpus cardiacum. In the glandular part of the corpus cardiacum, the glandular adipokinetic hormone-producing cells did not show any immunopositive staining. In the locust, additional immunopositive staining was observed in internolaterally located neurons of the tritocerebrum and in important integrative parts of the neuropil such as the central body and the mushroom bodies.

We have recently reported that mice homozygous (Cr-/-) for a null mutation in the calretinin gene have impaired long-term potentiation (LTP) induction in the dentate gyrus (S. Schurmans et al. (1997) Proc. Natl. Acad. Sci. USA, 94, 10415 ). Here, we investigated dentate LTP induction in mice heterozygous (Cr+/-) for the same mutation. Despite the presence of calretinin in neurons of these mice, although at reduced levels as compared with normal mice, LTP induction in dentate gyrus was totally impaired. Spatial memory and learning were found unaffected in Cr+/- mice, such as in Cr-/- mice. Altogether, our results suggest that calretinin is a critical component in the control of dentate synaptic plasticity in mice, and that levels of calretinin higher than those observed in Cr+/- mice are required to induce LTP in this area. The possible mechanisms leading to the absence of correlation between gene dosage and biological effects are discussed.

To determine the effect of beta-chemokines on HIV-1 infection of primary macrophages, and to search for chemokine derivatives devoid of biological effects but efficient at protecting CD4+ T lymphocytes and macrophages against HIV-1.Use of chemically synthesized molecules devoid of biological contaminants and monocyte-derived macrophages from healthy donors.Full-length RANTES was chemically synthesized together with three derivatives, truncated of seven, eight and nine amino acids at the amino-terminus ([8-68]RANTES, [9-68]RANTES and [10-68]RANTES), which were tested for their biological activity and antiviral effects.Whereas full-length and truncated RANTES derivatives bound to beta-chemokine receptor CCR-5 with the same affinity as recombinant RANTES, the truncated forms were not chemotactic and acted as CCR-5 antagonists in this respect, although a partial agonist effect was noted on cell metabolism. Full-length RANTES and [8-68]RANTES protected T lymphocytes and macrophages from infection by HIV-1, although 10-fold higher concentrations of the truncated analogues were necessary to achieve the same effect as full-length RANTES. With regard to the effect of RANTES on HIV-1 infection of primary macrophages, our results contrast with most previously reported data.These data indicate that through binding to CCR-5, truncated RANTES derivatives that are devoid of detectable biological effects may represent candidates as drugs to protect both lymphocytes and macrophages from HIV- 1.

Contrary to the prevailing attitude that error is a source of blame and punishment, errors can be an opportunity to discover a problem and institute activities to correct the problem to reduce the likelihood of recurrence. Often the source of error may be the system in which it occurred, not the person associated with it. Error in any domain, including healthcare, is difficult to identify and address because persons are reluctant to report errors for fear of self-incrimination. The discipline of human factors addresses issues related to human performance including use error. Human factors analysis provides insight into the etiology of use errors and how they can be reduced. Patient-controlled analgesia (PCA) pumps were developed to allow the patient or care-giver more control over pain relief. The PCA pumps can be programmed to deliver pain medication on a continuous basis, intermittently, or as a bolus. Selected adverse incidents involving PCA pumps that were due to use error and reported to the U.S. Food and Drug Administration are described. Finally, implications of those findings and the potential for reducing use error by applying considerations of the discipline of human factors are discussed.

We describe a case of pancreatic cystosis in an 18-year-old man suffering from cystic fibrosis, who presented with acute epigastric pain. Ultrasound and computed tomographic studies revealed multiple pancreatic cysts of various size, measuring up to 5 cm. Pancreatic macrocystosis is an extremely rare manifestation in cystic fibrosis.

Proliferation of thyroid follicular cells is controlled by three intra-cellular cascades [cAMP, inositol 1,4,5-triphosphate (IP3)/Ca2+/diacylglycerol (DAG), and tyrosine kinases] that are activated by distinct extracellular signals and receptors. We had previously generated a transgenic mouse model in which the cAMP cascade was permanently stimulated in thyroid cells by an adenosine A2a receptor (Tg-A2aR model). In the present work, we have generated a transgenic model characterized by the chronic stimulation of both adenylyl cyclase and phospholipase C in thyroid follicular cells. The bovine thyroglobulin gene promoter was used to direct the expression of a constitutively active mutant of the alpha 1B adrenergic receptor, which is known to couple to both cascades in transfected cell lines. The expression of the transgene resulted, as expected, in the activation of phospholipase C and adenylyl cyclase, as demonstrated by the direct measurement of IP3 and cAMP in thyroid tissue. The phenotype resulting from this dual stimulation included growth stimulation, hyperfunction, cell degeneracy attributed to the overproduction of free radicals, and the development of malignant nodules invading the capsule, muscles, and blood vessels. Differentiated metastases were found occasionally in old animals. The development of malignant lesions was more frequent and of earlier onset than in our previous Tg-A2aR model, in which only the cAMP cascade was stimulated. These observations demonstrate that the cAMP and IP3/Ca2+/DAG cascades can cooperate in vivo toward the development of thyroid follicular cell malignancies.

Infusion pumps are used in the hospital setting, nursing home, and increasingly, in the home. Medical Device Reports to the Food and Drug Administration of adverse events during the use of infusion pumps for a 10-year period are described. Examples of cases reported to the Food and Drug Administration are provided. The problems reported by medical facilities (hospitals, medical centers, hospital pharmacies, or nursing homes) are compared with those that occur in the home or reported by home health care agencies. Overall, there were no differences in the types of adverse events reported by medical facilities when compared with reports from home health care agencies. However, there were differences in the location of use of some of the infusion pumps studied, which could reflect the trend toward home care over the past decade.

We report here on a case of cholesteatoma of the upper urinary tract. This rare, but recurrent disease was managed successfully by means of repeated endourological treatment. Diagnosis was confirmed by histological examination of samples obtained by percutaneous extraction.

Publisher Summary This chapter discusses the generation and migration of partial melt beneath oceanic spreading centers. The narrowness of the zone of crustal emplacement at oceanic spreading centers indicates that melt formed in the mantle beneath a spreading center must be focused toward the spreading axis; it can be accomplished by lateral flow in sloping decompacting boundary layers at the top of the melting region. These layers form by the decompaction or dilation of the solid matrix in response to an excess melt pressure that develops beneath an impermeable boundary. The extraction efficiency of decompacting layers is determined by the temperature and upwelling distribution in the mantle. Mantle flow and melting beneath an offset spreading center are investigated in the chapter using three-dimensional numerical experiments. The flow consists of the superposition of passive flow driven by plate spreading and buoyant flow driven by thermal expansion and compositional density gradients due to melt extraction. Buoyant flow affects the distribution of melt production by increasing the along-axis variation in upwelling beneath the spreading center and generating melting in the upwelling limbs of off-axis thermally driven convective rolls. Approximate paths for the extraction of melt along the decompacting layers at the top of the melting region are calculated in the chapter. These paths predict the division of the melting region into separate melt extraction regions for different spreading segments. Predicted along-axis distributions of crustal thickness, topography, and gravity have greater variation at slow spreading rates in agreement with observations.

[1] Although the Pacific and Nazca plates share the East Pacific Rise (EPR) as a boundary, they exhibit many differing characteristics. The Pacific plate subsides more slowly and has more seamounts than the Nazca plate. Both the seismic and magnetotelluric components of the Mantle ELectromagnetic and Tomography Experiment (MELT) found pronounced asymmetry in mantle structure across the spreading axis near 17°S. The Pacific (west) side has lower S-wave velocities, exhibits greater shear wave splitting, and is more electrically conductive than the Nazca (east) side. These results suggest asymmetric mantle flow and melt distribution beneath the EPR. To better understand the causes for these asymmetric properties, we construct numerical models of melting and mantle flow beneath a midocean ridge migrating to the west over a fixed mantle. Although the ridge is migrating to the west, the migration has little effect on the upwelling rates, requiring a separate mechanism to create the asymmetry. Models that produce asymmetric melting with a temperature anomaly require large (>100°C) excess temperatures and may not be consistent with the observed subsidence and crustal thickness. A possible mechanism for creating asymmetry without a temperature anomaly is across-axis asthenospheric flow, possibly driven by pressures created by upwelling beneath the Pacific Superswell to the west. Pressure-driven asthenospheric flow follows the base of the lithosphere, extending the upwelling region to the west as it follows the thinning lithosphere toward the axis, and shutting off melting as it crosses the axis and encounters an increasingly thick lithosphere to the east.