Safe Cytotoxic Drug Preparation Using Closed-system Transfer Device: Technical and Practical Evaluation of a New Device (Vialshield/Texium) Comparatively to a Reference One (Phaseal).

Closed-system transfer devices enhance the drug handlers' protection against hazardous drugs exposure by prohibiting the escape of liquid or vapor from the system. PhaSeal (Becton Dickinson), a reference closed-system transfer device, includes a vial protector with an expansion chamber, and an injector with an enclosed needle. VialShield (CareFusion) is another more recent closed-system transfer device including an expansion-chamber and a non-return valve, designed to be used in association with Texium (CareFusion), a closed, needle-free male luer with its preassembled syringe. Evaluation of VialShield/Texium was done comparatively to a classic spike device (Spike Swan, Codan) and PhaSeal. Evaluation methods consisted in practical evaluation by pharmacy technicians (evaluation of ease to use by nine operators in practical conditions during a complete week of production), microbiological safety performance (by Media Fill Test), and leakage assessment (fluorescein, titanium tetrachloride smoke, and radioactive tracer). Results showed that 100% of those operators evaluated would be ready to use VialShield/Texium for daily use, whereas only 75% of them would be ready to use PhaSeal. The use of PhaSeal and VialShield/Texium increased the duration of preparations compared to Spike Swan. No microbiological growth was observed with any of the three devices. A leakage of smoke was observed only with Spike Swan. Fluorescein leakage assessment confirmed that PhaSeal is a performing closed system with a dry connection. Spike Swan showed fluorescein leaks. Fluorescein drops were visible on the connection sites of the VialShield/Texium. Nevertheless, no fluorescein was found on compress after connections swapping. Transfer performance, assessed using technetium-99m, was 98.1 ± 1.4%, 97.9 ± 1.1% and 97.0 ± 1.3% and dead volume of the devices, were 1.0 ± 0.8%, 1.7 ± 0.6%, and 3.0 ± 1.1% for Spike Swan, PhaSeal, and VialShield/Texium, respectively. VialShield/Texium appeared as a very interesting device with performances close to PhaSeal (except dry connection), with a higher satisfaction assessment from the operators.

Soluble CD146 boosts therapeutic effect of endothelial progenitors through proteolytic processing of short CD146 isoform.

AIMS: Endothelial colony-forming cells (ECFC) constitute an endothelial progenitor fraction with a promising interest for the treatment of ischaemic cardiovascular diseases. As soluble CD146 (sCD146) is a new factor promoting angiogenesis, we examined whether sCD146 priming could improve the therapeutic potential of ECFC and defined the involved mechanism. METHODS AND RESULTS: We investigated the effects of sCD146 priming on regenerative properties of ECFC in vivo. In a mouse model of hindlimb ischaemia, the homing of radiolabelled cells to ischaemic tissue was assessed by SPECT-CT imaging. Soluble CD146 priming did not modify the number of engrafted ECFC but improved their survival capacity, leading to an enhanced revascularization. The mechanism of action of sCD146 on ECFC was studied in vitro. We showed that sCD146 acts in ECFC through a signalosome, located in lipid rafts, containing angiomotin, the short isoform of CD146 (shCD146), VEGFR1, VEGFR2, and presenilin-1. Soluble CD146 induced a sequential proteolytic cleavage of shCD146, with an extracellular shedding followed by an intramembrane cleavage mediated by matrix metalloprotease (MMP)/ADAM and presenilin-1, respectively. The generated intracellular part of shCD146 was directed towards the nucleus where it associated with the transcription factor CSL and modulated the transcription of genes involved in cell survival (FADD, Bcl-xl) and angiogenesis (eNOS). This effect was dependent on both VEGFR1 and VEGFR2, which were rapidly phosphorylated by sCD146. CONCLUSIONS: These findings establish that activation of the proteolytic processing of shCD146, in particular by sCD146, constitutes a promising pathway to improve endothelial progenitors' regenerative properties for the treatment of cardiovascular diseases.

Stability of a highly concentrated solution of epirubicin for conventional transcatheter arterial chemoembolization.

INTRODUCTION: Epirubicin is widely used for conventional transcatheter arterial chemoembolization (cTACE) in patients with hepatocellular-carcinoma. However, there is no data about its stability in solution at concentration higher than 2 mg/L, yet needed when mixing it with a standard volume of Lipiodol(®) to produce an efficient water-in-oil emulsion. The aim of this study was therefore to evaluate the stability of a highly concentrated solution of epirubicin for cTACE and verify whether epirubicin solution could be prepared in advance. MATERIALS AND METHODS: Fifty milligrams of epirubicin were dissolved in 6 mL of 0.9% sodium chloride and conditioned in brown polypropylene syringe. Physical and chemical stability assays including particles and HPLC-DAD analysis were performed in triplicate, using series of 5 syringes stored over 72 h at 4±2 °C followed by 4h at 22±4°C. RESULTS: Neither weight loss nor pH or spectrum change occurred. No haze or turbidity was observed and the number of subvisible particles was below the recommended limits. Epirubicin concentration remained above 95% of the initial value over the 72 h of storage at +4 °C followed by 4h at 22±4 °C and no degradation was observed. CONCLUSION: Epirubicin at 50mg/6 mL in 0.9% NaCl conditioned in brown propylene syringe is stable for at least 72 h at 4±2 °C with additional 4h at 22±4 °C allowing its preparation in advance for programmed cTACE and the standardization of its use in clinical practice.

[Pertinence of Off-label Prescriptions of Innovating and Expensive Drugs in a University Hospital]. / Pertinence des prescriptions « hors AMM/RTU ¼ des molécules onéreuses dans un hôpital universitaire.

OBJECTIVES: Pertinence of off-label prescriptions of innovative and expensive drugs needs a strict scientific appraisal to prevent adverse reaction risks and financial drift. METHODS: Pertinence of such prescriptions has been analyzed in a University Hospital by bibliometric methods. Scientific publications issued from this clinical activity have been also evaluated. RESULTS: Oncology differed from other clinical specialties by a better pertinence in justifying off-label prescriptions (good evidence level in 46% vs. 21%, scientific publications issued from A/B ranked journals: 51% versus 41%). Quality of scientific production from oncologists was also better (publication impact factor [IF] mean: 4.571 versus 2.245). CONCLUSIONS: The better pertinence of off-label prescriptions by oncologists in comparison to others clinicians' ones was mainly due to a shorter field of indications but also to a more efficient organisation such as systematic prescription by seniors, dedicated computerized provider order entry, multidisciplinary team meetings and collaborative culture.

Visual compatibility of defibrotide with selected drugs during simulated Y-site administration.

PURPOSE: The visual compatibility of a solution of defibrotide (the only drug recommended for treatment and prophylaxis of hepatic venoocclusive disease) with solutions of various drugs commonly administered in bone marrow transplant procedures was studied. METHODS: Solutions of 43 drug products in concentrations typically used in clinical practice were evaluated in 1:1 mixtures with defibrotide solution in glass tubes kept at room temperature. The evaluated products included antiinfectious, corticoid, sedative, analgesic, and cardiovascular agents widely used for hematopoietic stem cell transplantation and other marrow transplant procedures; in most cases, test solutions were prepared via dilution in or reconstitution with sterile water, 0.9% sodium chloride injection, or 5% dextrose injection. The mixtures were visually observed immediately after manual mixing and at specified time points (60, 150, and 240 minutes). Visual compatibility was defined as the absence of color change, haze, fibers, particles, gas generation, and precipitate formation. The effect of mixing order on visual compatibility was ascertained. RESULTS: Of the 43 tested drug solutions, 36 were found to be visually compatible with the defibrotide solution over the entire four-hour study period. Solutions of 7 drugs (amikacin, furosemide, midazolam, mycophenolate mofetil, nicardipine, tobramycin, and vancomycin) were visually incompatible with defibrotide solution. In some cases, evidence of incompatibility was observed intermittently or was dependent on mixing order. CONCLUSION: Defibrotide solution was found to be visually compatible with solutions of 36 i.v. products that are likely to be coadministered with the drug in a bone marrow transplant unit. Seven drug solutions were visually incompatible with defibrotide solution.

Aseptic simulation test for cytotoxic drug production in isolators.

PURPOSE: The results of a media-fill test (MFT) study to validate processes for cytotoxic drug preparation inside and outside aseptic compounding isolators are presented. METHODS: Using an MFT protocol adapted to institution-specific production conditions, the pharmacy team at a hospital in France performed a series of tests to verify the efficacy of decontamination and sterile compounding procedures, as required by French compendial standards, while assessing the performance of its team of 12 isolator operators; all operators were tested on three occasions, producing 10 MFT samples per test for a total of 30 samples per operator. The team also tested alternative compounding systems (i.e., two closed-system transfer devices and a classic spike system) for use during power outages or other emergencies precluding drug preparation within isolators. MFTs were performed using a standard tryptone soy broth-based test kit under worst-case conditions. RESULTS: The hospital's facilities for cytotoxic drug preparation were found to be in conformance with applicable sterility standards. Bacterial growth was not detected in any of the MFT samples produced by isolator operators during the study (total n = 360). In one instance, an MFT sample prepared using a closed-system transfer device was found to be contaminated due to improper cleaning of the medication vial, highlighting the importance of strict adherence to proper decontamination procedures. CONCLUSION: A hospital's practices for preparation of sterile products according to applicable good manufacturing guidelines, as well as emergency procedures for cytotoxic drug preparation outside isolators, were validated by the results of an MFT study.

Cisplatin dose adjustment in patients with renal impairment, which recommendations should we follow?

BACKGROUND: Nephrotoxicity is the dose-limiting side effect of cisplatin justifying the assessment of renal function for dose adjustment. OBJECTIVE: To determine whether appropriate dose adjustment is made in patients with renal impairment using the Cockcroft-Gault (CG) or the abbreviated Modification of Diet in Renal Disease (aMDRD) formulas to estimate the glomerular filtration rate (GFR). SETTING: The study was conducted in a 1,000-bed university hospital. METHOD: Two years of cisplatin prescriptions were retrospectively compared to the 4 and 3 ranges estimated glomerular filtration rate (eGFR)-stratified dosing recommendations (4RR and 3RR respectively). MAIN OUTCOME MEASURE: Cisplatin dose in mg/m(2) based on kidney function and according to the dosing recommendations. RESULTS: Among 1,364 cycles of cisplatin, 156 (11.4 %) were prescribed for 70 patients with eGFR < 60 mL/min and a median age of 67.4 years. For 57 (36 %) of these cycles, doses were not reduced. When reduced, prescribed doses were not different than recommended doses according to 4RR using CG (% of protocol, 63 ± 12 vs. 64 ± 17) while it was significantly lower using aMDRD (% of protocol, 66 ± 12 vs. 81 ± 22, p < 0.01) and significantly higher according to 3RR using both CG and aMDRD (% of protocol, 63 ± 12 vs. 50 ± 3 and 66 ± 12 vs. 50.7 ± 4.0 respectively, p < 0.01). Prescription of at least one appropriate dose according to 4RR and using aMDRD was associated with a statistically significant higher median total cumulative dose (% of protocol, 89.9 vs. 75.1 % respectively, p < 0.01) without higher decrease of eGFR over time. CONCLUSION: Cisplatin dose adjustment in patients with renal impairment must be improved. Estimating GFR with the aMDRD formula and adding an intermediary level of dose reduction for patients with eGFR from 50 to 59.9 mL/min may result in a higher cumulative dose of cisplatin without higher renal toxicity, which may significantly impact on the effectiveness of the chemotherapy. A prospective evaluation remains needed to assess the benefit/risk ratio of this dose adaptation schedule, taking into account the variability of the GFR estimates.

Therapeutic benefit of a combined strategy using erythropoietin and endothelial progenitor cells after transient focal cerebral ischemia in rats.

OBJECTIVE: Many studies have demonstrated beneficial effects of either erythropoietin (EPO) or endothelial progenitor cell (EPC) treatment in cerebral ischemia. To improve post-ischemic tissue repair, we investigated the effect of systemic administration of endothelial colony-forming cells (ECFCs), considered as relevant endothelial progenitors due to their specific vasculogenic activity, in the presence or absence of EPO, on functional recovery, apoptosis, angiogenesis, and neurogenesis in a transient focal cerebral ischemia model in the adult rat. DESIGN: Experimental study. INTERVENTION: The rats were divided into four groups 24 hours after ischemia,, namely control, ECFCs, EPO, and ECFCs+EPO, and received a single intravenous injection of ECFCs (5 × 10(6) cells) and/or intraperitoneal administration of EPO (2500 UI/kg per day for 3 days). MEASUREMENT: Infarct volume, functional recovery, apoptosis, angiogenesis, and neurogenesis were assessed at different time points after ischemia. MAIN RESULTS: The combination of EPO and ECFCs was the only treatment that completely restored neurological function. The ECFCs+EPO treatment was also the most effective to decrease apoptosis and to increase angiogenesis and neurogenesis in the ischemic hemisphere compared to controls and to groups receiving ECFCs or EPO alone. CONCLUSION: These results suggest that EPO could act in a synergistic way with ECFCs to potentiate their therapeutic benefits.

[Amyotrophic lateral sclerosis: update on etiological treatment]. / Actualités dans le traitement étiologique de la sclérose latérale amyotrophique.

Amyotrophic lateral sclerosis is a rare neurodegenerative disease. It is characterized by motoneurons progressive degeneration. Associated with a paralysis of the legs, arms and the respiratory muscles, its evolution is lethal. Riluzole is the only drug available with an marketing authorisation (autorisation de mise sur le marché [AMM]) in this indication. In the beginning stages of the disease it demonstrated a modest efficacy by prolonging survival for a few months. Although the physiopathological mechanisms of this disease have not been totally solved, the progression of knowledge in recent years in this area led to the development of a large number of neuroprotective agents which showed effective results in animal models of ALS and which could be good candidates for the treatment of ALS. Several clinical trials have been conducted about antiglutamatergic, antioxidant, antiapoptotic agents and growing cell factors but they failed to demonstrate efficacy on survival or quality of life. Therefore, clinical trials using innovative therapeutics and stem cells are ongoing and offer more distant hope.

Transplanted late outgrowth endothelial progenitor cells as cell therapy product for stroke.

Endothelial progenitor cells (EPCs) seem to be a promising option to treat patients with ischemic diseases. Here, we investigated the effects of late outgrowth EPCs, or endothelial colony-forming cells (ECFCs), a recently defined homogeneous subtype of EPCs, in a rat model of transient middle cerebral artery occlusion (MCAO). Either vehicle or 4.10(6) ECFCs, isolated from human cord blood, were intravenously injected 24 h after 1 h MCAO in rats assigned to control and transplanted groups respectively. (111)In-oxine-labeled ECFCs specifically homed to ischemic hemisphere and CM-Dil prelabeled ECFCs preferentially settled in the inner boundary of the core area of transplanted animals. Although incorporation of cells into neovessels was hardly detectable, ECFCs transplantation was associated with a reduction in apoptotic cell number, an increase in capillary density and a stimulation of neurogenesis at the site of injury. These effects were associated with an increase in growth factors expression in homogenates from ischemic area and may be related to the secretion by ECFCs of soluble factors that could affect apoptosis, vascular growth and neurogenesis. Microscopic examination of the ischemic hemisphere showed that ECFCs transplantation was also associated with a reduction in reactive astrogliosis. In conclusion, we demonstrated that ECFCs injected 24 h after MCAO settled in the injured area and improved functional recovery. The neurological benefits may be linked to a reduction in ischemia-induced apoptosis and a stimulation of ischemia-induced angiogenesis and neurogenesis. These findings raise perspectives for the use of ECFCs as a well-characterized cell therapy product for optimal therapeutic outcome after stroke.

[Interests in angiogenesis inhibitor drugs approved for the treatment of cancers]. / Intérêts thérapeutiques des médicaments antiangiogéniques disponibles en cancérologie.

New blood vessel formation (angiogenesis) is fundamental to the process of tumor. Vascular Endothelial Growth Factors (VEGF) and their receptors are considered to be ones of the most important regulators of angiogenesis and new key targets for anti-cancer treatment. Three angiogenesis inhibitors are approved in France for patients with various malignancies. The main purpose of this review is to summarize the basic mechanisms of tumor angiogenesis and the reasons why angiogenesis inhibitors arouse therapeutic interest. However, for these drugs, fundamental pharmacodynamic effects observed in laboratory studies were not always translated to efficacy in clinical development. Moreover, many side effects were reported and may discourage from using it. Their optimal use should be necessary to minimize side effects and guarantee therapeutic progress.

CD146 short isoform increases the proangiogenic potential of endothelial progenitor cells in vitro and in vivo.

RATIONALE: CD146, a transmembrane immunoglobulin mainly expressed at the intercellular junction of endothelial cells, is involved in cell-cell cohesion, paracellular permeability, monocyte transmigration and angiogenesis. CD146 exists as 2 isoforms, short (sh) and long (lg), but which isoform is involved remains undefined. OBJECTIVE: The recently described role of CD146 in angiogenesis prompted us to investigate which isoform was involved in this process in human late endothelial progenitors (EPCs), with the objective of increasing their proangiogenic potential. METHODS AND RESULTS: Immunofluorescence experiments showed that, in subconfluent EPCs, shCD146 was localized in the nucleus and at the migrating edges of the membrane, whereas lgCD146 was intracellular. In confluent cells, shCD146 was redistributed at the apical membrane and lgCD146 was directed toward the junction. In contrast to lgCD146, shCD146 was overexpressed in EPCs as compared to mature endothelial cells and upregulated by vascular endothelial growth factor and SDF-1 (stromal cell-derived factor 1). Study of the properties of both isoforms in vitro provided evidence that shCD146 was involved in EPC adhesion to activated endothelium, migration, and proliferation, with a paracrine secretion of interleukin-8 or angiopoietin 2, whereas lgCD146 was implicated in stabilization of capillary-like structures in Matrigel and transendothelial permeability. In an animal model of hindlimb ischemia, transplantation of shCD146-modified EPCs selectively promoted both EPC engraftment and blood flow. CONCLUSIONS: Altogether, these findings establish that CD146 isoforms display distinct functions in vessels regeneration. Selective improvement of therapeutic angiogenesis by shCD146 overexpression suggests a potential interest of shCD146-transduced EPCs for the treatment of peripheral ischemic disease.

Soluble CD146 displays angiogenic properties and promotes neovascularization in experimental hind-limb ischemia.

CD146, an endothelial molecule involved in permeability and monocyte transmigration, has recently been reported to promote vessel growth. As CD146 is also detectable as a soluble form (sCD146), we hypothesized that sCD146 could stimulate angiogenesis. Experiments of Matrigel plugs in vivo showed that sCD146 displayed chemotactic activity on endogenous endothelial cells, and exogenously injected late endothelial progenitor cells (EPCs). Recruited endothelial cells participated in formation of vascular-like structures. In vitro, sCD146 enhanced angiogenic properties of EPCs, with an increased cell migration, proliferation, and capacity to establish capillary-like structures. Effects were additive with those of vascular endothelial growth factor (VEGF), and sCD146 enhanced VEGFR2 expression and VEGF secretion. Consistent with a proangiogenic role, gene expression profiling of sCD146-stimulated EPCs revealed an up-regulation of endothelial nitric oxide synthase, urokinase plasminogen activator, matrix metalloproteinase 2, and VEGFR2. Silencing membrane-bound CD146 inhibited responses. The potential therapeutic interest of sCD146 was tested in a model of hind limb ischemia. Local injections of sCD146 significantly reduced auto-amputation, tissue necrosis, fibrosis, inflammation, and increased blood flow. Together, these findings establish that sCD146 displays chemotactic and angiogenic properties and promotes efficient neovascularization in vivo. Recombinant human sCD146 might thus support novel strategies for therapeutic angiogenesis in ischemic diseases.

Sevoflurane preconditioning against focal cerebral ischemia: inhibition of apoptosis in the face of transient improvement of neurological outcome.

BACKGROUND: Preconditioning the brain with volatile anesthetics seems to be a viable option for reducing ischemic cerebral injury. However, it is uncertain whether this preconditioning effect extends over a longer period of time. The purpose of this study was to determine if sevoflurane preconditioning offers durable neuroprotection against cerebral ischemia. METHODS: Rats (Sprague-Dawley) were randomly allocated to two groups: nonpreconditioned control group (n = 44) and preconditioned group (n = 45) exposed to 2.7 vol% sevoflurane (45 min) 60 min before surgery. Animals in both groups were anesthetized with 3.0 vol% sevoflurane and subjected to transient middle cerebral artery occlusion. After 60 min of awake focal ischemia, the filament was removed. Functional neurologic outcome (range 0-18; 0 = no deficit), cerebral infarct size (Nissl staining), and apoptosis (Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling; cleaved caspase-3 staining) were evaluated at 3, 7, and 14 days after ischemia. RESULTS: Sevoflurane preconditioning significantly improved functional outcome and reduced infarct volume (109 +/- 43 vs. 148 +/- 56 mm(3)) 3 days after ischemia compared to the control group. However, after 7- and 14-day recovery periods, no significant differences were observed between groups. The number of apoptotic cells was significantly lower in the preconditioned group than in the control group after 3- and 7-day recovery periods. Fourteen days after ischemia, no differences were observed between groups. CONCLUSION: In this model of transient focal cerebral ischemia, sevoflurane preconditioning induced effective but transient neuroprotective effects. Sevoflurane preconditioning also decreased ischemia-induced apoptosis in a more sustained way because it was observed up to 7 days after injury.

Early anesthetic preconditioning in mixed cortical neuronal-glial cell cultures subjected to oxygen-glucose deprivation: the role of adenosine triphosphate dependent potassium channels and reactive oxygen species in sevoflurane-induced neuroprotection.

BACKGROUND: The purpose of the present study, on mixed cortical neuronal-glial cell cultures subjected to transient oxygen-glucose deprivation (OGD) was: i) to compare the neuroprotection afforded by sevoflurane added either before (preconditioning) or during (direct neuroprotection) the OGD and ii) to explore the possible involvement of adenosine triphosphate-sensitive potassium (KATP) channels and intracellular reactive oxygen species (ROS) levels in the mechanism of the early preconditioning effect of sevoflurane. METHODS: Mature mixed cortical neuronal-glial cell cultures were exposed to 90-min OGD in an anaerobic chamber followed by reoxygenation. Sevoflurane (0.03-3.4 mM) was randomly administered for 90 min and discontinued 60 min before OGD (early preconditioning) or during the 90-min OGD (direct neuroprotection). Cell death was quantified 24 h after the OGD by lactate dehydrogenase release into the bathing medium. Intracellular ROS generation was assessed at the end of sevoflurane preconditioning using 2',7'-dichlorofluorescin diacetate. RESULTS: Sevoflurane preconditioning elicited a potent threshold-dependent neuroprotective effect at concentrations higher than 0.07 mM and sevoflurane added during OGD elicited a dose dependent neuroprotective effect. Blockers of KATP channels (glibenclamide 0.3 microM and 5 hydroxydecanoic acid 50 microM), or ROS-scavengers (N-2-mercaptopropionyl glycine 100 microM and N-acetylcysteine 50 microM), although they did not affect cell viability, counteracted the neuroprotection produced by early sevoflurane preconditioning. Sevoflurane exposure during preconditioning induced a significant increase in ROS levels which was prevented by both ROS scavengers and blockers of KATP channels. CONCLUSION: Early sevoflurane preconditioning induced a threshold-dependent protection of mixed cortical neuronal-glial cell cultures against OGD by mechanisms that seem to involve opening KATP channels, thereby leading to generation of ROS.

Exposure of medical personnel to radiation during radionuclide therapy practices.

OBJECTIVES: Radioisotopes that emit beta radiation are used for the treatment of hepatocellular carcinoma, of arthritic patients (radiosynovectomy) and treatment of bone metastases with, respectively, I-labelled lipiodol, colloidal citrate of Y or and Sm-labelled EDTMP. Radiation energy of these radioisotopes that emit beta or beta and gamma radiation (from 300 to 2000 keV) leads to an increase in radiation dose received by nuclear medicine staff. In this paper we focused on clinical and laboratory staff exposure during these types of metabolic radiation therapies. METHODS: Cylindrical LiF thermoluminescence dosimeters were used to measure radiation-related whole-body doses (WBDs) and finger doses of the clinical staff. RESULTS: Exposure of the two radiopharmacists and three nurses taking part in I-labelled lipiodol, Y-colloid and Sm-EDTMP therapies, for 12 months in succession, were 146 microSv and 750 microSv, respectively, considering WBD, and 14.6 mSv and 6.5 mSv, respectively, considering finger doses. Extrapolated annual exposures (six radiosynovectomies per year) for the rheumatologists were estimated to be 21 microSv (WBD) and 13.2 mSv (finger dose). Extrapolated annual WBDs and finger doses (25 I-labelled lipiodol treatments per year) for radiologists were estimated to 165 microSv and 3.8 microSv, respectively. CONCLUSION: Fortunately, these doses were always lower than the limits reported in the European Directive EURATOM 96/29 05/13/1996 (WBD <20 mSv.year; finger dose: 500 mSv.year) but have to be added to those relative to other metabolic radiotherapies such as radioiodine treatments and new metabolic radiotherapies (Y-conjugated peptides or antibodies). Nevertheless, the global exposure of medical staff involved in all these clinical practices justifies dosimetry studies to validate protocols and radiation protection devices for each institution.

The neuronal excitatory amino acid transporter EAAC1/EAAT3: does it represent a major actor at the brain excitatory synapse?

EAAC1/EAAT3 is a transporter of glutamate (Glu) present at the post-synaptic neuronal element, in opposition to the two other main transporters, GLAST/EAAT1 and GLT1/EAAT2, expressed at the excitatory amino acid (EAA) synapse by surrounding astrocytes. Although, in the adult, EAAC1/EAAT3 exhibits a rather low expression level and is considered to make a minor contribution to Glu removal from the synapse, its early expression during brain development, before the astrocytes are functional, suggests that such a neuronal transporter is involved in the developmental effects of EAA and, possibly, in the biosynthesis and trophic role of GABA, which is excitatory in nature in different brain regions during the earlier stages of brain development. This neuronal Glu transporter is considered to have a dual action as it is apparently involved in the neuronal uptake of cysteine, which acts as a key substrate for the synthesis of glutathione, a major anti-oxidant, because the neurones do not express the Xc(-) transport system in the mature brain. Interestingly, EAAC1/EAAT3 activity/expression was shown to be highly regulated by neuronal activity as well as by intracellular signalling pathways involving primarily alpha protein kinase C (alphaPKC) and phosphatidylinositol-3-kinase (PI3K). Such regulatory processes could act either at the post-traductional level or at the transcriptional level. It is worth noting that EAAC1/EAAT3 exhibits specificity, compared with other EAA transporters, because it is present mainly in the intracellular compartment and only for about 20% at the plasma membrane. Variations in neuronal Glu uptake were shown to be associated with rapid changes in the trafficking of the transporter protein altering the membranar location of the transporter. More recent data show that astrocyte-secreted factors such as cholesterol could also influence rapid changes in the location of EAAC1/EAAT3 between the plasma membrane and the cytoplasmic compartment. Such a highly regulated process of EAAC1/EAAT3 activity/expression may have implications in the physiopathology of major diseases affecting EAA brain signalling, which is further supported by data obtained in animal models of hypoxia-anoxia, for example.

Technologist radiation exposure in routine clinical practice with 18F-FDG PET.

OBJECTIVE: The use of 18F-FDG for clinical PET studies increases technologist radiation dose exposure because of the higher gamma-radiation energy of this isotope than of other conventional medical gamma-radiation-emitting isotopes. Therefore, 18F-FDG imaging necessitates stronger radiation protection requirements. The aims of this study were to assess technologist whole-body and extremity exposure in our PET department and to evaluate the efficiency of our radiation protection devices (homemade syringe drawing device, semiautomated injector, and video tracking of patients). METHODS: Radiation dose assessment was performed for monodose as well as for multidose 18F-FDG packaging with both LiF thermoluminescence dosimeters (TLD) and electronic personal dosimeters (ED) during 5 successive 18F-FDG PET steps (from syringe filling to patient departure). RESULTS: The mean +/- SD total effective doses received by technologists (n = 50) during all of the working steps were 3.24 +/- 2.1 and 3.01 +/- 1.4 microSv, respectively, as measured with ED and TLD (345 +/- 84 MBq injected). These values were confirmed by daily TLD technologist whole-body dose measurements (2.98 +/- 1.8 microSv; 294 +/- 78 MBq injected; n = 48). Finger irradiation doses during preparation of single 18F-FDG syringes were 204.9 +/- 24 and 198.4 +/- 23 microSv with multidose vials (345 +/- 93 MBq injected) and 127.3 +/- 76 and 55.9 +/- 47 microSv with monodose vials (302 +/- 43 MBq injected) for the right hand and the left hand, respectively. The protection afforded by the semiautomated injector, estimated as the ratio of the doses received by TLD placed on the syringe shield and on the external face of the injector, was near 2,000. CONCLUSION: These results showed that technologist radiation doses in our PET department were lower than those reported in the literature. This finding may be explained by the use of a homemade syringe drawing device, a semiautomated injector, and patient video tracking, allowing a shorter duration of contact between the technologist and the patient. Extrapolation of these results to an annual dose (4 patients per day per technologist) revealed that the annual extrapolated exposure values remained under the authorized limits for workers classified to work in a radioactivity-controlled area.