Optical nonlinearity for few-photon pulses on a quantum dot-pillar cavity device.

Giant optical nonlinearity is observed under both continuous wave and pulsed excitation in a deterministically coupled quantum dot-micropillar system, in a pronounced strong-coupling regime. Using absolute reflectivity measurements we determine the critical intracavity photon number as well as the input and output coupling efficiencies of the device. Thanks to a near-unity input-coupling efficiency, we demonstrate a record nonlinearity threshold of only 8 incident photons per pulse. The output-coupling efficiency is found to strongly influence this nonlinearity threshold. We show how the fundamental limit of single-photon nonlinearity can be attained in realistic devices, which would provide an effective interaction between two coincident single-photons.

Evidence for confined tamm plasmon modes under metallic microdisks and application to the control of spontaneous optical emission.

We demonstrate strong confinement of the optical field by depositing a micron sized metallic disk on a planar distributed Bragg reflector. Confined Tamm plasmon modes are evidenced both experimentally and theoretically, with a lateral confinement limited to the disk area and strong coupling to TE polarized fields. Single quantum dots controllably coupled to these modes are shown to experience acceleration of their spontaneous emission when spectrally resonant with the mode. For quantum dots spectrally detuned from the confined Tamm plasmon mode, an inhibition of spontaneous emission by a factor 40±4 is observed, a record value in the optical domain.

Anomalous Hanle effect due to optically created transverse overhauser field in single InAs/GaAs quantum dots.

We report on experimental observations of an anomalous Hanle effect in individual self-assembled InAs/GaAs quantum dots. A sizable electron spin polarization photocreated under constant illumination is maintained in transverse magnetic fields as high as approximately 1 T, up to a critical field where it abruptly collapses. These striking anomalies of the Hanle curve point to a novel mechanism of dynamic nuclear spin polarization giving rise to an effective magnetic field generated perpendicular to the optically injected electron spin polarization. This transverse Overhauser field, confirmed by the cancellation of electron Zeeman splitting below the critical field, is likely to be a consequence of the strong inhomogeneous quadrupolar interactions typical for strained quantum dots.

Biomimetic doxorubicin loaded polymersomes from hyaluronan-block-poly(gamma-benzyl glutamate) copolymers.

Using "click chemistry" as an easy and versatile synthetic strategy to combine hyaluronan and polyglutamate blocks, we have prepared nanovesicles (polymersomes) that present a controlled size, excellent colloidal stability, and a high loading capacity for hydrophilic and hydrophobic drugs. The unique feature of our concept is the use of hyaluronan, a polysaccharide with known capacity for targeting cancer-related protein receptors, as the hydrophilic portion of a block copolymer system. The cytotoxicity and internalization mechanism of doxorubicin-loaded polymersomes have been evaluated in C6 glioma tumor cell lines. The dual purpose served by hyaluronan, as both a hydrophilic block critical to vesicle formation and a binding agent for biological targets, breaks new ground in terms of multifunctional nanomaterial design for drug delivery.

Different pattern of brain pro-/anti-oxidant activity between depleted and enriched uranium in chronically exposed rats.

Uranium is not only a heavy metal but also an alpha particle emitter. The main toxicity of uranium is expected to be due to chemiotoxicity rather than to radiotoxicity. Some studies have demonstrated that uranium induced some neurological disturbances, but without clear explanations. A possible mechanism of this neurotoxicity could be the oxidative stress induced by reactive oxygen species imbalance. The aim of the present study was to determine whether a chronic ingestion of uranium induced anti-oxidative defence mechanisms in the brain of rats. Rats received depleted (DU) or 4% enriched (EU) uranyl nitrate in the drinking water at 2mg(-1)kg(-1)day(-1) for 9 months. Cerebral cortex analyses were made by measuring mRNA and protein levels and enzymatic activities. Lipid peroxidation, an oxidative stress marker, was significantly enhanced after EU exposure, but not after DU. The gene expression or activity of the main antioxidant enzymes, i.e. superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), increased significantly after chronic exposure to DU. On the contrary, oral EU administration induced a decrease of these antioxidant enzymes. The NO-ergic pathway was almost not perturbed by DU or EU exposure. Finally, DU exposure increased significantly the transporters (Divalent-Metal-Transporter1; DMT1), the storage molecule (ferritin) and the ferroxidase enzyme (ceruloplasmin), but not EU. These results illustrate that oxidative stress plays a key role in the mechanism of uranium neurotoxicity. They showed that chronic exposure to DU, but not EU, seems to induce an increase of several antioxidant agents in order to counteract the oxidative stress. Finally, these results demonstrate the importance of the double toxicity, chemical and radiological, of uranium.

In vivo effects of chronic contamination with depleted uranium on vitamin D3 metabolism in rat.

The extensive use of depleted uranium (DU) in today's society results in the increase of the number of human population exposed to this radionuclide. The aim of this work was to investigate in vivo the effects of a chronic exposure to DU on vitamin D(3) metabolism, a hormone essential in mineral and bone homeostasis. The experiments were carried out in rats after a chronic contamination for 9 months by DU through drinking water at 40 mg/L (1 mg/rat/day). This dose corresponds to the double of highest concentration found naturally in Finland. In DU-exposed rats, the active vitamin D (1,25(OH)(2)D(3)) plasma level was significantly decreased. In kidney, a decreased gene expression was observed for cyp24a1, as well as for vdr and rxralpha, the principal regulators of CYP24A1. Similarly, mRNA levels of vitamin D target genes ecac1, cabp-d28k and ncx-1, involved in renal calcium transport were decreased in kidney. In the brain lower levels of messengers were observed for cyp27a1 as well as for lxrbeta, involved in its regulation. In conclusion, this study showed for the first time that DU affects both the vitamin D active form (1,25(OH)(2)D(3)) level and the vitamin D receptor expression, and consequently could modulate the expression of cyp24a1 and vitamin D target genes involved in calcium homeostasis.

Increased delta aminolevulinic acid and decreased pineal melatonin production. A common event in acute porphyria studies in the rat.

Tryptophan (TRP) is the precursor of melatonin, the primary secretory product of the pineal gland. Hepatic heme deficiency decreases the activity of liver tryptophan pyrrolase, leading to increased plasma TRP and serotonin. As a paradox, patients with attacks of acute intermittent porphyria (AIP), exhibit low nocturnal plasma melatonin levels. This study using a rat experimental model was designed to produce a pattern of TRP and melatonin production similar to that in AIP patients. Pineal melatonin production was measured in response to: (a) a heme synthesis inhibitor, succinylacetone, (b) a heme precursor, delta-aminolevulinic acid (Ala), (c) a structural analogue of Ala, gamma-aminobutyric acid. Studies were performed in intact rats, perifused pineal glands, and pinealocyte cultures. Ala, succinylacetone, and gamma-aminobutyric acid significantly decreased plasma melatonin levels independently of blood TRP concentration. In the pineal gland, the key enzyme activities of melatonin synthesis were unchanged for hydroxyindole-O-methyltransferase and decreased for N-acetyltransferase. Our results strongly suggest that Ala overproduced by the liver acts by mimicking the effect of gamma-aminobutyric acid on pineal melatonin in AIP. They also support the view that Ala acts as a toxic element in the pathophysiology of AIP.

Microglia used as vehicles for both inducible thymidine kinase gene therapy and MRI contrast agents for glioma therapy.

Microglia are phagocytic cells that are chemoattracted by brain tumors and can represent up to 70% of the tumor cell population. To get insight into gene therapy against glioma, we decided to take advantage of those microglia properties and to use those cells as vehicles to transport simultaneously a suicide gene (under the control of a heat-sensitive promoter) and contrast agents to localize them by magnetic resonance imaging before applying any therapeutic treatment. Thymidine kinase (TK) expression and its functionality after gancyclovir administration were investigated. After the heat shock (44 degrees C and 20 min), TK was expressed in 50% of the cells. However, after gancyclovir treatment, 90% of the cells died by apoptosis, showing an important bystander effect. Then, the cells were incubated with new lanthanide contrast agents to check both their potential toxicity and their MR properties. Results indicate that the nanoparticles did not induce any cell toxicity and yield a hypersignal on MR images at 4.7 T. These in vitro experiments indicate that microglia are good candidates as vectors in gene therapy against brain tumors. Finally, microglia containing gadolinium-grafted nanoparticles were injected in the close vicinity of C6 tumor, in a mouse. The hyperintensive signal obtained on in vivo images as well as its retention time show the potential of the novel contrast agents for cellular imaging.

Effect of acetaminophen administration to rats chronically exposed to depleted uranium.

The extensive use of depleted uranium (DU) in both civilian and military applications results in the increase of the number of human beings exposed to this compound. We previously found that DU chronic exposure induces the expression of CYP enzymes involved in the metabolism of xenobiotics (drugs). In order to evaluate the consequences of these changes on the metabolism of a drug, rats chronically exposed to DU (40mg/l) were treated by acetaminophen (APAP, 400mg/kg) at the end of the 9-month contamination. Acetaminophen is considered as a safe drug within the therapeutic range but in the case of overdose or in sensitive animals, hepatotoxicity and nephrotoxicity could occur. In the present work, plasma concentration of APAP was higher in the DU group compared to the non-contaminated group. In addition, administration of APAP to the DU-exposed rats increased plasma ALT (p<0.01) and AST (p<0.05) more rapidly than in the control group. Nevertheless, no histological alteration of the liver was observed but renal injury characterized by incomplete proximal tubular cell necrosis was higher for the DU-exposed rats. Moreover, in the kidney, CYP2E1 gene expression, an important CYP responsible for APAP bioactivation and toxicity, is increased (p<0.01) in the DU-exposed group compared to the control group. In the liver, CYP's activities were decreased between control and DU-exposed rats. These results could explain the worse elimination of APAP in the plasma and confirm our hypothesis of a modification of the drug metabolism following a DU chronic contamination.

Effects of chronic 137Cs ingestion on barrier properties of jejunal epithelium in rats.

Environmental contamination by 137Cs is of particular public health interest because of the various sources of fallout originating from nuclear weapons, radiological source disruptions, and the Chernobyl disaster. This dispersion may lead to a chronic ecosystem contamination and subsequent ingestion of contaminated foodstuffs. The aim of this study was to thus determine the impact of a chronic ingestion of low-dose 137Cs on small intestine functions in rats. The animals received 150 Bq per day in drinking water over 3 mo. At these environmental doses, 137Cs contamination did not modify the crypt and villus architecture. In addition, epithelial integrity was maintained following the chronic ingestion of 137Cs, as demonstrated by histological analyses (no breakdown of the surface mucosa) and electrical transepithelial parameters (no change in potential difference and tissue conductance). Furthermore, cesium contamination seemed to induce contradictory effects on the apoptosis pathway, with an increase in the gene expression of Fas/FasL and a decrease in the apoptotic cell number present in intestinal mucosa. No marked inflammation was observed following chronic ingestion of 137Cs, as indicated by neutrophil infiltration and gene expression of cytokines and chemokines. Results indicated no imbalance in the Th1/Th2 response induced by cesium at low doses. Finally, evaluation of the functionality of the jejunal epithelium in rats contaminated chronically with 137Cs did not demonstrate changes in the maximal response to carbachol, nor in the cholinergic sensitivity of rat jejunal epithelium. In conclusion, this study shows that chronic ingestion of 137Cs over 3 mo at postaccidental doses exerts few biological effects on the epithelium of rat jejunum with regard to morphology, inflammation status, apoptosis/proliferation processes, and secretory functions.

Absorption, accumulation and biological effects of depleted uranium in Peyer's patches of rats.

The digestive tract is the entry route for radionuclides following the ingestion of contaminated food and/or water wells. It was recently characterized that the small intestine was the main area of uranium absorption throughout the gastrointestinal tract. This study was designed to determine the role played by the Peyer's patches in the intestinal absorption of uranium, as well as the possible accumulation of this radionuclide in lymphoid follicles and the toxicological or pathological consequences on the Peyer's patch function subsequent to the passage and/or accumulation of uranium. Results of experiments performed in Ussing chambers indicate that the apparent permeability to uranium in the intestine was higher (10-fold) in the mucosa than in Peyer's patches ((6.21+/-1.21 to 0.55+/-0.35)x10(-6)cm/s, respectively), demonstrating that the small intestinal epithelium was the preferential pathway for the transmucosal passage of uranium. A quantitative analysis of uranium by ICP-MS following chronic contamination with depleted uranium during 3 or 9 months showed a preferential accumulation of uranium in Peyer's patches (1355% and 1266%, respectively, at 3 and 9 months) as compared with epithelium (890% and 747%, respectively, at 3 and 9 months). Uranium was also detected in the mesenteric lymph nodes ( approximately 5-fold after contamination with DU). The biological effects of this accumulation of depleted uranium after chronic contamination were investigated in Peyer's patches. There was no induction of the apoptosis pathway after chronic DU contamination in Peyer's patches. The results indicate no change in the cytokine expression (Il-10, TGF-beta, IFN-gamma, TNF-alpha, MCP-1) in Peyer's patches and in mesenteric lymph nodes, and no modification in the uptake of yeast cells by Peyer's patches. In conclusion, this study shows that the Peyer's patches were a site of retention for uranium following the chronic ingestion of this radionuclide, without any biological consequences of such accumulation on Peyer's patch functions.

Study of the tools available in biological dosimetry to estimate the dose in cases of accidental complex overexposure to ionizing radiation: the Lilo accident.

PURPOSE: To compare the efficiency of different cytogenetic tools in estimating the doses received by four people involved in the Lilo accident and to monitor the dose estimate over 4.5 years. MATERIALS AND METHODS: Several young Georgian frontier guards handled at least one of the 12 Caesium sources found in a former Russian military camp. Overexposure lasted from July 1996 to May 1997. The Institute for Radiological Protection and Nuclear Safety (IRSN) obtained blood samples taken at several intervals post-exposure from the four most highly-exposed people. Dose estimation was performed using dicentric and translocation scoring. RESULTS: The first dose estimations performed by dicentric scoring gave whole-body doses ranging from 0.4 to 1.3 Gy. Overexposure was complex and several mathematical models were used to take this complexity into account. This could provide information concerning the circumstances of overexposure. Concerning follow-up, the yield of dicentrics decreased by about 50% in the first 4 months following the end of overexposure whereas translocations were stable over the period of analysis. CONCLUSION: It has been useful to compare cytogenetic results with clinical results. The results presented here reveal good stability of translocations. However the first dose estimation was not attempted until 6 months after the last exposure.

[Cytochromes P450: xenobiotic metabolism, regulation and clinical importance]. / Les cytochromes P450: métabolisme des xénobiotiques, régulation et rôle en clinique.

Cytochromes P450 (CYPs) are a superfamily of 57 genes coding for drug metabolizing enzymes and endobiotic metabolizing enzymes (steroids, eicosanoids, vitamins...). This is the main metabolizing enzyme system for foreign compounds, including drugs, which has a primary role in organism protection against potential harmful insults from the environment (pollutants, pesticides...). The CYPs regulation is essentially transcriptional: nuclear receptors are recognized as key mediators for the control of drug metabolizing enzymes. Their ligands are exogenous and also endogenous molecules that can up-regulate or down-regulate these transcription factors. Treatment with drugs or xenobiotics, which are nuclear receptor agonists or antagonists, can lead to severe toxicities, loss of therapeutic effect or endobiotic metabolism disorders. Genetic polymorphisms of these enzymes have an important role in their activity and must be taken into account during drug administration. Then, CYP activity depends on genotype and environment; this is recently used as biomarker to determine human exposure to environmental molecules or to predict the susceptibility to certain pathologies.

Virtual crystal description of III-V semiconductor alloys in the tight binding approach.

We propose a simple and effective approach to construct the empirical tight-binding parameters of ternary alloys in the virtual crystal approximation. This combines a new, compact formulation of the strain parameters and a linear interpolation of the Hamiltonians of binary materials strained to the alloy equilibrium lattice parameter. We show that it is possible to obtain a perfect description of the bandgap bowing of ternary alloys in the InGaAsSb family of materials. Furthermore, this approach is in a good agreement with supercell calculations using the same set of parameters. This scheme opens a way for atomistic modeling of alloy-based quantum wells and quantum wires without extensive supercell calculations.

Intrinsic interface states in InAs-AlSb heterostructures.

We examine the formation of intrinsic interface states bound to the plane of In-Sb chemical bonds at InAs-AlSb interfaces. Careful parameterization of the bulk materials in the frame of the extended-basis spds (*)tight-binding model and recent progress in predictions of band offsets severely limit the span of tight-binding parameters describing this system. We find that a heavy-hole-like interface state bound to the plane of In-Sb bonds exists for a large range of values of the InSb-InAs band offset.

Translocation yields in peripheral blood lymphocytes from control populations.

PURPOSE: To record the latest information on control levels of translocations in cultured human lymphocytes. MATERIALS AND METHODS: Control-level data from seven European laboratories that are using fluorescence in situ hybridization (FISH) techniques for retrospective biological dosimetry have been combined in a meta-analysis. After correction for the differing probe combinations used, tests of consistency are performed. The combined data have been used to test for individual variation, systematic variation with age, gender and smoking habits. RESULTS: There is a strong variation of translocation yield with age but no variation was detectable with gender or smoking habits. After correction for age, homogeneity tests showed that about 10% of individuals were outside the 95% confidence limits as opposed to 5% expected. From a total of 385, there is an excess of about 20 individuals most of whom have an unexpectedly high yield of translocations. CONCLUSIONS: For retrospective biological dosimetry purposes a generic age-dependent control level can be assumed. No other lifestyle factors such as smoking appear to have a significant effect on translocation yield.

Review of translocations detected by FISH for retrospective biological dosimetry applications.

Several European laboratories have combined their research efforts to arrive at a consensus view on using fluorescence in situ hybridisation (FISH) for retrospective dosimetry. The aim of this review is to report these views and to highlight some areas where further work is needed. Translocations in the stable cells should be measured only in the cells that contain the full complement of the painted material. Two-way and one-way translocations should be combined with equal weight. The control level of translocations has a strong dependence on age, which has now been measured and the system has been calibrated. In conclusion, the technique works and a lifetime dose to the bone marrow from low-linear energy transfer radiation of 0.5 Gy above normal background levels can be measured for any individual. The main application is considered to provide an independent verification of lifetime doses to individuals who might form a part of an epidemiological study.

Immunocytochemical localisation of hydroxyindole-O-methyltransferase in pineal photoreceptor cells of several fish species.

Melatonin is an internal "Zeitgeber," involved in the timing and control of a number of rhythmic functions and behaviours. Its synthesising cells remain to be identified in the fish pineal. The last step in the melatonin biosynthetic pathway is catalysed by the enzyme hydroxyindole-O-methyltransferase. An affinity-purified antibody, directed against chicken pineal hydroxyindole-O-methyltransferase, was used in the present study to identify the melatonin synthesising cells in four fish species: a primitive chondrostean (sturgeon), a saltwater teleost (dorado), and two freshwater teleosts (pike, trout). Western blot immunolabeling of pike and trout pineal proteins revealed a single band at 38 KDa, which corresponds to the known molecular weight of the enzyme in bovine, rat, and chicken pineal. Regardless of the species, a specific immunocytochemical labeling, visualised by means of the peroxidase-antiperoxidase method, was exclusively associated with the photoreceptor cells. These results provide evidence that photoreceptors of the fish pineal are responsible for the biosynthesis of 5-methoxyindoles, including melatonin. In the pike, reactions were less intense in the distal portion of the pineal vesicle than in the other regions of the organ. It is questioned whether this might be related to the existence of a germinative zone, generating new photoreceptor cells in this distal portion. Hydroxyindole-O-methyltransferase has been previously demonstrated in mammalian pinealocytes, and modified photoreceptors of the avian pineal. It is now demonstrated in pineal photoreceptors of a primitive fish and of more evolved saltwater and freshwater fish. The results strengthen the view that these cells are related through phylogeny and that their well conserved melatoninergic function appears early in the course of evolution.

M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced carcinoma of the bladder. The French Federation of Cancer Centers experience.

70 patients with advanced transitional cell carcinoma of the bladder received methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC). Complete responses (CR) were obtained in 13 of the 67 (19%) evaluable patients and partial responses (PR) in 25 patients for an objective response rate of 57% (95% CI 45-69%). Of the 54 patients who have had a minimum follow-up of 2 years, 8 patients (15%) are disease-free or have stable residual disease. Median survival of the 70 patients was 13 months. Toxicity was acceptable with no drug-related deaths. Because of myelosuppression, only 15 patients (21%) received treatment without delays in drug administration or modifications from the planned schedule. Our results confirm that this regimen is effective, with some patients being long-term survivors.

Glucose and glutamine metabolism in C6 glioma cells studied by carbon 13 NMR.

The question as to whether glutamine and glucose are both required for optimal growth of glioma cells is studied through the role of these substrates on the metabolism of the cells. C6 rat glioma cells grow only very slowly when glutamine is omitted from the culture medium. The rates of glucose consumption and lactate production on confluent cells in glutamine-free medium were 0.88 +/- 0.09 and 1.06 +/- 0.25 mumol/h/mg protein, respectively. In the presence of 4 mM glutamine, glucose utilization increase to 60% leading to a 45% increase of lactate production. We have studied the kinetics of enrichment of intracellular glutamate at C2, C3 and C4 positions on cells incubated with 5 mM 99% enriched [1-(13)C]glucose in the presence or the absence of glutamine in the incubation medium. The specific enrichments at metabolic steady state of all carbon positions were the same under both conditions, but we observed a significantly reduced rate of 13C incorporation in the presence of glutamine, showing an isotopic dilution of tricarboxylic acid cycle intermediates and indicating the use of this amino acid as an anaplerotic substrate. The fact that no dilution occurred at the level of pyruvate suggests strongly the lack of glutaminolysis in these cells. The main conclusion from this work is that glutamine metabolism in C6 cells appears complementary to that of glucose as far as energy production and carbon sources for the growing of the cells are concerned: glutamine is mainly utilized for anaplerosis as carbon donor to replenish the tricarboxylic acid cycle; it is not a substrate for energy metabolism. In contrast, glucose is poorly anaplerotic and is essentially used as energetic fuel by the C6 cells.