Perfusion-weighted techniques in MRI grading of pediatric cerebral tumors: efficiency of dynamic susceptibility contrast and arterial spin labeling.

PURPOSE: Dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) perfusion MRI are applied in pediatric brain tumor grading, but their value for clinical daily practice remains unclear. We explored the ability of ASL and DSC to distinguish low- and high-grade lesions, in an unselected cohort of pediatric cerebral tumors. METHODS: We retrospectively compared standard perfusion outcomes including blood volume, blood flow, and time parameters from DSC and ASL at 1.5T or 3T MRI scanners of 46 treatment-naive patients by drawing ROI via consensus by two neuroradiologists on the solid portions of every tumor. The discriminant abilities of perfusion parameters were evaluated by receiver operating characteristic (ROC) over the entire cohort and depending on the tumor location and the magnetic field. RESULTS: ASL and DSC parameters showed overall low to moderate performances to distinguish low- and high-grade tumors (area under the curve: between 0.548 and 0.697). Discriminant abilities were better for tumors located supratentorially (AUC between 0.777 and 0.810) than infratentorially, where none of the metrics reached significance. We observed a better differentiation between low- and high-grade cancers at 3T than at 1.5-T. For infratentorial tumors, time parameters from DSC performed better than the commonly used metrics (AUC ≥ 0.8). CONCLUSION: DSC and ASL show moderate abilities to distinguish low- and high-grade brain tumors in an unselected cohort. Absolute value of K2, TMAX, tMIP, and normalized value of TMAX of the DSC appear as an alternative to conventional parameters for infratentorial tumors. Three Tesla evaluation should be favored over 1.5-Tesla.

[Computer-assisted therapy and video games in psychosocial rehabilitation for schizophrenia patients]. / L'utilisation des thérapies assistées par ordinateur et des jeux vidéo à visée thérapeutique dans les soins de réhabilitation psychosociale chez les sujets souffrant de schizophrénie, revue de la littérature.

OBJECTIVES: Video games and virtual reality have recently become used by clinicians for training or information media or as therapeutic tools. The purpose is to review the use of these technologies for therapy destined for schizophrenia patients. METHODS: We conducted a review in October 2016 using Pubmed, Scopus and PsychInfo using the following Medical Subject Headings (MESH): "video games", "virtual reality" and "therapy, computer-assisted/methods", each associated with "schizophrenia". Papers were included in the review if: (a) they were published in an English, Spanish or French-language peer-reviewed journal, (b) the study enrolled patients with schizophrenia or schizo-affective disorder, (c) the patients used a therapeutic video game or therapeutic virtual reality device. RESULTS: Eighteen publications were included. The devices studied are mainly therapeutic software developed specifically for therapeutic care. They can be classified according to their therapeutic objectives. These targets corresponded to objectives of psychosocial rehabilitation: improvement of residual symptomatology, cognitive remediation, remediation of cognition and social skills, improvement of everyday life activities, support for occupational integration. Very different devices were proposed. Some researchers analysed programs developed specifically for patients with schizophrenia, while others were interested in the impact of commercial games. Most of the studies were recent, preliminary and European. The impact of these devices was globally positive, particularly concerning cognitive functions. CONCLUSIONS: Computer-assisted therapy, video games and virtual reality cannot replace usual care but could be used as adjunctive therapy. However, recommending their use seems premature because of the recent and preliminary character of most studies. Moreover, a link is still lacking between this field of research in psychiatry and other fields of research, particularly game studies. Finally, it might be interesting to analyse more precisely the neuropsychological impact of existing commercial games which could potentially be useful for psychosocial rehabilitation.

Transition kinetics of mixed lipid:photosurfactant assemblies studied by time-resolved small angle X-ray scattering.

HYPOTHESIS: Photoswitchable surfactants are used in the design of many light-responsive colloids and/or self-assemblies. Photo-isomerization enables to control molecular equilibrium, and triggers transient reorganizations with possibly out-of-equilibrium intermediate states that have been overlooked. Here, we address this question by an in depth structural investigation of intermediate lipid-surfactant assemblies that occur during fast isothermal photo-triggered transition in lipid:surfactant mixtures. EXPERIMENTS: The structural parameters of mixed assemblies of azobenzene-containing cationic surfactant (AzoTMA) and dioleoylphosphatidylcholine (DOPC) lipids were studied by light scattering and time-resolved small angle X-ray scattering. Structural and compositional information about the assemblies and unimers in bulk were determined at the photostationary states, as well as at intermediate kinetic states formed during UV or blue light illumination. FINDINGS: DOPC:AzoTMA systems form mixed assemblies representative of phospholipid:cationic surfactant mixtures, that evolve from spheroid, to rod-like micelles, and vesicles with increasing DOPC fraction. Transient assemblies detected during the photo-triggered kinetics are similar to the ones found in stationary states. But changes of AzoTMA unimers in bulk can be considerably faster than mass reorganizations of the mixed assemblies, suggesting that out-of-equilibrium conditions are transiently reached. Mass reorganization of the surfactant-enriched assemblies is much faster than in the lipid enriched ones, providing insight into the role of lipids in a slow reorganization of the assemblies.

The occurrence of acidic drugs and caffeine in sewage effluents and receiving waters from three coastal watersheds in Atlantic Canada.

Pharmaceuticals, by design, induce biological responses in animals and humans at very low doses, making their presence in the aquatic environment an issue of concern. Prescription and over-the-counter drugs commonly found in wastewater are discharged on a continuous basis into the waters of two coastal watersheds in Atlantic Canada. Ten acidic drugs and caffeine were observed in the final effluents of sewage treatment facilities in Millcove (Halifax watershed), and Trenton (Pictou watershed), Nova Scotia. Naproxen and ibuprofen, two highly used non-steroidal anti-inflammatory drugs (NSAIDs), and caffeine, were the predominant compounds. Naproxen, ibuprofen, salicylic acid (metabolite of acetylsalicylic acid), diclofenac (NSAID) and gemfibrozil (lipid regulator) were also detected in the low ng/L range in the receiving waters of treated and untreated sewage outflows. Acidic drugs were not detected in the marine waters of the Cocagne watershed located in southeast New Brunswick. This watershed was evaluated for the possibility of contamination of near-shore coastal waters from domestic septic systems in the vicinity of a densely populated cottage area. The observation of traces of caffeine suggests some organic pollution in the area.

Down regulation by p60v-src of genes specifically expressed and developmentally regulated in postmitotic quail neuroretina cells.

The avian neuroretina (NR) is composed of photoreceptors and different neurons that are derived from proliferating precursor cells. Neuronal differentiation takes place after terminal mitosis. We have previously shown that differentiating NR cells can be induced to proliferate by infection with Rous sarcoma virus (RSV) and that cell multiplication requires expression of a functional v-src gene. We speculated that the quiescence of NR cells could be determined by specific genes. Cell proliferation could then result from the negative regulation of these genes by the v-src protein. By differential hybridization of a cDNA library, we isolated eight clones corresponding to genes expressed in postmitotic NR cells from 13-day-old quail embryos, transcriptional levels of which are significantly reduced in NR cells induced to proliferate by tsNY68, an RSV mutant with temperature-sensitive mitogenic activity. Partial sequencing analysis indicated that one RNA encoded the calmodulin gene, whereas the other seven showed no similarity to known sequences. By using v-src mutants that induce NR cell proliferation in the absence of transformation, we showed that transcription of six genes was negatively regulated by the v-src protein and that of four genes was correlated with NR cell quiescence. We also report that a subset of genes are specifically transcribed in neural cells and developmentally regulated in the NR. These results indicate that the v-src protein regulates expression of genes likely to play a role in the control of neural cell growth or differentiation.

Broadband supercontinuum interferometer for high-resolution profilometry.

In this paper, it is shown that a white light supercontinuum source generated in an air-silica microstructured optical fiber pumped with picosecond pulses offers the possibility to improve fringes visibility in interferometric acquisitions. Consequently, this source combined with a spectral interferometer, reaches high-resolution profilometric measurements. Phase calculation based on seven point algorithm can perform theoretically a subnanometer resolution. This method provides a one line profile of large surfaces from the analysis of a single shot image, without any mechanical scanning.

Mutagenic and alkylating activities of 3-methyl-1-phenyltriazenes and their possible role as carcinogenic metabolites of the parent dimethyl compounds.

3-Methyl-1-phenyltriazene and a series of ring-substituted derivatives (4-methylphenyl, 4-chlorophenyl, and 2,4,6-trichlorophenyl), structurally related benzenediazonium fluoborates and phenyl azides, as well as the recently isolated [1-methyl-3-(2,4,6-trichlorophenyl)-2-triazeno]methyl-beta-D-glucopyranoside uronic acid, were studied for their mutagenic activity in Salmonella typhimurium strains. Of these compounds, the 3-methyl-1-phenyltriazene derivatives and 2,4,6-trichlorobenzenediazonium fluoborate were found to be direct-acting mutagens; the glucuronide was active in strain TA 1530 only after deconjugation with beta-glucuronidase. The half-lives of the monomethylphenyltriazenes in vitro were determined and compared with their methylating activity towards 4-(4-nitrobenzyl)pyridine and their mutagenicity. The results are discussed in relation to the possible mechanism of action of the N,N-dimethylphenyltriazenes and their monomethyl derivatives as mutagens and organ-specific carcinogens.

Monoclonal antibody-directed analysis of cytochrome P-450-dependent monooxygenases and mutagen activation in the livers of DBA/2 and C57BL/6 mice.

Monoclonal antibodies (MAb 1-7-1 and Mab 2-66-3) specific for cytochrome P-450 (cyt. P-450) isozymes inhibited the metabolism of carcinogens, other xenobiotics, and endogenous compounds in two strains of mice. Postmitochondrial liver supernatant (S9) was prepared from untreated, 3-methylcholanthrene-treated, phenobarbital-treated, and pregnenolone 16 alpha-carbonitrile-treated C57BL/6 (B6) and DBA/2 (D2) mice. The modifying effect of two types of MAb to a 3-methylcholanthrene-induced cyt. P-450 and a phenobarbital-induced cyt. P-450 was investigated for: (a) S9-mediated mutagenicity of aflatoxin B1, benzo(a)pyrene 7,8-dihydrodiol, 2-acetylaminofluorene, and N-nitrosomorpholine in Salmonella typhimurium strains; and (b) the activity of aryl hydrocarbon hydroxylase, ethoxycoumarin O-deethylase, ethoxyresorufin O-deethylase, aminopyrine N-demethylase, and testosterone 6 beta-, 7 alpha-, and 16 beta-hydroxylases. With certain S9s, MAb-1-7-1 inhibited only those cytochrome P-450 isozymes involved predominantly in activity of aryl hydrocarbon hydroxylase, ethoxyresorufin O-deethylase, and ethoxycoumarin O-deethylase and mutagenicity of 2-acetylaminofluorene and benzo(a)pyrene 7,8-dihydrodiol; MAb 2-66-3 inhibited only those involved in aminopyrine N-demethylase and testosterone 6 beta-, 7 alpha, and 16 beta-hydroxylase activity and aflatoxin B1 mutagenicity. Both Mab 1-7-1 and MAb 2-66-3 inhibited cytochrome P-450 isozyme(s) implicated predominantly in testosterone 7 alpha-hydroxylation in S9 from pregnenolone 16 alpha-carbonitrile-treated B6 mice. MAb 1-7-1 did not inhibit N-nitrosomorpholine mutagenicity and MAb 2-66-3 increased it by 2- to 6-fold depending on the source of S9. Using these MAbs, it is thus possible to identify the contribution of the epitope-defined single or class of cyt. P-450 to specific metabolic reactions in S9 from untreated and inducer-treated mice.

Proliferation of chicken neuroretina cells induced by v-src, in vitro, depends on activation of the E2F transcription factor.

Quiescent chicken or quail retina neuroblasts (NR) can be induced to proliferate actively, in culture, by the v-src oncoprotein. The chE2F-1 transcription factor, a physiological partner of the retinoblastoma gene product, is highly expressed in vivo, in dividing chicken neuroretina cells (CNR). It is sharply down-regulated as cells enter the post-mitotic differentiation stage, thus suggesting that E2F activity is a prerequisite for NR cell proliferation. In the present paper, transient expression assays of different forms of chE2F-1 were used to investigate the function of E2F for switching CNR cells from a quiescent to a proliferative state in vitro. Attempts to substitute the effects of v-src by an ectopic expression of E2F-1 were unsuccessful. However, in the same conditions, E2F-1 supports full growth of CEF in serum-depleted medium. Deletion mutants of E2F-1, with potential dominant-negative properties, were transfected in RSV infected CNR cells. One of these truncated mutants induces a G1 phase block in RSV-transformed CNR cells indicating that, although E2F-1 overexpression cannot overcome the cell proliferation block of post-mitotic CNR cells E2F-1, activity is an important component of the growth signal pathway delivered by v-src in these nervous cells.

Isolation and characterization of a chicken homolog of the E2F-1 transcription factor.

In higher eukaryotes, the E2F-1 transcription factor is an essential and limiting component of cell cycle progression in late G1. E2F-1 heterodimerizes with members of the DP gene family and the resulting heterodimer regulates the expression of several proto-oncogenes and the genetic machinery of DNA replication. Cell cycle regulation of E2F activity is mediated through its association with the tumor suppressor Rb gene product. To examine the evolutionary conservation of the E2F-1 protein sequence and its developmental expression pattern we have isolated and sequenced the chick E2F-1 gene (chE2F-1) cDNA. The chicken protein is 34 amino acids (a.a) shorter than its human counterpart (403/437 a.a.) but has extremely well conserved bHLH and pRb binding domains, with respectively 94% and 83% identity. The position of the leucine zipper is also strictly conserved thereby accounting for ability of E2F-1 to form heterodimers with human and chicken DP-1. E2F-1 expression was analysed in synchronized cells as well as in embryonic or newborn chick tissues and appears to be closely correlated to the cell proliferation rate. In situ hybridization studies have shown very high expression levels in the neuroretina during the early stages of embryonic development when active neuroblast division occurs. In contrast, a sharp down-regulation is observed when cells become postmitotic. Overexpression of the chE2F-1 protein leads to oncogenic transformation only when a truncated version of the transgene lacking the pRb binding domain is used; the full length protein either has no effect or may be deleterious for cell survival.

The product of the v-src-inducible gene nr-13 is a potent anti-apoptotic factor.

Tumorigenesis can be induced either by activating cell proliferation or by inhibiting metabolic pathways regulating programmed cell death (apoptosis). There is evidence suggesting that p60(v-src) and other tyrosine kinases protect cells against apoptosis. This effect could contribute to cell transformation by the Rous sarcoma virus. Mechanism of cell death inhibition by p60(v-src) remains largely unknown. We have recently reported that in avian cells p60(v-src) activates the expression of nr-13, a bcl-2-related gene. In this paper, we demonstrate, using the bone marrow derived cell line Baf-3 as an experimental model, that the product of this avian gene (nr-13) is a potent anti-apoptotic factor. In addition, we report that, in quail neuroretinal cells, nr-13 expression is activated upon infection by the Rous sarcoma virus (RSV) but not by other oncogenic retroviruses like FSV or MH2, suggesting that nr-13 is a specific target of v-src. Activation of nr-13 expression may be a key step in cellular transformation by v-src.

Regulation of E2F-1 gene expression in avian cells.

E2F-1 is the prototype of a family of transcription factors playing a central role in the control of cell proliferation and apoptosis. E2F DNA binding activity is down-regulated during cellular differentiation, which is correlated with cell division arrest. We report here that the expression of E2F-1 itself is down-regulated in the developing quail neural retina between embryonic days E8-E10. This event occurs just after the massive arrest of the quail neuroretina cell division (E7-E8). To gain further insight into the regulatory mechanisms monitoring E2F-1 expression in differentiating neurons, we have cloned the quail E2F-1 promoter. In vivo DNA footprintings of this promoter have shown that a number of potential SP-1 and C/EBP response elements are constitutively occupied in the entire quail neuroretina of E5 and E14, whereas the two consensus palindromic E2F binding sites are only protected at E5. This suggests that these E2F elements participate in down-regulation of E2F-1 gene expression during avian neuroretina development. CAT reporter assays have shown that E2F-1 in association with its partner DP-1 transactivates its own promoter, whereas p105Rb inhibits the E2F-1 promoter. Both E2F-1/DP-1 and p105Rh require the presence of the E2F binding sites to mediate their effects. However, experiments performed with deletion mutants of the promoter strongly suggest that other regions located upstream of the E2F binding sites also mediate part of the E2F-1 transactivating effect on its own promoter. Altogether, these results suggest that the down-regulation of E2F-1 gene expression in differentiating neurons could be due, in part, to the E2F/Rb complexes binding to the E2F-1 promoter.

Regulation of cdc2 gene expression by the upstream stimulatory factors (USFs).

cdc2 gene expression is under the control of multiple factors. Although E2F/DP proteins have been reported to play a central role, they cannot account for all aspects of the fine modulation of cdc2 gene expression during cell cycle and embryonic development. To characterize the transcription factors that control cdc2 gene expression during nerve cell differentiation in avians, we have previously cloned the quail cdc2 gene promoter region. We had identified an octamer (CAGGTGGC) containing an E-box, which has important activity in regulating cdc2 transcription. Using in vivo genomic footprinting experiments, we show here that this motif, currently named IG, is the target of binding proteins at different stages of neuroretina development, confirming its importance as a regulatory response element for cdc2 gene expression. A subset of Helix-Loop-Helix family of transcription factors, known as Upstream Stimulatory Factors (USFs) specifically bind to this sequence as dimers. Moreover, our results indicate that USFs transactivate the promoter of cdc2 via the IG motif. These data may help to better understand the mechanisms that control cell division in differentiating nerve cells.

Overexpression of avian or mouse c-jun in primary chick embryo fibroblasts confers a partially transformed phenotype.

The coding sequences of avian (quail) or murine c-jun proto-oncogenes were introduced into a non-defective retroviral vector derived from Rous sarcoma virus (RSV) in which c-jun replaces v-src. Primary avian fibroblasts chronically infected with either one of these viruses exhibit some phenotypic traits characteristic of RSV-transformed cells, including sustained growth in low serum medium and ability to develop colonies from single cells in agar, even though they are still of normal morphology and contact inhibited. This altered growth control correlates with enhanced AP1-specific DNA binding activity as well as with higher levels of c-Jun products. Unexpectedly, repression of the endogenous c-Jun product is observed in cells overexpressing murine c-Jun. Cells expressing the avian and the murine c-Jun products display qualitatively similar phenotypes; nevertheless, for every transformed trait considered, the murine c-jun seemed more potent than its quail homologue. These data suggest that the avian or murine c-jun proto-oncogenes may trigger a subset of the 'transforming functions' normally induced by v-src, and which are more specifically related to growth in low serum and in the absence of solid support.

Serum factors and v-src control two complementary mitogenic pathways in quail neuroretinal cells in culture.

Quail neuroretinal cells (QNR cells) from 7-day-old embryos do not proliferate even in the presence of 8% fetal calf serum. After infection by the Rous sarcoma virus (RSV) they proliferate actively and exhibit a transformed phenotype; this effect is mediated by the oncoprotein pp60v-src. Secondary cultures infected by the thermosensitive strain tsNY68 of RSV are blocked in G0 either by thermal inactivation of pp60v-src at 41.5 degrees C or by serum deprivation at the permissive temperature (36.5 degrees C). Cell division is reinduced either by pp60v-src thermal renaturation or by subsequent serum addition. Our results indicate that v-src and serum control two synergic pathways leading to G0/G1 transition in QNR cells. In order to characterize genes related to the mitogenic and transforming effects of v-src in nerve cells, we have constructed a cDNA library from QNR cells transformed by tsNY68. We report the properties of five molecular clones isolated by differential screening of this library. Unlike immediate-early genes like c-fos, they are induced in mid and late G1. Four of them correspond to unknown mRNAs and the last one codes for nucleolin. This set of v-src-regulated genes is likely to code for functions deficient in terminally differentiated QNR cells and necessary for the progression in G1.

Viral inhibition of apoptosis.

Viral propagation is limited both by the host immune response and by apoptosis of infected cells. Viruses circumvent apoptosis by different mechanisms: direct inhibition of particular proteases involved in cell death, stimulation of anti-death pathways or regulation of the activity of transcription factors monitoring cell survival.

DNA synthesis in a mitochondrial lysate of Xenopus laevis oocytes. H strand replication in vitro.

Conditions for efficient replication in vitro of mitochondrial DNA L strand into H strand products have been established. Gel electrophoresis and hybridization analyses of the products show that neosynthesized H strands are progressively elongated from the D-loop region, and some of them are synthesized as full-length molecules. Evidence for initiation of these H strands de novo is presented. In contrast, there is no detectable L strand synthesis in vitro in this system. This may prove useful for analyzing the distinct molecular mechanisms operating at OH and OL. Use of specific inhibitors indicates that DNA synthesis in the mitochondrial lysate in vitro requires DNA polymerase gamma. These observations support the conclusion that replication in vitro in this system closely resembles the first steps of mitochondrial DNA replication in vivo.

Backscattered speckle size as a function of polarization: influence of particle-size and- concentration.

This report about backscattering measure-ments of the speckle produced by strongly-scattering liquid media shows that the size of the backscattered speckle depends on scattering and anisotropy coefficients. These measurements were aimed at assessing the effects of polarization characteristics of the incident laser beam and of the scattered light on speckle size. The samples under study consisted of monodisperse polystyrene microspheres in solutions, mixtures of different sized-microspheres, milk, blood and pig skin. Such measurements of speckle size in polarization give information on strongly scattering media, allow their discrimination and enable one to characterize the undergone changes.

p34(cdc2) and mitotic cyclin expression in the developing quail neuroretina.

After an initial proliferation phase, neurons of the central nervous system (CNS) of higher eukaryotes remain postmitotic during their entire lifespan. This requires that a very stringent control be exerted on the cell division apparatus, whose molecular mechanisms remain quite elusive. Here we have used quail neuroretina as a model to study the control of cell division in the developing CNS. In vertebrates, embryonic neuroretinal cells (NR cells) stop their proliferation at different times depending on the cell type. Most NR cells in the quail embryo become postmitotic between E7 and E8. To acquire a better understanding of the molecular events leading to quiescence in NR cells, we have analyzed the expression of cdc2 and of two activators of p34(cdc2): cyclin A and cyclin B2 in the developing neuroretina. We report that these three proteins are downregulated between E7 and E9, suggesting that a common mechanism could block their transcription in differentiating neurons. We also report, using an immunohistochemical approach, that p34(cdc2) downregulation is correlated with the appearance of the microtubule-associated protein tau. These results strongly suggest that inhibition of cdc2 gene expression is closely linked to the achievement of terminal differentiation in neurons. However, we also show that postmitotic ganglion cells precursors begin to synthesize the early neuronal differentiation marker beta3-tubulin while p34(cdc2) is still detectable in these cells, suggesting that p34(cdc2) or a closely related kinase could play a role in some "young" postmitotic neurons.