Lack of human-relevant adversity of MOSH retained in tissues: Analysis of adversity and implications for regulatory assessment.

Mineral oils (food grade white oil or liquid paraffin) have historically been safely used in a number of sensitive end-uses, including pharmaceutical, cosmetic and food. Recent concern that certain mineral hydrocarbons (branched and cyclo-alkanes) may accumulate in human tissues has prevented European Food Safety Authority (EFSA) from deriving guidance values for food exposures. Analysis of human and animal tissue indicate that an unresolved cloud of mostly highly branched alkanes and alkylated cycloalkanes within the C20-C35 range is consistently present in all tissues. This critical review thoroughly assesses the retention of "mineral oil saturated hydrocarbons" (MOSH) in human and animal tissues and evaluates if the presence of MOSH is considered adverse and appropriate to use for risk assessment, generation of guidance values for food exposure and/or generation of derivation of health-based guidance values. An adversity framework was utilized to perform an in-depth weight of the evidence analysis, and it was concluded that mere presence of MOSH does not translate to hazard identification, and is not considered adverse. In light of this conclusion, it would not be appropriate to utilize this endpoint as the point of departure to calculate a health guidance value.

[Feasibility of a psychoeducation group for patients with anorexia nervosa: An open study]. / Faisabilité d'un groupe de psychoéducation dans l'anorexie : une étude ouverte.

INTRODUCTION: Management of anorexia nervosa is difficult and few treatments have shown their effectiveness, justifying the exploration of new therapeutic approaches. Available evidence suggests an interest of psychoeducational groups in a significant number of psychiatric disorders. In patients suffering from anorexia, to date there are few groups or interventions available. We aimed to assess the feasibility and acceptability of a psycho-educational program promoting information about the disease and presenting techniques that can help to cope with anorexia and the functional impact it causes. The exploratory secondary objectives were to evaluate if such a group is associated with clinical improvement. METHOD: Twenty-seven patients suffering from anorexia nervosa, in three groups, received eight weekly interventions in addition to their usual care. The study was open-label and non-randomized. Patients were assessed three times (baseline, at the end of the group and three months later). The assessments were both qualitative (Eating Disorder Examination questionnaire, The Anorexia Nervosa Stage of Change Questionnaire, the Eating Disorders Quality of Life questionnaire, Work and Social Adjustment Scale) and qualitative. RESULTS: Seventy-eight percent of participants attended more than 75 % of the sessions. Seventy percent of participants found the group useful, and 95 % said it helped them improve their knowledge of the disease and its consequences. The average BMI of participants changed significantly with an average increase of 2.5kg between baseline and the three month assessment. There was an improvement of the eating disorders features in EDE-Q for the total score and for all subscores. The improvement in the total score was significant at the end of the group sessions, while the improvement in the sub scores became significant at three months. There was also a significant mood improvement at the end of the group. Finally, there was a significant improvement in daily functioning with a decrease in Work and Social Adjustment Scale scores and an improvement in quality of life. On qualitative assessment, patients were satisfied with the care proposal. They were able to appreciate the support and sharing of experience provided by the group formula. Most of them reported changes in their daily lives, either in their relationship to care and illness, or in their relationships with their loved ones, their leisure/work, their mood or their eating behavior. CONCLUSION: Both qualitative and quantitative results suggest that this group psychoeducation program is feasible and well accepted by patients in addition to usual management. Although the methodology does not allow any conclusions, the clinical improvements observed during the group are encouraging with regard to the safety of this type of intervention and its possible effectiveness and argue for a controlled study.

[T-cell prolymphocytic leukemia: potential diagnostic pitfalls]. / Leucémie prolymphocytaire T : un piège diagnostique à connaître.

BACKGROUND: Sezary syndrome (SS) presents clinically as erythroderma, which may be pigmented, and pruritic, associated with peripheral lymphadenopathies. Erythroderma may also occur in a broad range of reactive and malignant conditions including T-cell prolymphocytic leukemia (T-PLL). We report a case initially diagnosed as SS but ultimately diagnosed as T-PLL based upon skin involvement. CASE REPORT: A 70-year-old man was referred by his hematologist for management of SS. Physical examination revealed lymphadenopathies and mild diffuse erythema without infiltration. His WBC count was elevated at 8.3 G/L. A peripheral blood smear showed Sezary-like cells. Flow cytometry of peripheral blood revealed prolymphocytic T-cells staining positively for CD2, CD3, CD4 and CD7. Cytogenetic studies showed chromosomal abnormalities in terms of number and structure with missing chromosomes 6 and13, as well as deletion of chromosome 17. Finally, a diagnosis of T-PLL was made. Pentostatin was initiated pending treatment with alemtuzumab, but the patient's overall condition deteriorated rapidly and he died 10 days later. DISCUSSION: Diagnosis of LPLT is based upon a number of factors. In the case presented herein, the clinically atypical nature of the skin lesions prompted the dermatologist to review the diagnosis. The morphology of the circulating T-lymphocytes and their immunologic and phenotypic characteristics finally ruled out the diagnosis of Sezary syndrome, while their association with compatible cytogenetic anomalies enabled a diagnosis of prolymphocytic leukemia to be made instead. CONCLUSION: Prolymphocytic leukemia involves complex differential diagnosis with regard to Sezary syndrome, posing potential pitfalls for hematologists and dermatologists.

Acquired factor V inhibitor: Success of steroids in a patient with primary sclerosing cholangitis, ulcero haemorragic rectocolitis, biological Biermer's disease.

We report the case of a 43-years-old Turkish man with acquired deficiency of factor V (FV) diagnosed in a usual screening before a (recto) colonoscopy. In the biologic explorations, activated partial prothrombin time (APTT) was abnormally high and prothrombin time (PT) was low 18IU/dL with no anticoagulant drugs (the PT was normal 6 months ago). The controlled level of factor V was 3IU/dL with FV antibodies (9 Bethesda Units/mL). This patient had a previous history of primary sclerosing cholangitis (2000) and ulcero haemorrhagic rectocolitis (2002) and a fortuitous biological Biermer's disease was revealed. Corticosteroids were prescribed at 1mg/kg/day with decreasing during 6 months, patient had gradual regression of the caused bleeding and FV became greater than 90%, F V antibodies decreased to less than 0.7 Bethesda Units/mL. This case illustrates the presence of FV inhibitor in an autoimmune gastrointestinal context with regression of clinical (caused) signs and antibodies with corticosteroids.

Measuring the biological impact of drilling waste on the deep seafloor: An experimental challenge.

The depletion of traditional oil fields is driving the oil & gas industry to explore new exploitation sites previously considered as unprofitable. Deep-sea oil fields represent one of these new areas of exploitation. Well drilling during exploration and production operations generate large quantities of drilling waste whose biological impact on the deep-sea floor remains largely unknown. Because of the harsh abiotic factors characterizing this environment, the evaluation of this impact remains challenging. High hydrostatic pressure is the prominent factor which will affect in-situ biological processes. This review will examine the feedback on the various strategies used to evaluate the biological impact of deep-sea drilling waste deposition as well as the current technological limitations. Given the complexity of this issue, a good perspective strategy would be to trend towards the research and development of more relevant bioassays, especially considering the crucial factor of hydrostatic pressure.

Diagnosis and immediate treatment of acquired von Willebrand syndrome revealed by recurrent cerebral hemorrhage.

We report the case of a French woman with acquired von Willebrand syndrome who presents recurrent subarachnoid and intra-cerebral hemorrhage since 2012. She had no family or personal bleeding history. In the biologic explorations, APTT was abnormally high with no anticoagulant drugs (it was normal, historically). Two monoclonal IgG and IgM kappa proteins were detected without any lymphoproliferative disorder. Intravenous infusion of immunoglobulin is very effective in AVWS with immunoglobulin G monoclonal gammapathie of undetermined significance. We had a satisfactory correction of coagulation factors for about 30 days. The exploration of APTT is surely essential for the diagnosis and treatment.

The community effect, dorsalization and mesoderm induction.

The community effect is an interaction among muscle progenitor cells of amphibian gastrula, and is necessary for the initiation of muscle-specific gene expression. Dorsalization provides a signal that can convert ventral mesoderm cells to a muscle fate. Neither process involves mesoderm-inducing molecules. We suggest that the developmental significance of the community effect is to generate homogeneous but clearly demarcated groups of cells from progenitor cells arranged in a continuous gradient of developmental potential.

A two-step model for the fate determination of presumptive endodermal blastomeres in Xenopus embryos.

BACKGROUND: In Xenopus, the endoderm germ layer is derived from the vegetal blastomeres of cleavage-stage embryos. Cell transplantation experiments have revealed that the endodermal fate becomes gradually fixed during the late blastula stages. Sox17alpha, Mix.1, Mixer and GATA-4 encode vegetal zygotic transcription factors with endoderm-inducing activity. The accumulation of their transcripts during the late blastula stages may cause determination of the endodermal fate. VegT, a T-box transcription factor, the maternal transcripts of which are vegetally localised, is also required for endoderm formation. RESULTS: We analysed the events leading to the progressive accumulation of the transcripts for Sox17alpha, Mix.1, Mixer and GATA-4. Two phases could be distinguished in the endodermal programme. In phase 1, Sox17alpha, Mix.1, and the genes encoding transforming growth factor beta-related signalling molecules Xnr1, Xnr2 and Derrière were activated cell-autonomously at around the mid-blastula transition (MBT) by maternal determinants. In phase 2, TGFbeta signalling, possibly involving Xnr1, Xnr2 and Derrière, led to the activation of Mixer and GATA-4 in late blastula stages and to the reinforcement of the expression of Sox17alpha and Mix.1. Overexpression of VegT in animal caps triggered a developmental programme qualitatively similar to that observed in vegetal blastomeres, except that Xnr1 and GATA-4 were not activated by the early gastrula stage. CONCLUSIONS: Our results support a two-step model for endoderm determination between fertilisation and the onset of gastrulation. The initial cell-autonomous activation of early endodermal genes by maternal determinants including, but not limited to, VegT is relayed by the action of zygotic TGFbetas such as Xnr1, Xnr2 and Derrière.

Embryonic induction: is the Nieuwkoop centre a useful concept?

Regionalisation of the amphibian embryo is classically thought to involve induction by the Spemann organiser, itself induced by the Nieuwkoop centre. This model has now been extended to teleosts, with the identification of a gene that appears to define the zebrafish equivalent of the Nieuwkoop centre.

Developmental signalling: a careful balancing act.

Embryos of arthropods and chordates are patterned along the dorso-ventral axis by a gradient of secreted morphogens of the Bmp4/Dpp family. This gradient now appears to be shaped by the opposing activities of Bmp-sequestering proteins, on the one hand, and Bmp-releasing metalloproteases, on the other.

The vertebrate organizer: structure and molecules.

Since the identification of the first organizer gene, goosecoid, more than 15 organizer-specific genes have been characterized. Here, we present our current understanding of the roles of these molecules in amphibians fish and amniotes and show how there identification has confirmed Spemann's original proposition that the vertebrate organizer is subdivided into separate domains: the head, trunk and tail organizers.

Characterization of a mouse multigene family that encodes zinc finger structures.

The Drosophila segmentation gene Krüppel encodes multiple tandemly repeated units predicted to form DNA-binding zinc fingers. We have isolated 23 bacteriophages, containing nonoverlapping inserts from a mouse genomic DNA library, on the basis of cross-hybridization under nonstringent conditions to a probe corresponding to the Krüppel finger region. Nucleotide sequence analysis of six phage DNAs indicated that they all contained regions with similarity to Krüppel and potentially encoded zinc finger domains. Within these regions, the level of similarity to Krüppel was particularly high between successive fingers. Northern (RNA) blotting analysis suggested that the mouse sequences belonged to different genes, the expression of some of which was modulated during cell differentiation and development. Hybridization experiments suggested that the similarity between some of the genes extended outside of the finger regions. In conclusion, our data suggest that the mouse genome contains a large family of evolutionarily related genes encoding possible trans-acting factors. These genes are likely to play a regulatory role at the transcriptional level.

The serum-inducible mouse gene Krox-24 encodes a sequence-specific transcriptional activator.

The mouse gene Krox-24 is transiently activated during cell cycle reentry. It encodes a protein with three zinc fingers similar to those of the transcription factor Sp1. Here we present a biochemical characterization of the gene products. Krox-24 mRNA is translated into two proteins of 82 and 88 kilodaltons, designated p82Krox-24 and p88Krox-24, respectively. p82Krox-24 is initiated at the first AUG codon of the open reading frame, whereas synthesis of p88Krox-24 starts at a non-AUG codon located upstream. Both proteins were synthesized in HeLa cells infected with recombinant vaccinia viruses expressing Krox-24 cDNAs. Under these conditions, they were found phosphorylated on serine residues and glycosylated. The availability of the proteins made possible the determination of the DNA recognition sequence. In vitro, Krox-24 bound specifically to the sequence 5'-GCG(C/G)GGGCG-3'. This sequence is similar but not identical to the Sp1 target sequence. Insertion of an oligomer for the binding site in cis, close to the herpes simplex virus thymidine kinase promoter, rendered this promoter responsive to Krox-24. Krox-24 is therefore a sequence-specific transcriptional activator. Krox-24-binding sites were found upstream of several serum-inducible genes, raising the possibility that Krox-24 is involved in the regulation of these genes.

Final height and gonad function after total body irradiation during childhood.

Short stature and gonad failure can be a side effect of total body irradiation (TBI). The purpose of the study was to evaluate the factors influencing final height and gonad function after TBI. Fifty young adults given TBI during childhood were included. Twenty-seven had been treated with growth hormone (GH). Those given single 10 Grays (Gy) or fractionated 12 Gy TBI had similar characteristics, GH peaks, final heights and gonad function. After the end of GH treatment, 11/20 patients evaluated had GH peak >10 microg/l. Final height was <-2s.d. in 29 (58%). The height loss between TBI and final height (2.4+/-1.1 s.d.) was greater in those who were younger when irradiated (P<0.0001). When the GH-treated and -untreated patients were analyzed separately, this loss was correlated with the age at TBI at 4-8 years for the GH-treated and at 6-8 years for the untreated. Boys showed negative correlations between testicular volume and plasma follicle-stimulating hormone (FSH, P=0.0008) and between plasma FSH and inhibin B (P=0.005) concentrations. We concluded that the indications for GH treatment should be mainly based on the age at irradiation, taking into account the GH peak. The plasma FSH and inhibin B concentrations may predict sperm function.

Age-related changes in strategic variations during arithmetic problem solving: The role of executive control.

In this review, we provide an overview of how age-related changes in executive control influence aging effects in arithmetic processing. More specifically, we consider the role of executive control in strategic variations with age during arithmetic problem solving. Previous studies found that age-related differences in arithmetic performance are associated with strategic variations. That is, when they accomplish arithmetic problem-solving tasks, older adults use fewer strategies than young adults, use strategies in different proportions, and select and execute strategies less efficiently. Here, we review recent evidence, suggesting that age-related changes in inhibition, cognitive flexibility, and working memory processes underlie age-related changes in strategic variations during arithmetic problem solving. We discuss both behavioral and neural mechanisms underlying age-related changes in these executive control processes.

Assessing chronic fish health: An application to a case of an acute exposure to chemically treated crude oil.

Human alteration of marine ecosystems is substantial and growing. Yet, no adequate methodology exists that provides reliable predictions of how environmental degradation will affect these ecosystems at a relevant level of biological organization. The primary objective of this study was to develop a methodology to evaluate a fish's capacity to face a well-established environmental challenge, an exposure to chemically dispersed oil, and characterize the long-term consequences. Therefore, we applied high-throughput, non-lethal challenge tests to assess hypoxia tolerance, temperature susceptibility and maximal swimming speed as proxies for a fish's functional integrity. These whole animal challenge tests were implemented before (1 month) and after (1 month) juvenile European sea bass (Dicentrarchus labrax) had been acutely exposed (48h) to a mixture containing 0.08gL(-1) of weathered Arabian light crude oil plus 4% dispersant (Corexit© EC9500A), a realistic exposure concentration during an oil spill. In addition, experimental populations were then transferred into semi-natural tidal mesocosm ponds and correlates of Darwinian fitness (growth and survival) were monitored over a period of 4 months. Our results revealed that fish acutely exposed to chemically dispersed oil remained impaired in terms of their hypoxia tolerance and swimming performance, but not in temperature susceptibility for 1 month post-exposure. Nevertheless, these functional impairments had no subsequent ecological consequences under mildly selective environmental conditions since growth and survival were not impacted during the mesocosm pond study. Furthermore, the earlier effects on fish performance were presumably temporary because re-testing the fish 10 months post-exposure revealed no significant residual effects on hypoxia tolerance, temperature susceptibility and maximal swimming speed. We propose that the functional proxies and correlates of Darwinian fitness used here provide a useful assessment tool for fish health in the marine environment.

Induction of anterior neural fates in the ascidian Ciona intestinalis.

The sensory vesicle of ascidians is thought to be homologous to the vertebrate forebrain and midbrain (Development 125 (1998) 1113). Here we report the isolation of two sensory vesicle markers in the ascidian Ciona intestinalis, which are homologs of vertebrate otx and gsx homeobox genes. By using these markers to analyze the induction of anterior neural tissue in Ciona, we find that the restriction of anterior neural fate to the progeny of the anterior animal blastomeres is due to a combination of two factors. The vegetal blastomeres show a differential inducing activity along the anterior-posterior axis, while the competence to respond to this inducing signal is markedly higher in the anterior animal blastomeres than in the posterior animal blastomeres. This differential competence to respond is also observed in response to bFGF, a candidate neural inducer in ascidians (J. Physiol. 511.2 (1998) 347) and can be detected by the gastrula stage. Our results, however, indicate that bFGF can only induce a subset of the responses of the endogenous inducer, suggesting that additional signals in the embryo are necessary to induce a fully patterned nervous system.

Siamois functions in the early blastula to induce Spemann's organiser.

In Xenopus, the Spemann organiser is defined as a dorsal territory in the early gastrula that initiates development of the embryonic axis. It has been shown that the early zygotic transcription factor Siamois is essential for Spemann's organiser formation. By the onset of gastrulation, the organiser is patterned into a vegetal head organiser, which induces anterior structures upon transplantation, and a more animal trunk organiser, which induces a posterior neuraxis. However, it is unclear when these distinct organiser domains are initially specified. To shed light on this question, we analysed the temporal activity of Siamois, as this factor induces both head and trunk development, when ectopically expressed via mRNA injection. In this study, we expressed Siamois ectopically at different time points and analysed the extent of axial development. Using a hormone-inducible version of Siamois, we found evidence for a tight window of competence during which ventral cells can respond to Siamois by commencing both the head and the trunk genetic programmes. The competence to form Spemann's organiser was lost 2 h before gastrulation, although partial axis formation could still occur following delayed activation of Siamois. We demonstrate that this late response to Siamois involves a new role for this gene, which can indirectly repress ventral gene expression, in the absence of known organiser genes.

The human chordin gene encodes several differentially expressed spliced variants with distinct BMP opposing activities.

During early embryogenesis of both vertebrates and invertebrates, antagonism between bone morphogenetic proteins (BMPs) and several unrelated secreted factors including Chordin (Chd) is a general mechanism by which the dorso-ventral axis is established. High affinity binding of Chd sequesters the BMP ligands in the extracellular space, preventing interactions with their membrane receptors. Another level of regulation consists in processing of vertebrate Chd or its Drosophila counterpart Sog by astacine metalloproteases like Xolloid-BMP-1/Tolloid, respectively, which releases an active BMP. Recently, it was shown that cleavage of Sog by Tolloid could generate novel BMP inhibitory activity and that sog is also capable of stimulation of BMP activity in a tolloid-dependant way. Activity and/or cleavage of Chd/Sog are influenced by other secreted factors like twisted gastrulation. In this study, we have cloned cDNAs of the human chordin gene (CHRD) and characterized alternative splice variants that code for C-truncated forms of the protein. We have found that CHRD is expressed in fetal as well as in adult tissues with relatively high levels in liver, cerebellum and female genital tract, suggesting functions in late embryogenesis and adult physiology. We also show that spliced variants are present with specific patterns in various tissues. When tested in an axis-duplication assay in Xenopus, we find that these variants can antagonize BMP activity. Altogether, these results suggest that, in addition to processing by metalloproteases, alternative splicing (AS) is another mechanism by which sub-products of CHRD can be generated to influence BMP activity in different developmental and physiological situations.

Antagonist activity of DWnt-4 and wingless in the Drosophila embryonic ventral ectoderm and in heterologous Xenopus assays.

Wnt genes encode secreted signalling molecules involved in a number of basic developmental processes. In Drosophila, wingless and DWnt-4 are two physically clustered Wnt genes, which are transcribed in overlapping patterns during embryogenesis and, in several instances, are controlled by the same regulatory molecules. To address the question of the functional relationship of wingless and DWnt-4, we analysed how embryonic cells respond when they are exposed, simultaneously or not, to the encoded Wnt signals. We show that DWnt-4 has the capacity to antagonise Wingless signalling both in the Drosophila ventral epidermis and in a heterologous system, the Xenopus embryo. We provide evidence that DWnt-4 inhibits the Wingless/Wnt-1 signalling pathway upstream of the activation of transcriptional targets. This is the first report that antagonising Wnt signals exist in Drosophila.