[Pseudoxanthoma elasticum-like papillary dermal elastolysis: A case report]. / Élastolyse du derme papillaire « pseudoxanthome élastique-like ¼ : un cas.

BACKGROUND: Pseudoxanthoma elasticum-like papillary dermal elastolysis (PXE-PDE) is a rare disease clinically resembling pseudoxanthoma elasticum (PXE). Herein we report a typical case. PATIENTS AND METHODS: A 77-year-old woman consulted for an acquired papular eruption present for 4 years. Her history included breast cancer, which was considered to be in remission. The eruption had begun on the right armpit before extending to the right side of the chest, left armpit, neck and right inguinal fold. It was completely asymptomatic. It consisted of non-follicular flabby, skin-colored papules, without anetoderma. Histological examination with hematoxylin-eosin and orcein staining revealed papillary and mid-dermal elastolysis without elastorrhexis. Based on the clinical aspect of PXE as well as histologically demonstrated elastolysis, a diagnosis of PXE-PDE was made. DISCUSSION: PXE-PDE is a rare acquired entity that affects only women, usually after the age of 60 years. Although it is clinically similar to PXE, PXE-PDE may be differentiated through its late onset, the absence of systemic symptoms, and the attendant histological features. Dermoscopy may also contribute to differential diagnosis. Histological examination allows confirmation of the diagnosis and shows normal elastic fibers that may be either missing or present in vastly reduced quantities in the papillary and mid-dermis. The physiopathology continues to be unclear, but may involve skin aging, elastogenesis abnormalities and UV exposure. To date, no treatment has demonstrated its efficiency. CONCLUSION: PXE-PDE is a rare condition, but it displays typical histological and clinical features. Knowledge of this entity avoids unnecessary explorations and enables rapid reassurance of patients.

Oxygen profile and clogging in vertical flow sand filters for on-site wastewater treatment.

13 million people (about 20% of the population) use on-site wastewater treatment in France. Buried vertical sand filters are often built, especially when the soil permeability is not sufficient for septic tank effluent infiltration in undisturbed soil. Clogging is one of the main problems deteriorating the operation of vertical flow filters for wastewater treatment. The extent of clogging is not easily assessed, especially in buried vertical flow sand filters. We suggest examining two possible ways of detecting early clogging: (1) NH4-N/NO3-N outlet concentration ratio, and (2) oxygen measurement within the porous media. Two pilot-scale filters were equipped with probes for oxygen concentration measurements and samples were taken at different depths for pollutant characterization. Influent and effluent grab-samples were taken three times a week. The systems were operated using batch-feeding of septic tank effluent. Qualitative description of oxygen transfer processes under unclogged and clogged conditions is presented. NH4-N outlet concentration appears to be useless for early clogging detection. However, NO3-N outlet concentration and oxygen content allows us to diagnose the early clogging of the system.

Modelling aerobic biodegradation in vertical flow sand filters: impact of operational considerations on oxygen transfer and bacterial activity.

Oxygen renewal, as a prominent phenomenon for aerobic bacterial activity, deeply impacts Vertical Flow Constructed Wetland (VFCW) treatment efficiency. We introduce a multiphase model able to simulate multi-component transfer in VFCWs. It is based on a two-phase flow module, and a transport module. The flow module can quantify both water and air velocities throughout the filter during operation. The reactive transport module follows dissolved and gaseous oxygen concentrations, and the transport of solutes such as ammonium and readily biodegradable COD (Chemical Oxygen Demand). The consumption of components is governed by Monod-type kinetics. Heterotrophic and autotrophic bacteria, which are responsible for COD and ammonium degradation respectively, are part of the model components. The kinetics are based on the Constructed Wetlands Model 1. The results from the simulation tool were compared with existing experimental data, and two kinds of operation with VFCWs were investigated. The authors show strong interplay between oxygen renewal and bacterial consumption in case of sequential batch feeding with transient flooding of surface. Oxygen renewal is essentially convection mediated in such operation, while convection is not significant in non-flooding operation. Simulated bacterial patterns are impacted by the operation, both quantitatively and spatially. From a modelling point of view, the authors highlight some limitations of the biological model: the description of bacterial lysis processes needs to be enhanced, as well as ammonium adsorption to organic matter.

Diphasic transfer of oxygen in vertical flow filters: a modelling approach.

Oxygen renewal, as a prominent phenomenon for aerobic bacterial activity, deeply impacts vertical flow constructed wetland (VFCW) treatment efficiency. The authors introduce a multiphase model able to simulate oxygen transfer in VFCWs. It is based on a two-phase flow module, and a transport module. The transport module is able to deal with convection/diffusion phenomena, inter-phase (air-water) mass exchange, and first-order kinetics. The first results displayed for the air phase allow us to draw the following ideas on the design of vertical filters. The ponding phenomenon is more efficient for oxygen renewal than non-ponding batch loading: it provides a higher value, sooner, and deeper in the filter. In non-colonised filters and for standard batch loading, oxygen convection in the air phase is predominant for oxygen renewal. The seepage front limits oxygen renewal through the bottom of the filter and leads to an insufficient oxygen concentration on the lowest part of the filter.

TP63 P2 promoter functional analysis identifies ß-catenin as a key regulator of ΔNp63 expression.

The ΔNp63 protein, a product of the TP63 gene that lacks the N-terminal domain, has a critical role in the maintenance of self renewal and progenitor capacity in several types of epithelial tissues. ΔNp63 is frequently overexpressed in squamous cell carcinoma (SCC) and in some other epithelial tumours. This overexpression may contribute to tumour progression through dominant-negative effects on the transcriptionally active (TA) isoforms of the p53 family (TAp63, TAp73 and p53), as well as through independent mechanisms. However, the molecular basis of ΔNp63 overexpression is not fully understood. Here, we show that the expression of ΔNp63 is regulated by the Wnt/ß-catenin pathway in human hepatocellular carcinoma (HCC) and SCC cell lines. This regulation operates in particular through TCF/LEF sites present in the P2 promoter of TP63. In addition, we show that ΔNp63 and ß-catenin are frequently coexpressed and accumulated in oesophageal SCC, but not in HCC. These results suggest that activation of the ß-catenin pathway may contribute to overexpression of ΔNp63 during tumour progression, in a cell type-specific manner.

Somatic mutation databases as tools for molecular epidemiology and molecular pathology of cancer: proposed guidelines for improving data collection, distribution, and integration.

There are currently less than 40 locus-specific databases (LSDBs) and one large general database that curate data on somatic mutations in human cancer genes. These databases have different scope and use different annotation standards and database systems, resulting in duplicated efforts in data curation, and making it difficult for users to find clear and consistent information. As data related to somatic mutations are generated at an increasing pace it is urgent to create a framework for improving the collecting of this information and making it more accessible to clinicians, scientists, and epidemiologists to facilitate research on biomarkers. Here we propose a data flow for improving the connectivity between existing databases and we provide practical guidelines for data reporting, database contents, and annotation standards. These proposals are based on common standards recommended by the Human Genome Variation Society (HGVS) with additions related to specific requirements of somatic mutations in cancer. Indeed, somatic mutations may be used in molecular pathology and clinical studies to characterize tumor types, help treatment choice, predict response to treatment and patient outcome, or in epidemiological studies as markers for tumor etiology or exposure assessment. Thus, specific annotations are required to cover these diverse research topics. This initiative is meant to promote collaboration and discussion on these issues and the development of adequate resources that would avoid the loss of extremely valuable information generated by years of basic and clinical research.

Recent advances in p53 research: an interdisciplinary perspective.

The TP53 gene is one of the most studied genes in human cancer. In recent years, considerable interest was focused on mutant p53, the abnormal protein product of TP53 somatic or germline alleles with missense mutations that often accumulate in cancer cells. There is now compelling experimental evidence that many mutations can exert mutant-specific, gain-of-function effects by perturbing the regulation of expression of multiple genes. This notion is supported by the observation that targeted mutant p53 expression enhances the formation of specific cancers in the mouse even in the absence of wild-type p53 expression. In addition, clinical studies are producing a wealth of functional pathway data demonstrating correlations between specific TP53 mutations and gene expression patterns identified by transcriptome studies. These correlations imply that alteration of p53 function is critical in shaping gene expression patterns in cancer. Finally, progress is being made in the development of new therapeutic approaches targeting p53 alterations. Key advances regarding the structural, biochemical and functional properties of normal and mutant p53 proteins, their abnormal regulation and distribution in human cancers, and their associations with clinical and pathological cancer characteristics are reviewed. New opportunities for translational research for improving cancer detection, prognosis, prevention and therapy based upon the integration of this knowledge are described.

Properties of the six isoforms of p63: p53-like regulation in response to genotoxic stress and cross talk with DeltaNp73.

TP63, a member of the TP53 gene family, encodes two groups of three isoforms (alpha, beta and gamma). The TAp63 isoforms act as transcription factors. The DeltaNp63 isoforms lack the main transcription activation domain and act as dominant-negative inhibitors of transactivation (TA) isoforms. To clarify the role of these isoforms and to better understand their functional overlap with p53, we ectopically expressed each p63 isoform in the p53-null hepatocellular carcinoma cell line Hep3B. All TA isoforms, as well as DeltaNp63alpha, had a half-life of <1 h when transiently expressed and were degraded by the proteasome pathway. The most stable form was DeltaNp63gamma, with a half-life of >8 h. As expected, TA isoforms differed in their transcriptional activities toward genes regulated by p53, TAp63gamma being the most active form. In contrast, DeltaNp63 isoforms were transcriptionally inactive on genes studied and inhibited TA isoforms in a dose-dependent manner. When stably expressed in polyclonal cell populations, TAp63beta and gamma isoforms were undetectable. However, when treated with doxorubicin (DOX), p63 proteins rapidly accumulated in the cells. This stabilization was associated with an increase in phosphorylation. Strikingly, in DOX-treated polyclonal populations, increase in TAp63 levels was accompanied by overexpression of DeltaNp73. This observation suggests complex regulatory cross talks between the different isoforms of the p53 family. In conclusion, p63 exhibits several transcriptional and stress-response properties similar to those of p53, suggesting that p63 activities should be taken into consideration in approaches to improve cancer therapies based on genotoxic agents.

Comparison of AMPLICOR and Hybrid Capture II assays for high risk HPV detection in normal and abnormal liquid-based cytology: use of INNO-LiPA Genotyping assay to screen the discordant results.

The study was aimed to evaluate the feasibility of detecting human papillomavirus (HPV) in women with normal or abnormal cervical smears using the Roche Amplicor MWP HPV Test. We compared by AMPLICOR Test and Hybrid Capture II (HCII) Test, the prevalence of HR-HPV in 470 cervical samples including 55 samples with WNL cytology, 208 ASC-US, 193 LGSIL and 14 HGSIL. Samples with discordant results were retested with INNO-LiPA Genotyping HPV Test v2. The HR-HPV positivity in WNL cytology samples was similar (21.8%) by AMPLICOR and HCII. In ASC-US, the HPV positivity was 42.3% by both tests. In LGSIL, HPV positivity was 66.3% and 66.8% by AMPLICOR and HCII, respectively. In HGSIL, 92.8% of samples were positive by AMPLICOR and 85.7% by HCII. The agreement of both tests was 96.2% with a Kappa value of 0.92. Eighteen cases were discordant: 9 HCII positive/AMPLICOR negative and 9 HCII negative/AMPLICOR positive. The INNO-LiPA test revealed HPV positivity in every case. Interestingly, all HCII+/AMPLICOR- samples were found to harbour HPV53. As for the HCII-/AMPLICOR+ samples, 8 demonstrated a multiple infection with HR 16- and/or 18- and/or 56-phylogenetically related HPV types. Moreover, two of these samples were co-infected with HPV6 and two other with HPV54. By using consensus HR-HPV as our reference HPV positivity, the sensitivity (96.6%) and specificity (100%) of AMPLICOR was similar to that of HCII Test. The AMPLICOR HPV Test is sensitive, specific, feasible and appropriate for routine HPV detection.

Control of sigma virus multiplication by the ref(2)P gene of Drosophila melanogaster: an in vivo study of the PB1 domain of Ref(2)P.

Ref(2)P has been described as one of the Drosophila proteins that interacts with the sigma virus cycle. We generated alleles to identify critical residues involved in the restrictive (inhibiting viral multiplication) or permissive (allowing viral multiplication) character of Ref(2)P. We demonstrate that permissive alleles increase the ability of the sigma virus to infect Drosophila when compared to null alleles and we confirm that restrictive alleles decrease this capacity. Moreover, we have created alleles unfunctional in viral cycling while functional for Ref(2)P fly functions. This type of allele had never been observed before and shows that fly- and virus-related activities of Ref(2)P are separable. The viral status of Ref(2)P variants is determined by the amino-terminal PB1 domain polymorphism. In addition, an isolated PB1 domain mimics virus-related functions even if it is similar to a loss of function toward fly-related activities. The evolutionary tree of the Ref(2)P PB1 domain that we could build on the basis of the natural allele sequences is in agreement with an evolution of PB1 domain due to successive transient selection waves.

TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes.

A large amount of data is available on the functional impact of missense mutations in TP53 and on mutation patterns in many different cancers. New data on mutant p53 protein function, cancer phenotype and prognosis have recently been integrated in the International Agency for Research on Cancer TP53 database (http://www-p53.iarc.fr/). Based on these data, we summarize here current knowledge on the respective roles of mutagenesis and biological selection of mutations with specific functional characteristic in shaping the patterns and phenotypes of mutations observed in human cancers. The main conclusion is that intrinsic mutagenicity rates, loss of transactivation activities, and to a lesser extent, dominant-negative activities are the main driving forces that determine TP53 mutation patterns and influence tumor phenotype. In contrast, current experimental data on the acquisition of oncogenic activities (gain of function) by p53 mutants are too scarce and heterogenous to assess whether this property has an impact on tumor development and outcome. In the case of inherited TP53 mutations causing Li-Fraumeni and related syndromes, the age at onset of some tumor types is in direct relation with the degree of loss of transactivation capacity of missense mutations. Finally, studies on large case series demonstrate that TP53 mutations are independent markers of bad prognosis in breast and several other cancers, and that the exact type and position of the mutation influences disease outcome. Further studies are needed to determine how TP53 haplotypes or loss of alleles interact with mutations to modulate their impact on cancer development and prognosis.

Genetic and molecular features of Su(P), a gene that interacts with ref(2)P in male fertility of Drosophila melanogaster.

The ref(2)P gene is involved in the control of sigma rhabdovirus multiplication in Drosophila melanogaster. ref(2)P activity is also necessary for male fertility. However, in one-third of laboratory strains tested, males that lacked ref(2)P activity were fertile. In all such strains studied, the male sterility phenotype was abolished due to the presence of a particular allele at the Su(P) locus, at 73B1-2. These spontaneous suppressor alleles were dominant. We were able to induce dominant suppressor alleles at the Su(P) locus by X-ray mutagenesis and hybrid dysgenesis, suggesting that null alleles of Su(P) confer the dominant suppressor phenotype. The Su(P) gene was cloned by P element tagging. The P element-tagged alleles identified a Su(P) transcript as a 1.4-kb mRNA produced in the soma of both males and females, which is also abundant in ovaries.

[A proposal for a method of reporting cervico-uterine smears]. / Proposition de méthode de réponse des frottis cervico-utérins.

A method for reporting Papsmears is proposed. Paperwork is limited to choosing a few codes on a working list prepared according to the Bethesda system and the ADICAP coding system. The method is easy to use. It reduces the work load of time for cytologists and secretaries. It allows harmonization and structurization of the look and the filling of reports for Papsmears. It may be easily adapted for vaginal smears. It leads to a report complete and adapted to the Bethesda system. It gives the possibility of adding comments and additional codes. It avoids most mistakes about öbligatory codes. It makes easier to perform statistical evaluation and to initiate a quality control program.

[Participation of women in cervical cancer screening. Results of the first 5 years of a pilot program in the province of Doubs]. / Participation féminine au dépistage des cancers du col de l'utérus. Résultats des 5 premières années du programme pilote du département du Doubs.

OBJECTIVE: To analyze women participation and test results during the 1993 to 1997 screening cycle. METHODS: The program was managed by a multidisciplinary health professional committee who determined the screening policy according to the recommendations of the French consensus (Lille 1990). All smears and cervical histological tests taken from women living in the area were collected by centralizing data from cytopathological laboratories. RESULTS: Within five years, 71% of women in the 20-65 years age group had at least one smear. After the age of 29, participation rate decreased with age. The prevalence of unsatisfactory smears was 1.4/1000 and 3% of screened women had an abnormal smear (squamous intraepithelial lesion or carcinoma). A follow-up test was registered for 83% of women with an abnormal smear. Lesions were confirmed by histology in 77% of women with a histological test. CONCLUSION: In the context of initiating a national screening program, our study shows that implementing women invitation and follow-up and quality control procedures are necessary to improve the results of ongoing cervical cancer screening.

[False negatives and quality assurance in cervico-uterine cytology]. / Faux négatifs et assurance de qualité en cytologie cervico-utérine. A l'occasion d'une relecture à partir de 522 lésions histologiques.

Determining the false negative rate of cervical smear interpretation is an important part of quality assessment and a necessary step for any improvement program. We report our experience of negative smear rescreening of 522 histologically proven high-grade lesions or cancers, over a 5 to 7 year preceding period. False negative rate was 6.88% as calculated with a narrow definition of error, i.e. intra-epithelial lesions and atypical squamous cells of undetermined significance. It was 10.78% as calculated with a broad definition of error, including minor anomalies such as repair and parakeratosis. Bibliographic data account for 0 to 94% false negative diagnoses, owing to great disparities in calculating the false negative rate as well as in rescreening. However, a 10% traditionally calculated and standardised false negative rate is a reasonable and achievable goal in a view of quality improvement. Systematic random rescreening of 10% of negative smears is ineffective.

The duplicated Saccharomyces cerevisiae gene SSM1 encodes a eucaryotic homolog of the eubacterial and archaebacterial L1 ribosomal proteins.

A previously unknown Saccharomyces cerevisiae gene, SSM1a, was isolated by screening for high-copy-number suppressors of thermosensitive mutations in the RNA14 gene, which encodes a component from the polyadenylation complex. The SSM1 a gene codes for a 217-amino-acid protein, Ssm1p, which is significantly homologous to eubacterial and archaebacterial ribosomal proteins of the L1 family. Comparison of the Ssm1p amino acid sequence with that of eucaryotic polypeptides with unknown functions reveals that Ssm1p is the prototype of a new eucaryotic protein family. Biochemical analysis shows that Ssm1p is a structural protein that forms part of the largest 60S ribosomal subunit, which does not exist in a pool of free proteins. SSM1 a is duplicated. The second gene copy, SSM1b, is functional and codes for an identical and functionally interchangeable Ssm1p protein. In wild-type cells, SSM1b transcripts accumulate to twice the level of SSM1a transcripts, suggesting that SSM1b is responsible for the majority of the Ssm1p pool. Haploid cells lacking both SSM1 genes are inviable, demonstrating that, in contrast with its Escherichia coli homolog, Ssm1p is an essential ribosomal protein. Deletion of the most expressed SSM1b gene leads to a severe decrease in the level of SSM1 transcript, associated with a reduced growth rate. Polysome profile analysis suggests that the primary defect caused by the depletion in Ssm1p is at the level of translation initiation.

Localization of domains within the Drosophila Ref(2)P protein involved in the intracellular control of sigma rhabdovirus multiplication.

The ref(2)P gene of Drosophila melanogaster interferes with sigma rhabdovirus multiplication. This gene is highly variable, and the different alleles are considered permissive or restrictive according to their effects on virus replication. In all cases, the mechanisms involve intracellular interactions between the sigma virus and Ref(2)P proteins. We showed that the N-terminal domain of the Ref(2)P protein was required for its activity in vivo. The protein was inactive in the null p(od)2 mutant when its first 82 amino acids were deleted. The p delta n gene was constructed so that the first 91 amino acids coded for by the restrictive alleles could be expressed in vivo. It was active in a transformed line. This sequence was sufficient to impart a restrictive phenotype to an adult D. melanogaster fly after it was injected with the virus. However, the truncated protein expressed by p delta n did not have an effect on the hereditary transmission of the sigma virus to the offspring of the infected flies, even though it contained the restriction site. The native Ref(2)P protein has been previously shown to have conformation-dependent epitopes common with some of those of the viral N protein. We demonstrated the following. (i) These epitopes were found in a domain of the Ref(2)P protein distinct from the site involved in restriction. (ii) They were modified in the N protein of the haP7 sigma virus mutant selected as being adapted to the restrictive alleles of the ref(2)P gene; only one mutation in the N gene, leading to an amino acid substitution, distinguished the haP7 mutant from the original virus. (iii) The virus strains partially or totally adapted to the effects of the full restrictive protein expressed by pp were always found to multiply to a lesser extent in the presence of the protein expressed by p delta n. These data suggest that two distinct domains of the Ref(2)P protein are involved in the control of sigma virus multiplication.

Pharmacopee comorienne : approches ethnobotaniques et chimiques

Cette approche porte sur 13 plantes utilisees dans la pharmacopee comorienne; dans des pays limitrophes et meme aux Antilles. Elles ont ete recoltees; identifiees et mises en herbier au CNDRS (Centre de Documentation et de la Recherche Scientifique). les pincipaux constituants ont fait l'objet d'un criblage chimique et il s'en est suivi un debut de discussion en fonction des donnees de la litterature