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Biomedical subjects

P Paul

Publications and source records attributed to P Paul.

At least 19 recordsLinked to original sources
PubMed2005

[NK cells: new insights on physiology and clinical implication in diseases].

INTRODUCTION: Natural killer cells are cytotoxic lymphocytes of innate immunity. These last ten years our knowledge about the mechanisms that regulates NK cell function has greatly improved. Our purpose is to present a review of these new acquisitions and their potential implications in human disease. CURRENT KNOWLEDGE AND KEY POINTS: NK cell function is regulated by a repertoire of NK cell receptors and is diversified by recognition of MHC class I by a multigenic and multi-allelic family of NK receptors. Analysis of NK cell repertoire has been used to investigate features that characterize NK cells in pathological situations. Apart from their direct cytotoxic potential to eliminate target cells, recently identification of mechanisms that control NK cell mediated cytokine production and cross talk with dendritic cells emphasize the role of NK cells in the regulation of acquired immune response. FUTURE PROSPECTS AND PROJECTS: These findings have lead to a better knowledge of the importance of the NK cells in several human diseases. It has been shown that NK cells are actors of the immunosurveillance of tumoral and infectious challenges. Allo or auto reactivity of the NK cell compartment have also been suggested in autoimmune diseases, infertility or foetal loss and transplantation. Ongoing research on NK cells in the fields of human diseases is increasing and will clarify the utility of the evaluation of the NK cell compartment and their receptors in clinical practice.

Animals↗
PubMed2004

Characterization of a new HLA-C allele: Cw*0719.

We describe a new human leukocyte antigen (HLA)-Cw*07 allele that differs from Cw*0718 by a single-coding nucleotide. DNA-based genotyping identified a clinical sample from a Black African-American patient that differed from known Cw alleles. The allele was amplified independently with a haplo-specific primer and sequenced in its entirety.

Exons↗
PubMed2003

Monocyte enrichment from leukapharesis products for the generation of DCs by plastic adherence, or by positive or negative selection.

BACKGROUND: DCs for use in immunotherapy are frequently generated from peripheral blood monocytes. However, there are different approaches to monocyte enrichment. METHOD: Plastic adherence is a widely used method for the enrichment of monocytes collected in a leukapheresis procedure. Alternatively,monocytes may be enriched by positive selection using magnetic beads coupled to CD14 Abs, or by cell depletion using beads coupled to Abs against CD2 and CD19 to remove non-monocytes. RESULTS: Positive selection resulted in the highest purity of immature DCs (97 +/- 1%), but in a low yield (8 +/- 3%). In contrast, depletion of non-monocytes gave a good yield (21 +/- 6%), but insufficient purity (42 +/- 10%). Conventional adherence procedures resulted in a good yield (25 +/- 5%) and reasonable purity (72 +/- 4%). All three monocyte enrichment procedures resulted in DCs that underwent maturation upon exposure to a combination of lipopolysaccharide and IFN-gamma. These DCs had a typical immune phenotype, they released similar amounts of IL-12, and had the capacity to support MLR. CONCLUSION: Our data provide a basis to choose a monocyte enrichment procedure that favors high purity or a high yield. However, if a manual open system suffices, plastic adherence is a reasonable alternative.

Antigens, Surface↗
PubMed2003

The effect of iron therapy on the growth of iron-replete and iron-deplete children.

This prospective, double-blind, placebo-controlled trial was designed to study the effect of iron therapy on the growth of iron-replete and iron-deficient children, and to study the change in iron status in iron-deficient children with iron therapy. One hundred and fifty children (aged 6-24 months) were included in the study. After an informed written consent, 100 healthy children, who were iron replete (group I) according to preset criteria, were randomly allocated to receive iron supplements 2 ng/kg/day (group IA) or placebo (group IB). Fifty iron-deficient children (group II) were administered iron syrup 6 mg/kg/day. Growth parameters (weight, length and head-circumference) and hematological parameters were studied for 4 months. Iron therapy, as compared with placebo, produced a significant improvement of mean monthly weight gain (p < 0.001) and linear growth (p < 0.001) in the iron-deficient children. However, it significantly decreased the weight gain (p < 0.001) and linear growth (p < 0.001) of iron-replete children. Caution should therefore be exercised while supplementing iron to children with apparently normal growth and when the iron status of the child is not known.

Anemia, Iron-Deficiency↗
PubMed2002

[General practitioners' practices and attitudes in regard to suicidal behavior].

As demonstrated at the recent Consensus Conference on the "suicidal crisis" held by the French Psychiatry Union and the National Agency for the Accreditation and the Evaluation of Care, suicide is recognised as a current public health problem. The general practitioner's role is situated on two levels: in a preliminary stage, the early identification of risk, and in a secondary stage, the provision of care at the time of a suicide attempt and then the provision of on-going follow-up care in partnership with other special services. The study aimed at evaluating general practitioners' practices when encountered with suicidal patients and assessing their management of suicidal behaviour, as well as difficulties met and their expectations. Responses to a questionnaire were received from 290 general practitioners in one regional department in France. The results revealed that two-thirds of the respondents considered the identification of suicidal tendencies as being difficult, in particular with regard to the detection of young people at risk. General hospitals are the most common structures where patients are referred to in the event of a suicide attempt, as a facility that is permanently open and capable of delivering ambulatory care. A majority of the general practitioners expressed the need for training which was focused on methods for the early identification of risk as well as the development of listening skills.

Aftercare↗
PubMed2001

Tumor-specific up-regulation of the nonclassical class I HLA-G antigen expression in renal carcinoma.

HLA-G is a nonclassical class I antigen mainly expressed at the maternofetal interface during pregnancy where it is thought to down-modulate maternal immune response against the semiallogeneic fetus. Recent studies indicate that ectopic up-regulation of HLA-G expression on melanoma cells may also favor their escape from antitumor immune response. HLA-G expression was here investigated on paraffin-embedded tumor and adjacent normal renal tissues of 18 renal cell carcinoma (RCC) patients. We provide evidence that HLA-G antigen is differentially expressed in carcinoma and normal renal cells and that up-regulation of this antigen in the tumor cells is more frequent than alterations of other MHC class I or class II antigens. We also demonstrated that HLA-G cell surface expression and secretion is maintained in a tumor cell line (DM) established from an HLA-G-positive RCC lesion. Furthermore, we show that type I (alpha and beta) and, in particular, type II (gamma) IFN treatment enhances steady-state mRNA levels and cell surface expression of HLA-G in the DM cell line. As several studies suggest that HLA-G displays various functional features that allow down-modulation of immune response in vitro, we propose that selective in vivo expression of HLA-G may participate in the impairment of antitumor immunity in RCC.

Adult↗
PubMed2001

Activation of p53 transcriptional activity requires ATM's kinase domain and multiple N-terminal serine residues of p53.

The ATM protein kinase regulates the cell's response to DNA damage by regulating cell cycle checkpoints and DNA repair. ATM phosphorylates several proteins involved in the DNA-damage response, including p53. We have examined the mechanism by which ATM regulates p53's transcriptional activity. Here, we demonstrate that reintroduction of ATM into AT cells restores the activation of p53 by the radio-mimetic agent bleomycin. Further, p53 activation is lost when a kinase inactive ATM is used, or if the N-terminal of ATM is deleted. In addition, AT cells stably expressing ATM showed decreased sensitivity to Ionizing Radiation-induced cell killing, whereas cells expressing kinase inactive ATM or N-terminally deleted ATM were indistinguishable from AT cells. Finally, single point-mutations of serines 15, 20, 33 or 37 did not individually block the ATM-dependent activation of p53 transcriptional activity by bleomycin. However, double mutations of either serines 15 and 20 or serines 33 and 37 blocked the ability of ATM to activate p53. Our results indicate that the N-terminal of ATM and ATM's kinase activity are required for activation of p53's transcriptional activity and restoration of normal sensitivity to DNA damage. In addition, activation of p53 by ATM requires multiple serine residues in p53's transactivation domain.

Antimetabolites, Antineoplastic↗
PubMed2001

HLA-G2, -G3, and -G4 isoforms expressed as nonmature cell surface glycoproteins inhibit NK and antigen-specific CTL cytolysis.

HLA-G is a nonclassical MHC class I molecule that plays a major role in maternal-fetal tolerance. Four membrane-bound (HLA-G1 to -G4) and two soluble (HLA-G5, and -G6) proteins are generated by alternative splicing. Only HLA-G1 has been extensively studied in terms of both expression and function. We provide evidence here that HLA-G2, -G3, and -G4 truncated isoforms reach the cell surface of transfected cells, as endoglycosidase H-sensitive glycoproteins, after a 2-h chase period. Moreover, cytotoxicity experiments show that these transfected cells are protected from the lytic activity of both innate (NK cells) and acquired (CTL) effectors. These findings highlight the immunomodulatory role that HLA-G2, -G3, and -G4 proteins will assume during physiologic or pathologic processes in which HLA-G1 expression is altered.

Adult↗
PubMed2001

Altered HLA-G transcription in pre-eclampsia is associated with allele specific inheritance: possible role of the HLA-G gene in susceptibility to the disease.

Pre-eclampsia is a disorder of human pregnancy occurring in 5-10% of all births, and represents the leading cause of infant morbidity and mortality and maternal death. In pre-eclampsia, invasion of fetal trophoblasts into maternal arteries during early pregnancy is shallow or absent. Here we examined the hypothesis that HLA-G, a non-classical class I HLA expressed in cytotrophoblasts, may act as a key gene in pre-eclampsia. We analysed HLA-G at the level of transcription and genotyped a silent CAC-CAT polymorphism in exon 3 and a 14-bp insertion/deletion in the 3' untranslated region. A deficit in levels of the HLA-G3 transcript was observed in mild pre-eclampsia compared to normal placentas. The distribution of HLA-G polymorphisms was different between normal and pre-eclampsia samples. A correlation between the alteration in transcription of the HLA-G gene and certain HLA-G genotypes was also observed. Thus we provide the first evidence for a possible role of HLA-G in genetic susceptibility to, and pathogenesis of pre-eclampsia.

Alleles↗
PubMed2001

Resolution of cis-trans ambiguities between HLA-DRB1 alleles using single-strand conformation polymorphisms and sequencing.

DNA-based typing of HLA alleles occasionally results in the inability to assign a specific allele because of ambiguity in associating two or more polymorphisms to the same or to alternate homologs (cis/trans ambiguity). Since most individuals are heterozygous at a given HLA locus, the highest level of confidence in definition is obtained when the alleles are tested in isolation. By using single-strand conformation polymorphisms (SSCP) to separate heterozygous HLA-DRB1 alleles, followed by sequencing of separated conformers, we have achieved resolution of previously ambiguous assignments without the need for additional probes or primers.

Alleles↗
PubMed2001

Knowledge of epidemiology and statistics for an ophthalmic practitioner.

Ophthalmologists are frequently confronted with treatment options that claim to be better than those currently in use. Statistically significant P values are invariably provided by way of proof. For many ophthalmologists a simple look at this revered P value is enough evidence that a statistically significant result has indeed been obtained. Unfortunately, traditional interpretation of a study based on the P value at an arbitrary cut-off (P<0.05 or any other value) limits the ability to fully appreciate clinical implications. In this article the authors introduce the reader to and illustrate the use of "confidence intervals" as opposed to P values in examining the applicability of study results. Further, what is statistically significant may not necessarily be clinically significant; perhaps not enough for the practitioner to change from the currently preferred method of treatment. To resolve this, the authors have also used common ophthalmic examples to introduce the "number needed to treat", as a simple clinical approach for the practising ophthalmologist wishing to assess the clinical significance of treatment options.

Clinical Trials as Topic↗
PubMed2000

A specific interferon (IFN)-stimulated response element of the distal HLA-G promoter binds IFN-regulatory factor 1 and mediates enhancement of this nonclassical class I gene by IFN-beta.

Type I interferons display a broad range of immunomodulatory functions. Interferon beta increases gene expression at the transcriptional level through binding of factors to the interferon-stimulated response element (ISRE) within the promoters of interferon-inducible genes, such as HLA class I. Despite mutation of the class I ISRE sequence within the nonclassical HLA-G class I gene promoter, we show that interferon beta enhances both transcription and cell surface expression of HLA-G in trophoblasts and amniotic and thymic epithelial cells that selectively express it in vivo. Deletion and mutagenesis analysis of a putative interferon-regulatory factor (IRF)-1 binding site within the HLA-G promoter show that HLA-G transactivation is mediated through an ISRE sequence 746 base pairs upstream from ATG, which is distinct from the interferon-responsive element described within proximal classical class I gene promoters. Electrophoretic mobility shift analysis and supershift analysis further demonstrate that interferon-responsive transcription factors, including IRF-1, specifically bind to the HLA-G ISRE. Our results provide evidence that IRF-1 binding to a functional ISRE within the HLA-G promoter mediates interferon beta-induced expression of the HLA-G gene. These observations are of general interest considering the implication of HLA-G in mechanisms of immune escape involved in fetal-maternal tolerance and other immune privilege situations.

Amnion↗
PubMed2000

Metal-assisted unusual hydroxylation at the carbon atom of the triazine ring in dinuclear ruthenium(II) and osmium(II) complexes bridged by 2,4,6-tris(2-pyridyl)-1,3,5-triazine: synthesis, structural characterization, stereochemistry, and electrochemical studies.

The reaction of cis-[M(bpy)2Cl2] (M = Ru(II), and Os(II) with 2,4,6-tris(2-pyridyl)-1,3,5-triazine (tptz) in refluxing ethanol-water resulted in the formation of dinuclear complexes of the composition [(M(bpy)2)2(tptz-OH)](PF6)3.nH2O (n = 1 for Ru and n = 0 for Os). In this reaction an unusual metal-induced hydroxylation at the carbon atom of the triazine ring of bridged tptz occurred. However, hydroxylation did not occur in the corresponding mononuclear complexes under similar reaction condition. A comparative study revealed that sufficient electrophilicity on the carbon atom and free movement of the attached pyridyl ring promoted the hydroxylation reaction. The hydroxylated dinuclear complexes exist in two stereoisomeric forms, a rac form (delta delta/lambda lambda) and a meso form (delta lambda/lambda delta). Both diastereoisomers have been isolated in pure form and characterized. The molecular structures of the rac form of Ru(II) complex (3-II) and meso form of the Os(II) complex (4-I) have been established by single-crystal X-ray studies. Crystal data: complex 3-II, monoclinic, C2/c, a = 24.584(7) A, b = 14.309(4) A, c = 41.044(13) A, beta = 92.84(2) degrees, V = 14420.0(7) A3, Z = 8, R = 0.179, wR2 = 0.479; complex 4-I, triclinic, P1, a = 13.444(7) A, b = 14.576(5) A, c = 19.641(7) A, alpha = 98.21(3) degrees, beta = 101.67(4) degrees, gamma = 105.80(4) degrees, V = 3546.0(3) A3, Z = 2, R = 0.093, wR2 = 0.279. The poor data quality of 3-II did not allow anisotropic refinement of non-hydrogen atoms except Ru and P. A PLUTO drawing of this compound is given only to support the molecular structure. 1H NMR data have been used to characterize the diastereoisomers. The dinuclear complexes exhibit unusual electrochemical behavior; cathodic shifts of the metal-centered oxidations and ligand-based first reduction compared to mononuclear complexes have been observed. There is a splitting in the metal-centered oxidation potentials, indicating strong electronic communication between the metal centers. Comproportionation constants (Kcom) of the mixed-valence species have been calculated; the values are in the range 6.03 x 10(4)-4.7 x 10(6). It appears that a metal-metal interaction occurred by an electron-transfer mode across the low-lying pi* orbital of the bridged tptz.

Journal Article↗
PubMed2000

HLA-G, -E, -F preworkshop: tools and protocols for analysis of non-classical class I genes transcription and protein expression.

Non-classical MHC class I HLA-E, -F, and -G molecules differ from classical class I histocompatibility antigens by specific patterns of transcription, protein expression, and immunological functions. Restriction of the expression pattern of these non-classical antigens may play a key role in modulation of immune responses during pregnancy and diseases but remains to be additionally defined. A specific component of the second International Conference on HLA-G and the 13th HLA-G Histocompatibility Workshop will be dedicated to the analysis of transcription and expression of non-classical class I genes in normal and pathological tissues. In a first step, referred to as the preworkshop, we here report the analysis and conclusions of a working group which was constituted to gather and validate optimal reagents and protocols allowing RT-PCR analysis of HLA-E, -F, -G transcript levels and flow cytometry and immunochemistry analysis of HLA-G expression in cells and tissues. As a result of this work, use of specific primers and probes detecting alternative transcripts of HLA-E, -F, and G have been validated in transfected cells expressing differential pattern of HLA class I antigens. Analysis of the specificity and affinity of collected antibodies has allowed definition of reagents to be proposed for immunochemistry and flow cytometry analysis of HLA-G expression in normal and pathological tissues during the workshop. This work has allowed constitution of an extended workshop group which is now initiating analysis of non-classical class I transcription and expression in various cells and tissues, a collective contribution that will additionally refine our view of the expression of these antigens in normal and pathological situations.

Antibodies, Monoclonal↗