Biomedical subjects
Publications and source records attributed to J F Moreau.
We report a case of renal sarcoidosis revealed by a malignant hypertension associated with renal insufficiency. Ultrasonographic and CT findings are described. The lesions showed multifocal hypoechogenic areas within the renal parenchyma. The disease was pathologically proved after US guided biopsy.
OBJECTIVE: To study the relationship between the CD4+ cell response after initiation of protease inhibitors and the occurrence of opportunistic infections and survival. DESIGN: Prospective observational cohort study. METHODS: HIV-1-seropositive subjects followed-up in HIV centres of Bordeaux University Hospital, Southwest France who were prescribed at least one available protease inhibitor between January and December 1996 were included in this analysis. A Cox model estimated the independent effect of baseline covariates and CD4+ cell response, considered as a time-dependent covariate, on the occurrence of new AIDS-defining opportunistic infection, new AIDS-defining events, new AIDS-defining opportunistic infection or death. RESULTS: A total of 556 HIV-positive patients were prescribed at least one protease inhibitor: 34% saquinavir, 52% indinavir, and 14% ritonavir. Median CD4+ cell count at baseline was 95 x 10(6)/l and mean plasma HIV RNA was 5.0 log10 copies/ml. After a median follow-up of 230 days, 65 patients experienced a new episode of opportunistic infection, 79 patients experienced at least one AIDS-defining event, and 24 had died. On average, the increase in CD4+ cell count was 42 x 10(6)/l (SD, 74) after a median of 49 days. In the multivariate analysis of opportunistic infection or death, each 50% higher CD4+ cell count at baseline was associated with a 23% reduction [95% confidence interval (CI), 14-30] of risk. Each 50% increase in CD4+ cell count during follow-up was associated with a 9% reduction (95% CI, 2-15) of risk, adjusted for the presence of AIDS prior to protease inhibitor therapy (hazard ratio, 3.76 versus absence of AIDS; P < 0.01) and haemoglobin level (hazard ratio, 0.48 if > 11 g/dl versus <11 g/dl; P < 0.01). CONCLUSION: Our results show, at least indirectly, how protease inhibitors might produce clinical stabilization. This result may be due to improved functionality of CD4+ cells in patients started on protease inhibitors.
Comparison of the binding properties of non-glycosylated, glycosylated human leukemia inhibitory factor (LIF) and monoclonal antibodies (mAbs) directed at gp190/LIF-receptor beta subunit showed that most of the low affinity (nanomolar) receptors expressed by a variety of cell lines are not due to gp190. These receptors bind glycosylated LIF produced in Chinese hamster ovary cells (CHO LIF) (Kd = 6.9 nM) but not Escherichia coli-derived LIF or CHO LIF treated with endoglycosidase F. CHO LIF binding to these receptors is neither affected by anti-gp190 mAbs nor by anti-gp130 mAbs and is specifically inhibited by low concentrations of mannose 6-phosphate (Man-6-P) (IC50 = 40 microM), suggesting that they could be related to Man-6-P receptors. The identity of this LIF binding component with the Man-6-P/insulin-like growth factor-II receptor (Man-6-P/IGFII-R) was supported by several findings. (i) It has a molecular mass very similar to that of the Man-6-P/IGFII-R (270 kDa); (ii) the complex of LIF cross-linked to this receptor is immunoprecipitated by a polyclonal anti-Man-6-P/IGFII-R antibody; (iii) this antibody inhibits LIF and IGFII binding to the receptor with comparable efficiencies; (iv) soluble Man-6-P/IGFII-R purified from serum binds glycosylated LIF (Kd = 4.3 nM) but not E. coli LIF. The potential role of Man-6-P/IGFII-R in LIF processing and biological activity is discussed.
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OBJECTIVE: Leukaemia inhibitory factor (LIF) is a polyfunctional cytokine integrated in cytokine networks and its concentration has been shown to be elevated in bronchoalveolar lavage fluid of patients with the acute respiratory distress syndrome (ARDS). The aim of our study was to evaluate the production of LIF by culturing blood cells from patients with ARDS. PATIENTS: 8 patients with ARDS, 8 patients with pneumonia and 5 healthy subjects. MEASUREMENTS AND RESULTS: The blood samples were taken on day 1 after onset of ARDS. LIF was measured, in the cell-free supernatant, with an enzyme-linked immunosorbent assay after 24 h, 48 h and 72 h of blood cell culture. LIF was detectable in some patients in the ARDS group: at i) at 24 h and 48 h: in 2 patients ii) at 72 h in 4/5 patients (140 +/- 231 pg/ml). Only in the 4 patients in whom LIF was measured at 72 h was ARDS associated with the multiple organ dysfunction syndrome. Furthermore, among the 5 patients with ARDS who subsequently died, 4 had a detectable LIF. CONCLUSIONS: We have observed that LIF was produced only in ARDS, but not in all patients. The production of LIF seems to be a good indicator of the severity of ARDS. These preliminary results must be confirmed by a larger study.
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BACKGROUND: We investigated the possible role of antiphospholipid (APA) and anti-human 2-glycoprotein I (beta2-GPI) antibodies (Ab) in thrombosis and atherosclerosis in human immunodeficiency (HIV)-positive patients, in whom they seem to be more frequent. METHODS: We measured APA and anti-beta2-GPI Ab in 58 HIV-positive patients together with markers of disease progression, circulating beta2-GPI, plasma lipids, biological markers of endothelial activation and integrity (plasma thrombomodulin, von Willebrand factor, vascular cell adhesion molecule 1) and with antimalonic dialdehyde antibodies (anti-MDA Ab). RESULTS: We found a 41% frequency of IgG APA in the HIV-positive patients. APA IgMs were rarely positive (7%), and anti-beta2-GPI IgGs were positive in 3-4% patients. There was no correlation between APA or anti-beta2-GPI Ab and the presence of opportunistic infections. Although plasma thrombomodulin, von Willebrand factor and vascular cell adhesion molecule 1 were significantly increased in the HIV-positive patients, APA was correlated only with vascular cell adhesion molecule 1, suggesting that APAs are correlated with endothelial activation but not with vascular endothelial lesions. A correlation between APA and anti-MDA IgG was demonstrated using multivariate analysis (r=0.542, P < 0.0001), suggesting a relationship between the targets of these antibodies. Finally, IgG APAs are frequent in HIV infection but are not correlated with biological markers of endothelial injury. CONCLUSION: Our results do not support a role for APA or anti-beta2-GPI in HIV-associated silent vascular endothelial damage. However, the role of these autoantibodies in clinically relevant thrombotic events should be investigated in HIV-positive patients.
Human interleukin for DA cells, also called leukaemia inhibitory factor (LIF), is of cardinal importance for successful murine embryo implantation. Recent studies suggest it may also play an important role in human embryo implantation. Our objective was to study the hormonal regulation of the production/secretion of LIF by the human endometrium. Endometrial LIF secretion in specimens obtained from women without ovarian function (n+/-14) at day 10 (4 mg of oestradiol regimen) or day 20 (oestradiol plus 300 mg of progesterone) of a simulated menstrual cycle was examined. LIF was detected in all cultured explants obtained both in the proliferative and secretory phase of the stimulated cycles. The levels of cytokine production by day 10 endometrial culture explants were 5-fold higher than by day 20 endometrial samples (mean+/-SEM, 24.3+/-8.6 versus 4.5+/-2.1 pg/mg, P < 0.01). This suggests that progesterone significantly down-regulates the endometrial LIF secretion. The effect of progesterone on LIF secretion by the endometrium in vitro was also examined. Explants of endometrium obtained from the same patients on day 10 of cycle were treated with 0.5 ng/ml of progesterone in vitro. This progesterone treatment significantly reduced LIF secretion by endometrial explants in vitro (mean+/-SEM, 20.3+/-4.8 versus 10.7+/-2.3 pg/mg, P < 0.05). These results suggest that LIF endometrial production is regulated by progesterone both in-vivo and in-vitro. The possible mechanisms of LIF regulation are discussed briefly.
OBJECTIVE: We report three cases of a rare form of cavernoma developed within the wall of the common bile duct. CONCLUSION: To our knowledge, this kind of portal cavernoma has not been described in the literature. Because the cavernoma may be easily confused with other causes of bile duct wall thickening, color Doppler sonography is mandatory for a correct diagnosis.
Leukemia Inhibitory Factor (LIF) has a wide variety of biological activities. It regulates the differentiation of embryonic stem cells, neural cells, osteoblasts, adipocytes, hepatocytes and kidney epithelial cells. It also triggers the proliferation of myoblasts, primordial germ cells and some endothelial cells. Many of these biological functions parallel those of interleukin-6, Oncostatin M, ciliary neurotrophic factor, interleukin-11 and cardiotrophin-1. These structurally related cytokines also share subunits of their receptors which could partially explain the redundancy in this system of soluble mediators. In vivo LIF proves important in regulating the inflammatory response by fine tuning of the delicate balance of at least four systems in the body, namely the immune, the hematopoietic, the nervous and the endocrine systems. Although we are far from its therapeutic applications, the fast increasing knowledge in this field may bring new insights for the understanding of the cytokine biology in general.
The specific binding of leukemia inhibitory factor (LIF) or oncostatin-M (OSM) to transmembrane gp190 or gp130 leads to their oligomerization which is necessary for signal transduction. Although, sgp190 and sgp130 counterparts also exist, their biological significance remains to be determined. Interestingly, sgp190 forms have been identified in large amounts in normal mouse sera but so far not in human sera. During gestation, murine sgp190 increases 20-fold to 30-fold, while sgp190 RNA levels increase mostly in the liver, uterus and placenta. Sandwich ELISAs were used to detect the presence and follow the evolution of LIF concentrations and its sgp190 receptor subunit in the sera of healthy pregnant and non-pregnant women. The LIF concentrations in whole blood of pregnant women were significantly lower than those of non-pregnant women, whereas they returned to these latter values soon after delivery. In 51 non-pregnant women, the mean sgp190 concentration was 4.3 0.3 ng/ml. It rose slowly but steadily, increasing 4-fold from the 4th to th 34th week of amenorrhea, at which time, it accelerated more rapidly until reaching 41 weeks of amenorrhea, 12 times the mean control value. Several hours prior to delivery, the sgp190 concentration dropped sharply before returning to control levels 2 days later. The marked increase of sgp190 measured in pregnant women extends to humans the observation previously made in mice and suggests a pivotal role for this cytokine system not only during implantation and early embryo development but also throughout pregnancy and more specifically in the biological function of placenta.
Functional expression of CD40 has recently been described on the surface of HUVEC, and activation of these cells with CD40 ligand (CD40-L) leads to increased adhesion molecule expression. Here, we analyzed the effect of CD40 triggering on cytokine production by HUVEC. CD40-L-transfected fibroblasts, in contrast to their untransfected counterparts, as well as a soluble recombinant human CD40-L/murine CD8alpha chimeric molecule were able to importantly increase (by a mean of fourfold) the production of leukemia inhibitory factor (LIF) by HUVEC. CD40-L displayed an additive effect with IL-4, IL-1alpha, and TNF-alpha on the enhancement of LIF secretion. Cyclosporin A did not affect LIF synthesis by resting or CD40-L-activated HUVEC, whereas dexamethasone diminished the basal level of LIF production and abrogated the CD40-L effect. The secretions of two other proinflammatory cytokines, granulocyte-macrophage CSF and IL-6, were also increased in the presence of CD40-L. However, CD40-L neither affected HUVEC proliferation nor rescued them from IFN-gamma- and TNF-alpha induced apoptosis. Together, these results indicate that endothelial cell activation by CD40-L may play an important role not only in leukocyte recruitment through enhancement of adhesion molecule expression, but also in the maintenance of an inflammatory loop through the increase in proinflammatory cytokine secretion.
Leukemia inhibitory factor (LIF), oncostatin-M (OSM), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT1) act through transmembrane receptors which share the gp190 glycoprotein chain. The understanding of its involvement in the biology of these cytokines is of importance since these systems have recently been shown to participate in major inflammatory and neoplastic processes such as myelomatosis (Rose-John, S., Heinrich, P.C., 1994. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem. J. 300, 281). In addition, this family of receptors also shares the gp130 transducing chain, with the IL6 and IL11 receptors. Because IL6 and gp130 were the first members to be discovered, most of the available reagents are directed at them. In this respect, monoclonal antibodies have played a major role in elucidating these receptor/ligand interactions and exploring the pathophysiological aspects of their biology. So far, no such reagents have been described for the gp190. We now report the production and characterization of 16 monoclonal antibodies directed against human gp190. They were obtained using recombinant chimeric or truncated proteins produced in a eukaryotic CHO cell line. One was able to block the biological activity of LIF. Because gp190 comprises two hematopoietin binding domains, crude epitope mapping was possible using the same reagents. While more of these antibodies are required, the present set validate the technological approach used for their preparation and should improve our understanding of this class of cytokines.
The authors report on the development of a new sandwich enzyme-linked immunoabsorbent assay (ELISA) for the quantitation of the human cytokine leukaemia inhibitory factor/human interleukin for DA cells (LIF/HILDA) with high accuracy and sensitivity (23 pg/ml), in less than 5 h and in various biological fluids. The antibodies used in this assay were raised against recombinant glycosylated LIF expressed in vivo following inoculation of recombinant vaccinia viruses, and screened with the biologically active cytokine in a flow cytometry assay using cells expressing a membrane-bound form of LIF. Furthermore, this home-made assay was compared with two commercially available ELISA kits. The results led to the conclusion that these three assays are far from being equivalent between each other, in terms of sensitivity towards non-glycosylated vs glycosylated LIF. Two major parameters must be incriminated: the glycosylation status of the LIF molecule used as the calibrator, and the binding characteristics of the monoclonal antibodies used to set up these assays toward LIF derived from Escherichia coli or from eukaryotic cells. This points out the importance of these parameters for the design of ELISAs meant for the quantitation of glycosylated cytokines in biological fluids.
Obstructive azoospermia represents approximately 10 % of cases of male hypofertility. It is classified according to the volume of ejaculate. When the latter is normal a proximal obstruction is suspected. Scrotal sonography can help to detect dilation of the epididymal head when clinical findings are equivocal. Ejaculatory duct obstruction (EDO) is suspected when the volume of ejaculate is low. The use of transrectal ultrasonography (TRUS) plays a major role in the investigation of these patients, and endorectal MRI is a very useful adjunct in selected cases. The most common cause of EDO is congenital bilateral absence of vas deferens, which is now thought to be a genital form of cystic fibrosis in 80 % of cases. Consequently, a definitive diagnosis must be made before any attempt at in vitro fertilization. TRUS accurately visualizes abnormalities of the caudal junction of the vas deferens and seminal vesicles, yielding a definitive diagnosis without scrototomy. Other causes of EDO are congenital cysts compressing the distal part of the ejaculatory ducts and inflammatory distal stenosis. The former are accurately identified by TRUS, but the latter give more or less marked signs of obstruction which are only of value in azoospermic patients with a low-volume ejaculate. More invasive imaging is required to diagnose partial obstruction of the ED. Surgical vasography is still the reference, but puncture of the seminal vesicles under TRUS guidance is an attractive alternative, as it permits aspiration of seminal fluid (to seek motile sperm) and vasography without scrototomy. Lastly, endorectal MRI well assesses the relationships between the proximal prostatic urethra and the posterior wall of the ejaculatory ducts, which need to be precisely known when endoscopic resection of the ejaculatory ducts is planned.
OBJECTIVES: To compare results of color Doppler-guided ultrasonography (CDUS) versus those of systematic biopsies in 591 patients with an elevated serum PSA level and to correlate them with digital rectal examination (DRE) findings. METHODS: Biopsies were directed into hypervascularized (CDUS+) or hypovascularized (CDUS-) hypoechoic peripheral zone nodules (443 cases). When transrectal ultrasound (TRUS) was normal (148 cases), biopsies were directed into hypervascular area. Six additional posterior biopsies were also performed in every patient, together with four anterior biopsies in 117 patients with normal DRE and prostate weight above 40 g. RESULTS: Biopsies were positive in 339 patients (57%). Positive biopsy rate (PBR) of directed biopsies was 84% in hypervascular abnormalities (264 of 316) and 17% in hypovascular nodules (23 of 134) (P < 0.001). PBR of combined biopsies was 84% in CDUS+ patients (266 of 316) and 26% in CDUS- patients (73 of 275) (P < 0.001). Comparison of TRUS and CDUS showed a sensitivity of 0.9 and 0.78, respectively, and a specificity of 0.46 and 0.8, respectively. Of the 131 patients with a PSA level between 4 and 10 ng/mL and a normal DRE, PBR was 59% (22 of 37) when CDUS was positive and 11% (10 of 94) when it was negative, regardless of TRUS abnormalities (P < 0.001). Nonpalpable cancers with a negative CDUS showed a significantly (P < 0.001) lower Gleason score (5.5 +/- 0.9) than that of CDUS+ cancer (6.5 +/- 1.1). Eleven cancers were diagnosed by only anterior positive biopsies. All of them had a negative CDUS and a PSA level above 10 ng/mL. CONCLUSIONS: CDUS does not modify prostate biopsy policy except in patients with negative CDUS, normal DRE, and PSA level between 4 and 10 ng/mL, where deferment of biopsy can be advocated. Anterior biopsies are only useful in patients with a PSA level above 10 ng/mL and a negative CDUS.
Color Doppler ultrasound (CDUS) seems to be an effective imaging technique for the diagnosis of renal vascular diseases. It is already the modality of choice for the detection of acute renal vein thrombosis and nonocclusive intrarenal vascular disorders including iatrogenic arteriovenous fistula and false aneurysm, particularly in patients with impaired renal function that precludes the use of iodinated contrast agents. Although proximal Doppler interrogation remains an important step in diagnosing renal artery (RA) stenosis, useful hemodynamic information can be obtained from the distal arterial bed. When CDUS fails in identifying proximal RAs, normal waveform velocity and morphology obtained from intrarenal arteries enable one to rule out RA occlusion and most of the severe stenoses (> or = 80%). Such information, which is not subject to a significant risk of technical failure, seems to be particularly useful in studying patients with acute renal failure of suspected vascular origin. Despite the extreme variability in reported performance between studies, CDUS has seemed to be a valuable tool compared with other noninvasive modalities in the diagnosis of RA stenosis. Whereas a CDUS-based strategy is already accepted in numerous specialized centers, a thorough evaluation of diagnostic criteria and extensive training of operators will allow CDUS to be widely accepted for the screening of patients at high risk for renovascular hypertension.