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Biomedical subjects

B Descamps-Latscha

Publications and source records attributed to B Descamps-Latscha.

At least 37 records · Page 2Linked to original sources
PubMed1999

Proteinase 3, a potent secretagogue in airways, is present in cystic fibrosis sputum.

We evaluated the roles of proteinase 3 (PR3) and human neutrophil elastase (HNE), two neutrophil serine proteinases in the mechanisms leading to airway inflammation and hypersecretion in cystic fibrosis (CF). Using specific enzyme-linked immunosorbent assay (ELISA), we found higher levels of PR3 than HNE in sputum from CF patients. Using two inhibitors, ICI (Imperial Chemical Industries) 200,355 (which inhibits both HNE and PR3) and secretory leukoproteinase inhibitor (SLPI) (which inhibits only HNE), we showed that PR3 was enzymatically active in sputum, and its activity, as assessed by SLPI-resistant serine proteinase activity, correlated highly with its antigenic concentration measured by ELISA. Interestingly, sputum pellet-associated serine proteinase activity was mostly due to HNE. PR3 purified from neutrophil azurophil granules triggered airway gland secretion, as measured by the release of radiolabeled molecules from cultured bovine tracheal serous cells pulse-labeled with Na235SO4. This secretory activity was inhibited by ICI 200,355. PR3 concentration in CF sputum was highly correlated with taurine concentration, a reliable marker of airway inflammation and respiratory scores (e.g., FEV1%), whereas no significant correlation was observed with HNE. We verified that Pseudomonas aeruginosa proteinases did not interfere with the assessment of PR3 and HNE. Indeed, the PR3/HNE ratio was greatest in patients chronically infected by P. aeruginosa. We suggest that PR3 may play a role in the hypersecretory process that is characteristic of CF.

Adolescent↗
PubMed1998

Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure.

We previously demonstrated the presence of advanced oxidation protein products (AOPP), a novel marker of oxidative stress in the plasma of uremic patients receiving maintenance dialysis. The present study in a cohort of 162 uremic patients showed that plasma concentrations of AOPP increased with progression of chronic renal failure and were closely related to advanced glycation end products (AGE)-pentosidine (r = 0.52, p < 0.001), taken as a marker of AGE. In vivo, the relevance of AOPP and AGE-pentosidine in monocyte-mediated inflammatory syndrome associated with uremia was evidenced by close correlations between AOPP or AGE-pentosidine and monocyte activation markers, including neopterin, IL-1R antagonist, TNF-alpha, and TNF soluble receptors (TNF-sR55 and TNF-sR75). To determine the mechanisms by which AOPP and AGE could be directly involved in monocyte activation, AOPP-human serum albumin (HSA) and AGE-HSA were produced in vitro by treating HSA with oxidants or glucose, respectively. Spectroscopic analysis confirmed that AOPP-HSA contains carbonyls and dityrosine. Both AOPP-HSA and AGE-HSA, but not purified dityrosine, were capable of triggering the oxidative burst of human monocytes in cultures. The AOPP-HSA-induced respiratory burst was dependent on the chlorinated nature of the oxidant and on the molar ratio HSA/HOCI. Collectively, these data first demonstrate that AOPP act as a mediator of oxidative stress and monocyte respiratory burst, which points to monocytes as both target and actor in the immune dysregulation associated with chronic uremia.

Adult↗
PubMed1997

Incidence and risk factors of atherosclerotic cardiovascular accidents in predialysis chronic renal failure patients: a prospective study.

BACKGROUND: Accelerated atherosclerosis resulting in an abnormally high incidence of coronary and cerebrovascular occlusive accidents has been repeatedly reported in dialysis patients, but incidence and risk factors of such complications in chronic renal failure (CRF) predialysis patients are debated. METHODS: We prospectively assessed the incidence of first myocardial and cerebral infarction episodes in a cohort of 147 CRF patients (99 male) followed from January 1985 to December 1994. Relevant clinical and laboratory risk factors for atherogenesis were determined at yearly intervals. They included blood pressure, smoking, blood lipids, fibrinogen, and homocysteine which were compared in patients with (CVA+) or without (CVA-) occurrence of cardiovascular (CV) atherosclerotic accidents. RESULTS: Incidence of CV accidents was nearly three times higher in CRF patients than in the French general population in both genders. In particular, incidence of myocardial infarction in male patients aged 45-55, 55-65 and > 65 years was 7.6, 18.2, and 27.8/1000 patient-years, respectively, compared to 3.4, 8.9, and 10.4/1000 subject-years in the general population. Although age and degree of renal failure at onset of CV events or at end of follow-up did not differ between CVA+ and CVA- groups, cigarette smoking (24.5 [SD 24.3] vs 8.2 [14.7] pack-years, P < 0.0001) and systolic blood pressure (159 [19] vs 148 [19] mmHg, P < 0.001) were markedly higher in CVA+ patients. Similarly, mean plasma HDL-cholesterol was lower, whereas LDL-cholesterol, triglycerides, apoB, Lp(a), fibrinogen, and homocysteine levels all were significantly higher in CVA+ than in CVA- patients. Multivariate Cox analysis identified cigarette smoking, systolic pressure, HDL cholesterol, and fibrinogen as independent risk factors for developing CV accidents. CONCLUSIONS: Incidence of atherosclerotic CV complications is abnormally high in predialysis CRF patients, suggesting that the uraemic state per se is associated with atherogenesis. As several of the identified clinical and metabolic risk factors for such accidents are potentially remediable by specific therapeutic interventions, prophylactic measures should be initiated long before start of renal replacement therapy.

Aged↗
PubMed1997

Hyperhomocysteinemia is associated with atherosclerotic occlusive arterial accidents in predialysis chronic renal failure patients.

Hyperhomocysteinemia has been shown to constitute an independent risk factor for premature occlusive arterial disease. Moderate hyperhomocysteinemia is present in chronic uremic patients, who often develop premature atherosclerosis, but no direct evidence of an association between the occurrence of atherosclerotic cardiovascular accidents (CVAs) and hyperhomocysteinemia has yet been reported in such patients. We serially determined total plasma homocysteine (Hcy) levels in a cohort of 93 consecutive chronic renal failure, undialyzed patients (57 males, 36 females) with creatinine clearance (Ccr) < 50 ml/min.1.73 m2 and age > or = 50 years at start of follow-up, together with serial assessment of Ccr and blood lipid parameters. From January 1989 to December 1995, 24 patients (group 1) experienced myocardial infarction (18 cases, 13 males) or cerebral infarction (6 cases, 3 males) while the remaining 69 (group 2) remained free of CVAs. Patients in groups 1 and 2 did not differ with respect to age (66 +/- 1.8 vs. 65 +/- 1.1 years, mean +/- Se) or serum creatinine (227 +/- 24 vs. 251 +/- 36 mumol/l) at onset of a CVA (group 1) or at the end of follow-up (group 2). The mean Hcy level was significantly higher in group 1 (20.7 +/- 1.6 vs. 12.8 +/- 0.5 mumol/l, p < 0.0001), as was the proportion of patients with Hcy in excess of 14 mumol/l, the upper limit in healthy controls (83 vs. 30%, p < 0.0001). Logistic regression analysis identified Hcy as an independent risk factor for CVA, with an odds ratio of 11.4 (95% confidence interval 3.5-37.7), which remained significant after adjustment on other variables. We conclude that an elevated Hcy level is associated with a risk of occlusive arterial accidents in patients with chronic renal failure and that hyperhomocysteinemia contributes to the accelerated atherosclerosis complicating chronic uremia.

Aged↗
PubMed1996

Disturbed myeloperoxidase-dependent activity of neutrophils in cystic fibrosis homozygotes and heterozygotes, and its correction by amiloride.

The present study addresses the question of a possible linkage between the cystic fibrosis (CF) genetic autosomal recessive disorder and disturbance in neutrophil function. Neutrophil-dominated chronic airway inflammation is present at an early age in children with CF, even in the absence of detectable infection. As evidenced by extracellular superoxide anion release (measured by lucigenin luminescence) or intracellular hydrogen peroxide production (measured by 2',7'-dichlorofluorescein (DCF) fluorescence), no significant difference in the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity of isolated neutrophils was observed in noninfected CF children (homozygotes), their mothers or fathers (CF heterozygotes), and controls. In contrast, both myeloperoxidase (MPO)-dependent oxygenation activity (measured by luminol luminescence) and chloramine release were increased significantly in both CF homozygotes and heterozygotes as compared with controls. In the presence of either amiloride (a sodium channel inhibitor and sodium/proton antiport blocker) or EIPA (5-ethyl-N-isopropyl-amiloride, a specific inhibitor of the antiport), or choline buffer, intracellular MPO activity was decreased significantly in controls and in the CF homozygotes and heterozygotes, thus bringing intracellular MPO-dependent activity in CF subjects back to the level of controls. Extracellular release of MPO, measured by an ELISA to provide an activity-independent assessment of the enzyme, was increased only in CF homozygotes, and was decreased by amiloride and choline buffer, but not by EIPA. We conclude that a modification of intracellular pH and/or ionic concentrations may be related to the altered MPO enzymatic activity observed in CF neutrophils.

Adolescent↗
PubMed1996

Characterization of a recombinant proteinase 3, the autoantigen in Wegener's granulomatosis and its reactivity with anti-neutrophil cytoplasmic autoantibodies.

Using the baculovirus/insect cells system, we have expressed a recombinant proteinase 3 (PR3) -- the neutrophil-derived serine protease autoantigen in Wegener's granulomatosis -- as a glycosylated intracellular and membrane-associated protein. Oligosaccharides accounted for the difference in molecular weights between recombinant (34 kDa) and neutrophil-PR3 (29 kDa). Whereas rabbit-anti-PR3 IgG recognized both recombinant and neutrophil-derived PR3, autoantibodies from Wegener patient sera recognized only neutrophil-derived PR3. Although oligosaccharides were not involved in PR3 epitope recognition, autoantibodies did not recognize the amino acid primary structure of recombinant PR3. Improper disulfide bond formation and/or lack of post-translational events in insect cells, may affect the conformation and/or lack of post-translational events in insect cells, may affect the conformation of PR3, precluding its reactivity with sera from WG patients.

Amidohydrolases↗
PubMed1996

Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure.

A profound imbalance between oxidants and antioxidants has been suggested in uremic patients on maintenance hemodialysis. However, the respective influence of uremia and dialysis procedure has not been evaluated. Circulating levels of copper-zinc superoxide dismutase (CuZn SOD), glutathione peroxidase (GSH-Px), and reductase (GSSG-Rd), total GSH and GSSG were determined in a large cohort of 233 uremic patients including 185 undialyzed patients with mild to severe chronic renal failure, and 48 patients treated by peritoneal dialysis or hemodialysis. Compared to controls, erythrocyte GSH-Px and GSSG-Rd activities were significantly increased at the mild stage of chronic uremia (p < .001), whereas erythrocyte CuZn SOD activity was unchanged, total level of GSH and plasma GSH-Px activity were significantly decreased, and GSSG level and GSSG-Rd activity were unchanged. Positive Spearman rank correlations were observed between creatinine clearance and plasma levels of GSH-Px (r = .65, p < .001), selenium (r = .47, p < .001), and GSH (r = .41, p < .001). Alterations in antioxidant systems gradually increased with the degree of renal failure, further rose in patients on peritoneal dialysis and culminated in hemodialysis patients in whom an almost complete abolishment of GSH-Px activity was observed. In conclusion, such disturbances in antioxidant systems that occur from the early stage of chronic uremia and are exacerbated by dialysis provide additional evidence for a resulting oxidative stress that could contribute to the development of accelerated atherosclerosis and other long-term complications in uremic patients.

Antioxidants↗
PubMed1996

Advanced oxidation protein products as a novel marker of oxidative stress in uremia.

Evidence suggests an imbalance between antioxidant and oxidant-generating systems resulting in oxidative stress in uremic patients. As plasma proteins are critical targets for oxidants, we developed a novel spectrophotometric assay which allows to detect advanced oxidation protein products (AOPP) in uremic plasma. By size-exclusion chromatography AOPP are retrieved in two distinct peaks at 600 and below 80 kDa in uremic plasma, while no such peaks are found in control plasma. Further biochemical characterization revealed that AOPP are carried by oxidized plasma proteins, especially albumin and do not have oxidant properties. AOPP increased in a dose-dependent manner following in vitro exposure of plasma or purified human serum albumin (HSA) to hypochlorous acid. Advanced glycation end products of human serum albumin (AGE-HSA) also increased AOPP levels. In vivo, plasma level of AOPP was the highest in patients on hemodialysis, followed by those on peritoneal dialysis and by undialyzed patients with advanced chronic renal failure. AOPP levels correlated with plasma concentrations of dityrosine and AGE-pentosidine, as indices of oxidant-mediated protein damage, but not with thiobarbituric reactive substances as lipid peroxidation markers. A close correlation was also found between AOPP and neopterin levels, suggesting that AOPP could be part in the monocyte-mediated inflammatory disorders associated with uremia. In conclusion, we propose the measurement of AOPP as a reliable marker to estimate the degree of oxidant-mediated protein damage in uremic patients and to predict the potential efficacy of therapeutic strategies aimed at reducing such an oxidative stress.

Biomarkers↗
PubMed1996

Pregnancy in women with reflux nephropathy.

Reflux nephropathy is one of the most prevalent renal diseases and a leading cause of chronic renal failure in women-of childbearing age. To evaluate the issue and possible complications of pregnancy in women with reflux nephropathy, we retrospectively analyzed fetal and maternal outcome in 158 women who had 375 pregnancies between 1965 and 1994. The overall fetal death rate was 10.2% and tended to decrease in the 1985 to 1994 decade as compared to the preceding period (8.4% vs. 12.6%). The relative risk of fetal death was 4.8 times greater hypertension was present at conception than in normotensive patients. Fetal death rate was also higher in patients with impaired renal function that in those with serum creatinine < 0.11 mmol/liter at conception (36.7% vs. 7.7%, P < 0.0001). Urinary tract infection accounted for frequent morbidity but seldom resulted in fetal mortality. Maternal renal disease was unaffected by pregnancy, excepted for 4 of the 21 patients with pre-existing renal failure who exhibited an irreversibly accelerated course after pregnancy. We conclude that pregnancy is essentially successful and uneventful in patients diagnosed with reflux nephropathy who have normal blood pressure and preserved renal function, whereas the fetal prognosis is more compromised and there is a risk of accelerated progression of maternal renal disease when serum creatinine concentration is in excess of 0.22 mmol/ liter. This suggests that women with reflux nephropathy should preferably conceive before having reached that stage of renal failure.

Adolescent↗
PubMed1996

T cells and B cells in chronic renal failure.

Recent knowledge into the pathophysiological mechanisms mediating the immune abnormalities characteristic of end-stage renal disease (ESRD) has focused on the dual activation versus deficiency state of immunocompetent cells. Despite major advances in renal replacement therapy, notably hemodialysis, no significant improvement in the immune status of uremic patients has been achieved. After a brief review of the role of T cells and B cells in the normal immune response, the functional and phenotypic T and B cell abnormalities observed in uremic patients are presented. Special emphasis is placed on our recent findings indicating that these abnormalities are observed at an early stage in the course of chronic renal failure, worsen with the progression of uremia, and are exacerbated by the dialysis procedure. The previous hypotheses that could reconcile the so-called Janus-faced behavior of T cells in uremia are updated in light of the recent findings obtained in the search of therapeutic strategies that could counteract the impaired responsiveness of patients with ESRD to vaccination against hepatitis B virus. Perspectives of research aimed at elucidating the respective role of T helper cell subpopulations (Th1 and Th2) could contribute to understanding of the mechanisms of the multifaceted process of uremia-related immune dysregulation and of the rationale for possible immunointervention strategies.

Animals↗
PubMed1996

The advanced glycation endproduct pentosidine and monocyte activation in uremia.

RATIONALE: Advanced glycation endproducts (AGEs) contribute to the pathogenesis of vascular complications in diabetes, aging and end-stage renal disease (ESRD). Immune abnormalities in patients with chronic renal failure and those treated by dialysis contribute to high rates of morbidity and mortality. We therefore sought a relationship between a circulating marker of immune dysfunction and plasma levels of the AGE pentosidine. METHOD: We studied non-diabetic patients with mild to advanced renal failure (n = 60), and with ESRD treated by hemodialysis (HD) (n = 44) and peritoneal dialysis (PD) (n = 19). The plasma protein content of the well characterized AGE, pentosidine was measured using HPLC. In the same samples the monocyte activation product neopterin was measured by RIA. RESULTS: Plasma levels of pentosidine and neopterin increased in parallel with the progression of renal failure. Pentosidine and neopterin were highly correlated in all patients even after adjustment for Ccr. This correlation was also present in patients with ESRD. CONCLUSION: These data suggest that the AGE pentosidine is associated with monocyte activation in renal failure, an interaction which may contribute to accelerated rates of complication and death by as yet unknown mechanisms.

Arginine↗
PubMed1996

Age and gender-related incidence of chronic renal failure in a French urban area: a prospective epidemiologic study.

OBJECTIVE: To determine the age- and gender-related incidence of chronic renal failure in a French urban area. METHODS: Prospective study of adult patients newly identified as having established, chronic renal failure defined by serum creatinine (Scr) > or = 200 mumol/l, with the cooperation of all nephrology and dialysis units in the Ile de France district (10,660,000 inhabitants) during a 1-year period. RESULTS: 2775 patients (1780 males, 995 females) were referred with Scr > or = 200 mumol/l between July 1991 and June 1992, an overall incidence of 260/million population. 847 had advanced renal failure (Scr > or = 500 mumol/l) and 541 patients (19.5%) were > or = 75 years of age. The age-related incidence was 92, 264, 523 and 619/million population in the age groups 20-39, 40-59, 60-74 and > or = 75 years old, respectively. The annual incidence was twice as high in males than in females up to 75 years and three times as high in patients > or = 75 years (1124 vs 356/million population). Based on the proportion of patients reaching end-stage renal failure within one year of referral, the minimal estimation of the need for supportive therapy is 81/million/year. CONCLUSIONS: This epidemiological study in a large French urban area indicates an incidence of 260 patients per million population annually referred to nephrology units for chronic renal failure defined by Scr > or = 200 mumol/l, with a marked preponderance of males and a dramatic increase of incidence with age in both genders.

Adult↗
PubMed1995

Influence of pregnancy on the course of primary chronic glomerulonephritis.

According to some nephrologists, pregnancy has damaging effects on renal function in primary glomerulonephritis, but the evidence is conflicting. We evaluated the effect of pregnancy on the occurrence of end-stage renal failure (ESRF) in 360 patients with various histological forms of primary glomerulonephritis but with normal renal function (serum creatinine < or = 0.11 mmol/L) at presentation. In actuarial analyses, overall ESRF-free survival did not significantly differ between women who became pregnant after clinical onset of renal disease (n = 171) and those who did not conceive (n = 189). Furthermore, in a case-control study pregnancy did not emerge as a risk factor for progression to ESRF (odds ratio 1.15 [95% CI 0.61-2.18]), whereas the type of glomerulonephritis and hypertension were major determinants. We conclude that pregnancy does not affect the course of renal disease in patients who have normal renal function at conception.

Adult↗
PubMed1995

HIV predominantly induces IL-1 receptor antagonist over IL-1 synthesis in human primary monocytes.

Interaction of HIV with cultured human monocytes triggers not only cytokine production but also the release of natural cytokine inhibitors such as the soluble TNF receptors, levels of which are increased in the circulation of HIV-infected patients. We found that HIV-1 LAI induced the production by human monocytes from HIV-seronegative donors of another type cytokine inhibitor, the IL-1Ra receptor antagonist (IL-1Ra). HIV mainly induced the secreted form (83%) of IL-1Ra through de novo mRNA synthesis. IL-1Ra production was triggered at an early step of the infection process and involved the HIV envelope protein and the CD4 receptor. HIV-triggered IL-1Ra production occurred after a lag time, suggesting an indirect mechanism. Neutralizing Abs to IL-1 beta and IL-10 had no effect, while simultaneous treatment with anti-TNF-alpha, anti-granulocyte-macrophage CSF, and anti-TGF-beta nearly abrogated IL-1Ra release, supporting an indirect induction through the concerted action of the co-produced cytokines. IL-1Ra was induced by HIV in a mean 1,000-fold increase over IL-1 alpha beta, a ratio 20-fold higher than that obtained with LPS. This production masked 80% of IL-1 bioactivity in HIV-induced monocyte supernatants. These results suggest that the net balance between pro-inflammatory cytokines and their natural inhibitors could be critical in the control of the inflammatory process associated with HIV infection.

Cells, Cultured↗
PubMed1995

In vivo soluble tumor necrosis factor receptor release in OKT3-treated patients. Differential regulation of TNF-sR55 and TNF-sR75.

Administration of monoclonal antibodies to CD3 triggers acute and massive release of several cytokines, including tumor necrosis factor alpha (TNF-alpha), essentially T cell-derived. This cytokine release is responsible for the spontaneously reversible acute clinical syndrome observed in most OKT3-treated patients. We found that the first OKT3 injection in human renal allograft recipients led to the release in significant amounts of soluble TNF receptors (TNF-sR55 and TNF-sR75) that are considered main natural inhibitors of TNF bioactivity. As for OKT3-induced TNF-alpha, peak TNF-sR levels were observed 1 hr postinjection, and this release was limited to the first monoclonal antibody injection. A distinct regulation of OKT3-mediated release of TNF-sR75 and TNF-sR55 was observed, since (1) in clear contrast with OKT3-mediated TNF-sR75 induction, TNF-sR55 release was completely blocked by a high dose of corticosteroids prior to OKT3 injection and (2) secretion of TNF-sR75 but not TNF-sR55 correlated with immunoreactive TNF-alpha release. In hemodialyzed patients prior to transplantation and OKT3 treatment, a condition characterized by chronic TNF-alpha release, TNF-sR efficiently block TNF bioactivity. In contrast, the system is overwhelmed by the massive acute TNF-alpha release that follows the first OKT3 injection: in such a condition TNF-sR looses its capacity to counteract TNF bioactivity.

Adrenal Cortex Hormones↗