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Biomedical subjects

P Moulin

Publications and source records attributed to P Moulin.

At least 55 records · Page 3Linked to original sources
PubMed1999

Occurrence of hyperhomocysteinemia 1 year after gastroplasty for severe obesity.

Severe obesity exposes one to an increased risk of cardiovascular mortality. Gastroplasty has been shown to induce substantial weight loss and to improve the atherogenic profile of severely obese subjects. However, vitamin deficiencies after gastroplasty have been reported. Because hyperhomocysteinemia, an independent risk factor for cardiovascular disease, is influenced by nutritional status (and especially by folate intake), we hypothesized that a marginal folate deficiency induced by gastroplasty could promote hyperhomocysteinemia. Thus, plasma homocysteine concentrations were measured by high-performance liquid chromatography in 53 severely obese patients (body mass index = 42 +/- 1), before and 1 yr after vertical gastroplasty. Plasma homocysteine concentrations increased, on an average, from 9.9 +/- 0.4 to 12.8 +/- 0.6 micromol/L (P < 0.0001). This increase in homocysteine levels was observed in two thirds of the subjects, leading to clear-cut hyperhomocysteinemia (>15 micromol/L) in 32%. The changes in homocysteine concentrations were correlated to weight loss (P < 0.001) and to decrease in plasma folate concentrations (P < 0.01). Whereas gastroplasty induced a mean 32-kg weight loss and a striking improvement in conventional risk factors, the occurrence of iatrogenic hyperhomocysteinemia might hamper the benefit of surgery on cardiovascular risk in most of the patients. Our results further support use of a systematic efficient folate supplementation after gastroplasty.

Adult↗
PubMed1999

Regulation of aquaporin-1 and nitric oxide synthase isoforms in a rat model of acute peritonitis.

The loss of ultrafiltration (UF) that accompanies acute peritonitis is a common problem in peritoneal dialysis (PD). It has been suggested that changes in nitric oxide (NO)-mediated vascular tone and permeability might be involved in the loss of UF, whereas channel-mediated water permeability should not be affected. This study used a model of acute peritonitis in rats to characterize changes in PD parameters, in correlation with: (1) expression studies of water channel aquaporin-1 and NO synthase (NOS) isoforms and (2) enzymatic assays for NOS in the peritoneum. Compared with controls, rats with peritonitis had a higher removal of plasma urea, a faster glucose absorption, and a loss of UF. Additional changes, including high protein loss, elevated leukocyte counts in dialysate, positive bacterial cultures, edema, and mononuclear infiltrates, were similar to those observed in PD patients with acute peritonitis. Acute peritonitis in rats induced a major increase in total NOS activity, which was inversely correlated with free-water permeability. The increased NOS activity was mediated by both inducible (Ca2+-independent) and endothelial (Ca2+-dependent) NOS isoforms and was reflected by increased peritoneal staining for nitrotyrosine. In contrast, aquaporin-1 expression was unchanged in rats with peritonitis. These findings cast light on the pathophysiology of permeability changes and loss of UF that characterize acute peritonitis. In particular, these data suggest that a local production of NO, mediated by different NOS isoforms, might play a key role in these changes.

Acute Disease↗
PubMed1999

[The vascular risk in the diabetic: the lipid factor, from epidemiologic data to intervention trials].

It might seem likely that the lipid abnormalities observed in diabetes could be treated more efficiently by fibrates than by statins, whereas subgroup analysis in three intervention trials has shown that statins prevent cardiovascular diseases in diabetic patients. The magnitude of relative risk reduction in these trials was similar to that observed in non-diabetic populations, but the greater absolute risk for diabetic patients led to increased absolute benefit. These data concerned only secondary prevention in well-controlled diabetic patients with combined hyperlipidaemia. Subgroup analysis based on LDL-cholesterol concentration in cardiovascular prevention trials with statin and the results of fibrate trials performed in the general population suggest that fibrates could still be recommended for hypertriglyceridaemic diabetic patients whose LDLc is lower than 1.4 g/l. This hypothesis needs to be tested in the light of results of ongoing fibrate trials specifically conducted in diabetic patients.

Cardiovascular Diseases↗
PubMed1999

VLDL-bound lipoprotein lipase facilitates the cholesteryl ester transfer protein-mediated transfer of cholesteryl esters from HDL to VLDL.

In recent years, it has been established that lipoprotein lipase (LPL) is partly associated with circulating lipoproteins. This report describes the effects of physiological amounts of very low density lipoprotein (VLDL)-bound LPL on the cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester transfer (CET) from high density lipoprotein (HDL) to VLDL. Three patients with severe LPL deficiency exhibited a strong decrease in net mass CET that was more than 80% lower than that of common hypertriglyceridemic subjects. Recombination experiments showed that this was due to an abnormal behavior of the VLDL fraction. Replacement of the latter by normal VLDL totally normalized net mass CET. We therefore prepared VLDL containing controlled amounts of bound LPL that we used as CE acceptors in experiments involving unidirectional radioisotopic CET measurements. These were carried out either in the absence or in the presence of inhibitors of LPL lipolytic activity. When LPL-induced lipolysis was totally blocked, the stimulating effect of the enzyme on the CETP-dependent CET was only reduced by about 50%, showing that it did not entirely result from its lipolytic action. These data were dependent upon neither the type of LPL inhibitor (E600 or THL) nor the source of CETP (delipidated plasma or partially purified CETP). Thus, in addition to the well-known stimulating effect of LPL-dependent lipolysis on CET, our work demonstrates that physiological amounts of VLDL-bound LPL may facilitate CET through a mechanism partially independent of its lipolytic activity.

Animals↗
PubMed1999

Paraoxonase protection of LDL against peroxidation is independent of its esterase activity towards paraoxon and is unaffected by the Q-->R genetic polymorphism.

High density lipoprotein (HDL)-associated paraoxonase (PON) seems to play a major role in the protection of low density lipoprotein (LDL) against peroxidation by HDL, and the partly purified enzyme exerts a dose-dependent protective effect. A common polymorphism of the human gene (192 Q-->R) modulates paraoxonase activity but purified enzyme from either genotype is equally effective against LDL peroxidation. The inhibition of Cu2+-induced LDL peroxidation by HDL was monitored by lipid peroxide assay and change in LDL electrophoretic mobility. We show that HDL from type 2 diabetic patients with the QQ or RR genotype (n = 12 for each) reduce, to the same extent, both peroxide production (by 60.6 +/- 20.0 and 63.9 +/- 23.5%) and relative change in mobility (61.3 +/- 21.8 and 61.4 +/- 26.5%) despite a 6-fold difference in paraoxonase activity (47.4 +/- 4.4 vs. 299.7 +/- 23.7 U/l, P < 0.0001). Protection was, however, related to paraoxonase activity, but with a different efficiency in each group corresponding to a better protection per unit of enzyme in the QQ genotype group. Inactivation of PON activity by heating (56 degreesC, 10 min) or by EDTA was totally without effect on protection, which remained correlated with the paraoxonase activity measured prior to inactivation. In summary, these results suggest that the protein bearing both paraoxonase and arylesterase activities also possesses a third thermostable property, closely associated with paraoxon hydrolysis activity and unaffected by PON genetic variability.

Aryldialkylphosphatase↗
PubMed1998

Lack of association between carotid intima-media thickness and paraoxonase gene polymorphism in non-insulin dependent diabetes mellitus.

Paraoxonase (PON) is an HDL-bound enzyme capable of hydrolyzing lipid peroxides and believed to be in part responsible for the protective effect of HDL against LDL oxidation. Its activity is mainly determined by a gene polymorphism of the PON 1 gene (Glu-Arg 192). Low activity has been related to an elevated incidence of myocardial infarction. In several case-control studies, however, the high activity B allele is paradoxically more prevalent in patients. We have re-investigated this relationship, using carotid intima-media thickness (IMT) as a surrogate continuous variable for macroangiopathy. Genotypes were determined in 197 non insulin-dependent diabetic patients (HbAlc 8.8+/-0.15%, BMI 28.3+/-0.36). IMT, measured by high resolution mode B ultrasound, was the same for all genotypes (AA: 0.83+/-.013, AB 0.82+/-.017 and BB: 0.81+/-.034 mm). Bearers of the B allele displayed higher Lp(a) concentration (AA: 197+/-28, AB: 221+/-26, BB: 225+/-45 mg/l, P=0.024) with a significant linear trend (P < 0.005). Multiple regression showed age and systolic blood pressure, but not Lp(a), to be the main determinants of IMT variability without the contribution of the PON genotype. No consistent differences could be found between genotypes in the peroxidizability of LDL (lag-time, rate of diene production and maximal concentration). Our data support the view that there is no association between the early changes of atherosclerosis as defined by carotid IMT and variation in codon 192 of PON 1.

Age Factors↗
PubMed1998

Association between plasma HDL-cholesterol concentration and Taq1B CETP gene polymorphism in non-insulin-dependent diabetes mellitus.

The effects of CETP gene Taq1B polymorphism on plasma lipoproteins were investigated in 176 patients with non-insulin-dependent diabetes mellitus. The distribution of CETP genotypes was similar to that previously described in the general population. A significant association was found between CETP genotype and both CETP and HDL cholesterol (HDL-c) concentrations. B1B1 had the highest CETP and the lowest HDL-c whereas B2B2 had the lowest CETP and the highest HDL-c. However, HDL-c was not correlated with CETP concentration, even when genetic groups were separately considered. By multivariate analysis, the determinants of HDL were body mass index, triglycerides concentration, net mass CE transfer, and CETP genotype. No association was found between CETP genetic groups and HDL or LDL size distribution. In contrast, net mass CET was positively and HDL and LDL sizes were negatively correlated with plasma triglyceride concentration. Overall, our work demonstrates that, in a population of diabetic patients where lipoprotein-related parameters vary over a large range, the association of CETP gene polymorphism with HDL-c is independent of plasma CETP concentration.

Adult↗
PubMed1997

Natural killer cell cytokine production, not cytotoxicity, contributes to resistance against blood-stage Plasmodium chabaudi AS infection.

Our recent study showed that IL-12 treatment of susceptible A/J mice induces Th1-mediated, protective immunity against lethal blood-stage Plasmodium chabaudi AS infection. To further understand the mechanism of this protection, we examined NK cell cytotoxic (NKCC) and cytokine secretory functions in untreated and IL-12-treated A/J mice, along with resistant C57BL/6 (B6) mice. Normal A/J mice receiving six daily doses of 0.1 microg IL-12 exhibited significant increases in NKCC in total spleen cell populations. Defective NKCC evident in vitro in enriched NK cells from infected A/J mice was corrected by addition of 10 ng/ml IL-12 and was comparable with that seen in B6 mice. In vivo and in vitro analyses revealed that enriched NK cells from day 6 infected A/J mice were defective not only in NKCC, but also in IFN-gamma, and to a certain extent, TNF-alpha secretion, which could also be corrected by IL-12 treatment. Depletion of NK cells from resistant B6 mice resulted in a more severe course of infection, while NK cell-depleted, IL-12-treated A/J mice had significantly higher parasitemia, as well as 100% mortality, suggesting the importance of NK cells in IL-12-mediated protection. NKCC-defective bg/bg mice produced optimum IFN-gamma and TNF-alpha and recovered from infection similar to bg/+ controls; in vivo depletion of these cytokines resulted in significantly higher parasitemia early in infection. Based on these results, we conclude that IFN-gamma, and possibly TNF-alpha, secretion by NK cells during early infection plays a major role in protective immunity to blood-stage malaria.

Adjuvants, Immunologic↗
PubMed1997

Physiological Responses to Stress Conditions and Barophilic Behavior of the Hyperthermophilic Vent Archaeon Pyrococcus abyssi.

The physiology of the deep-sea hyperthermophilic, anaerobic vent archaeon Pyrococcus abyssi, originating from the Fiji Basin at a depth of 2,000 m, was studied under diverse conditions. The emphasis of these studies lay in the growth and survival of this archaeon under the different conditions present in the natural habitat. Incubation under in situ pressure (20 MPa) and at 40 MPa increased the maximal and minimal growth temperatures by 4(deg)C. In situ pressure enhanced survival at a lethal high temperature (106 to 112(deg)C) relative to that at low pressure (0.3 MPa). The whole-cell protein profile, analyzed by one-dimensional sodium dodecyl sulfate gel electrophoresis, did not change in cultures grown under low or high pressure at optimal and minimal growth temperatures, but several changes were observed at the maximal growth temperature under in situ pressure. The complex lipid pattern of P. abyssi grown under in situ and 0.1- to 0.5-MPa pressures at different temperatures was analyzed by thin-layer chromatography. The phospholipids became more complex at a low growth temperature at both pressures but their profiles were not superimposable; fewer differences were observed in the core lipids. The polar lipids were composed of only one phospholipid in cells grown under in situ pressure at high temperatures. Survival in the presence of oxygen and under starvation conditions was examined. Oxygen was toxic to P. abyssi at growth range temperature, but the strain survived for several weeks at 4(deg)C. The strain was not affected by starvation in a minimal medium for at least 1 month at 4(deg)C and only minimally affected at 95(deg)C for several days. Cells were more resistant to oxygen in starvation medium. A drastic change in protein profile, depending on incubation time, was observed in cells when starved at growth temperature.

Journal Article↗
PubMed1997

Growth hormone (GH) retesting and auxological data in 131 GH-deficient patients after completion of treatment.

GH state and auxological data after completion of GH therapy are reported in 131 patients (79 males, 52 females). They were treated from 1980-1994 for partial (n = 98) or complete (n = 33) GH deficiency (GHD), either idiopathic (n = 121) or organic (n = 10). A single stimulation test (clonidine+betaxolol) was used, and only 50 patients (38%) maintained a blunted response (GH peak below 10 micrograms/L). Although 9 of the 10 patients with organic GHD had an abnormal low GH peak, 67% of patients with idiopathic GHD normalized their GH secretion. This was particularly true of partial GHD patients (71% vs. 36% of complete GH-deficient patients). Based on a retest GH peak below 5 micrograms/L, only 23% of the patients were considered to be GH deficient and therefore candidates for GH treatment during adulthood. We found no significant difference between hormonal state at completion of treatment and initial GH deficiency, pubertal state, or sex, although we did find a significantly lower GH peak value before and after treatment in patients with elevated body mass index. Of the 14 obese children who were treated, 50% had an abnormally low serum insulin-like growth factor-I level, arguing for true GHD, and only two children remained obese at cessation of treatment. Auxological data showed that with a mean duration of treatment of 3.6 +/- 2.0 yr, patients classified as having complete GHD before treatment had significantly greater catch-up growth as expressed in SDS for height than patients with partial GHD (0.6 +/- 1.1 vs. 1.1 +/- 0.7 SDS, P < 0.05), and that boys grew better than girls (1.4 +/- 0.8 vs. 1.6 +/- 0.6 SDS) for height, P < 0.01). That catch-up growth was not correlated with the result of GH peak after cessation of treatment.

Adolescent↗
PubMed1997

Characterization of a new case of autoimmune type I hyperlipidemia: long-term remission under immunosuppressive therapy.

Only a few cases of type I hyperlipidemia occurring in patients with autoimmune disease have been reported. We describe the case of a 35-yr-old woman suffering from severe type I hyperchylomicronemia. A combination of various hypolipidemic treatments, including strict hypolipidemic dietary therapy and administration of fibrates or n-3 fatty acids, was inefficient. Because of a history of familial autoimmunity, we introduced an immunosuppressive therapy that resulted in consistent long term and stable remission. Two attempts to reduce the immunosuppressor dose resulted in major relapses. To explain the defect of chylomicron hydrolysis, we investigated the postheparin plasma lipase activities. Hepatic triglyceride lipase activity was normal, whereas that of lipoprotein lipase (LPL) was reduced to about 30% of normal. Immunosuppressive therapy resulted in a complete and durable normalization of LPL activity. Using Western blot analysis, we found in the plasma of the patient a circulating IgG specifically directed against LPL, which became undetectable during immunosuppressive therapy. Western blot analysis revealed that the whole circulating anti-LPL autoantibody was bound to chylomicrons. Proteins extracted from patient's chylomicrons were able to induce a dose-related inhibition of LPL activity in vitro, whereas that of hepatic triglyceride lipase remained unchanged. These data constitute the first description of autoimmune hyperchylomicronemia due to an exclusive defect of LPL activity, and they show that a complete remission has been obtained after immunosuppressive therapy. Finally, our finding that the anti-LPL autoantibody is bound to chylomicrons emphasizes their previously unrecognized ability to transport LPL, already described for other lipoprotein fractions.

Adult↗
PubMed1997

[Genetic factors in familial combined hyperlipidemia and insulin resistance syndrome associated with dyslipidemia].

Familial combined hyperlipidemia, (FCHL) and dyslipidemia occurring in insulin resistant syndrome (IRS) share similar lipid abnormalities. Additionally insulin resistance is frequent in families affected by FCHL. The genetics of FCHL, an oligogenic disorder influenced by environmental factors is not established. Many genes that modulate dyslipidemia such as, LPL, apo E, the cluster A I-C III-A IV, have been identified. However the major gene which determines hypertriglyceridemia remains unknown. The community between HCF and insulin resistance syndrome might have:--either a metabolic origin: the increase in FFA which is a characteristic of IRS, capable to stimulate the hepatic production of triglycerides;--and/or a common genetic mechanism involving the alteration of many genes implied in the control of lipoprotein metabolism and insulin sensitivity.

Humans↗
PubMed1996

Menstrual breakdown of human endometrium can be mimicked in vitro and is selectively and reversibly blocked by inhibitors of matrix metalloproteinases.

The mechanisms underlying the menstrual lysis leading to shedding of the human endometrium and its accompanying bleeding are still largely unknown. In particular, whether breakdown of the endometrial fibrillar extra-cellular matrix that precedes bleeding depends on aspartic-, cysteine-, serine-, or metalloproteinases remains unclear. In the present study, menstrual regression of the human endometrium was mimicked in organ culture. Whereas sex steroids could preserve tissue integrity only in nonperimenstrual explants, matrix breakdown upon sex steroid deprivation was completely and reversibly inhibited at all stages of the menstrual cycle by specific inhibitors of matrix metalloproteinases, but not by inhibitors of the other classes of proteinases. Matrix metalloproteinases are thus identified as the key class of proteinases involved in the initiation of menstruation.

Collagen↗
PubMed1996

Cholesteryl ester transfer protein: an enigmatic protein.

The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from high-density lipoproteins (HDL) into very-low-density lipoproteins (VLDL) with a reciprocal exchange of triglycerides. Plasma CETP is mainly bound to HDL and is involved in the interconversion of these lipoproteins. In experimental models such as transgenic mice, CETP activity decreases HDL cholesterol and increases the cholesteryl ester content of apo B-containing lipoproteins. In humans, CETP activity and concentration are positively correlated with VLDL-LDL cholesterol. Clinical studies suggest that the effect of CETP on HDL cholesterol depends on the amount of acceptor lipoproteins. CETP activity is negatively correlated with HDL cholesterol only in hypertriglyceridemic states. Various CETP gene mutations have been reported, they induce hyper-alpha-lipoproteinemia. On the other hand, the impact of the variability of CETP gene on HDL cholesterol variations in Caucasians is controversial. CETP is often involved in secondary dyslipidemia and is susceptible to modify the composition of plasma lipoproteins in an atherogenic way. The real impact of CETP activity on atherosclerosis is still unknown. CETP is susceptible to play a proatherogenic role since it mediates a redistribution of plasma cholesterol from lipoproteins associated with a protection against atherosclerosis into the proatherogenic apo B-containing lipoproteins. However, CETP mediates one of the steps of the reverse cholesterol transport, an antiatherogenic process that channels cholesterol from peripheral tissues back to the liver.

Animals↗
PubMed1995

Interrelations between sex hormone-binding globulin (SHBG), plasma lipoproteins and cardiovascular risk.

The incidence of coronary artery disease is significantly higher in men than in women, at least until menopause. This gender difference could be explained by the action of sex steroids on the lipoprotein profile. In prepubertal children, high-density lipoprotein (HDL) cholesterol and triglyceride levels are similar between sexes, while adult men have generally lower HDL cholesterol and higher triglyceride levels than premenopausal adult women. Most cross-sectional studies have reported that sex hormone binding globulin (SHBG) and testosterone levels correlate positively with HDL cholesterol levels between sexes. Thus SHBG by modulating the balance in the biodisposal of testosterone and estradiol, might have a profound effect on the risk of cardiovascular disease. However, adjustment for body weight and body fat distribution weakens the association between SHBG, testosterone and HDL cholesterol. The negative correlation of fasting insulin with SHBG and HDL cholesterol levels in both sexes, and some evidence that insulin is an inhibitor of SHBG production in vitro, has suggested that hyperinsulinism might negatively regulate SHBG and HDL levels. It remains to be determined whether the inverse relationship between SHBG and insulin levels is coincidental or has a causal effect on the increase of atherosclerosis. Decreased SHBG has been shown to be predictive of the incidence of non-insulin-dependent diabetes mellitus in women but not in men, and of subsequent development of cardiovascular disease and overall mortality in postmenopausal women. SHBG is an index of androgenism in women and of insulin-resistance in both sexes, and might be useful in epidemiological studies of cardiovascular risk. However, in men, SHBG is not predictive of the occurrence of cardiovascular disease. Whether SHBG might have an intrinsic protective effect on the arterial wall through SHBG-receptors is still highly speculative.

Adult↗
PubMed1995

Decreased cholesteryl ester transfer protein (CETP) mRNA and protein and increased high density lipoprotein following lipopolysaccharide administration in human CETP transgenic mice.

The plasma cholesteryl ester transfer protein (CETP) mediates the exchange of HDL cholesteryl esters (CE) and VLDL triglycerides leading to catabolism of HDL. There is some evidence that HDL ameliorates the toxicity of LPS, and LPS is known to influence several enzymes affecting HDL metabolism. Therefore, the effects of LPS on CETP and plasma lipoproteins were examined in human CETP transgenic mice. Administration of LPS to mice expressing a CETP transgene linked to its natural flanking sequences (NFR-CETP Tg) resulted in a rapid marked decrease in hepatic CETP mRNA and plasma CETP concentration. Corticosteroid injection produced a similar decrease in hepatic CETP mRNA and adrenalectomy abolished this response to LPS. LPS caused disproportionate reductions in plasma CETP activity compared to mass, and was found to be a potent inhibitor of CETP activity when added directly to plasma. LPS was injected into mice expressing (A) a human apoA-I transgene, (B) apoA-I and NFR-CETP transgenes, or (C) apoA-I and LPS-inducible metallothionein promoter-driven CETP transgenes, producing (A) minimal changes in HDL cholesterol, (B) decreased plasma CETP and increased HDL cholesterol, and (C) increased plasma CETP and decreased HDL cholesterol. Thus, LPS administration produces a profound decrease in hepatic CETP mRNA, primarily as a result of adrenal corticosteroid release. The decrease in plasma CETP activity after LPS administration may reflect both this effect as well as a direct interaction between CETP and LPS. The decrease of CETP in response to LPS has major effects on HDL levels, and may represent an adaptive response to preserve or increase HDL and thereby modify the response to LPS.

Animals↗