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C Mathieu

Publications and source records attributed to C Mathieu.

At least 55 records · Page 3Linked to original sources
PubMed2001

Posttransplantation diabetes mellitus in FK-506-treated renal transplant recipients: analysis of incidence and risk factors.

BACKGROUND: The development of posttransplantation diabetes mellitus has a major impact on the quality of life and long-term outcome. METHODS: One hundred thirty-nine patients without known glucose metabolism abnormalities and treated with FK-506, methylprednisolone, and mycophenolate mofetil/azathioprine were analyzed for incidence of and risk factors for developing impaired fasting glycemia (IFG) and diabetes mellitus (DM). RESULTS: Using the American Diabetes Association criteria, 15% developed IFG and 32% developed DM in the first year after transplantation. High trough levels of FK-506 during the first month after transplantation (especially >15 ng/ml) and high body mass index (BMI) were significant risk factors for IFG or DM. Patients with (steroid-treated) acute rejections in addition to high trough levels of FK-506 were most prone to develop DM, whereas high BMI conferred risk of developing IFG. Patients with posttransplantation glycemic abnormalities also had higher levels of serum triglycerides at the time of transplantation, but they needed a lower dose of FK-506 to obtain higher trough levels of FK-506, suggesting metabolic differences already present before transplantation. The only risk factor retained for persistent IFG or DM beyond the first year was a higher number of trough levels of FK-506 >15 ng/ml during the first month after transplantation. CONCLUSIONS: Induction with an FK-506 based immunosuppressive regimen resulted in a high incidence of glucose metabolism disorders in renal transplantation recipients. Higher trough levels of FK-506 during the first month, acute rejections, and higher BMI were the most obvious risk factors.

Adult↗
PubMed2001

Transforming growth factor-beta inhibits lymphokine activated killer cytotoxicity of bone marrow cells: implications for the graft-versus-leukemia effect in irradiation allogeneic bone marrow chimeras.

BACKGROUND: We have previously shown that allogeneic bone marrow (BM) chimeras preconditioned with total lymphoid irradiation and low-dose total body irradiation (TLI/TBI) develop a stronger graft-versus-leukemia (GVL) effect than chimeras preconditioned with high-dose total body irradiation only (TBI). Here, we report on the possible role of cytokines in the mechanism underlying this GVL effect. METHODS: Splenic mRNA levels of the cytokines interleukin (IL)-1, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-15, interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta (TGF-beta), and of inducible nitric oxide synthetase were determined by reverse transcription-polymerase chain reaction in TLI/TBI- or TBI-conditioned C3H/AKR BM chimeras challenged with AKR-type BW5147.3 leukemia cells. Ex vivo TGF-beta protein production by splenocytes was determined using ELISA. The possibility that cytokines influence the GVL effect by modulating the activity of IL-2-activated lymphocytes (LAK cells) was investigated by in vitro assays on donor-type BM cells. RESULTS: Of all cytokine mRNA levels studied, those of TGF-beta and IL-7 were different between groups; both were significantly more elevated in TBI- than in TLI/ TBI-conditioned or normal mice. Differences were apparent after conditioning and were not influenced by additionally injected BM or leukemia cells. Cultured splenocytes of TBI-conditioned animals produced significantly more TGF-beta protein than those of TLI/TBI-conditioned ones or normal controls. r-TGF-beta but not r-IL-7 suppressed in vitro LAK activity of donor-type BM cells against BW5147.3 cells in a dose-dependent way. CONCLUSIONS: High-dose TBI-induced, host-derived splenic TGF-beta may inhibit generation of LAK cells from subsequently transplanted donor BM cells, suppressing their capacity to generate cytotoxicity upon injection of leukemia cells. The cytokine profile, induced by irradiation in host hematopoietic organs, can significantly modify posttransplant immunological processes such as the GVL effect and graft-versus-host disease (GVHD).

Animals↗
PubMed2001

Role of interleukin-12 in the induction of mucosal inflammation and abrogation of regulatory T cell function in chronic experimental colitis.

IL-12 promotes Th1 cell differentiation and cell-mediated immunity. In the present study, the potential role of IL-12 was analyzed in an experimental colitis model in scid mice reconstituted with syngeneic CD45RBhighCD4+ T cells. Real-time reverse transcription-PCR studies demonstrated that IL-12 p40 mRNA in inflamed colon is induced shortly after T cell transfer and maintained at a stable level after week 4, at the time when wasting disease starts. Administration of anti-IL-12 on days 0,14, and 28 (early treatment) or on days 28, 42, and 56 (delayed treatment) after T cell transfer, effectively prevented or, respectively cured wasting disease and colitis in scid recipients. Anti-IL-12 treatment abrogated mucosal inflammation with significantly diminished leukocyte infiltration (CD4 cells, macrophages) and CD54 expression, and down-regulated proinflammatory cytokines IFN-gamma and IL-2. Of note, although splenic CD4+ T cells are unable to induce disease as a result of the presence of regulatory CD45RBlow cells, splenic CD4+ T cells, preactivated by IL-12 and anti-CD3 in vitro, were highly pathogenic in inducing severe mucosal inflammation, suggesting that IL-12 and anti-CD3 abrogated regulatory T cell function. These findings indicate that IL-12 is important for the induction of experimental colitis through effects on proinflammatory cytokine production and on regulatory T cell function.

Animals↗
PubMed2001

An overview of real-time quantitative PCR: applications to quantify cytokine gene expression.

The analysis of cytokine profiles helps to clarify functional properties of immune cells, both for research and for clinical diagnosis. The real-time reverse transcription polymerase chain reaction (RT-PCR) is becoming widely used to quantify cytokines from cells, body fluids, tissues, or tissue biopsies. Being a very powerful and sensitive method it can be used to quantify mRNA expression levels of cytokines, which are often very low in the tissues under investigation. The method allows for the direct detection of PCR product during the exponential phase of the reaction, combining amplification and detection in one single step. In this review we discuss the principle of real-time RT-PCR, the different methodologies and chemistries available, the assets, and some of the pitfalls. With the TaqMan chemistry and the 7700 Sequence Detection System (Applied Biosystems), validation for a large panel of murine and human cytokines and other factors playing a role in the immune system is discussed in detail. In summary, the real-time RT-PCR technique is very accurate and sensitive, allows a high throughput, and can be performed on very small samples; therefore it is the method of choice for quantification of cytokine profiles in immune cells or inflamed tissues.

Animals↗
PubMed2001

[High risk alcohol consumption in a sample of patients of the Lausanne University Medical Polyclinic].

OBJECTIVES AND METHODS: This study indicates the prevalence, the characteristics, and the screening methods of patients with at risk alcohol drinking at the University Medical Clinic of Lausanne. RESULTS: The results reported demonstrate that one patient out of six is a drinker at risk without criteria for alcohol-dependance. The questionnaire AUDIT (Alcohol Use Disorders Identification Test) with a cut-off of five points seems to be the best screening test for at risk alcohol consumption. CONCLUSIONS: The high prevalence of at risk drinking in this study, combined with scientific evidence of the efficiency of brief interventions in changing drinking habits, emphasises the importance of alcohol screening for all patients attending outpatient medical settings.

Adolescent↗
PubMed2001

Male-to-female excess in diabetes diagnosed in early adulthood is not specific for the immune-mediated form nor is it HLA-DQ restricted: possible relation to increased body mass index.

UNLABELLED: AIMS/HYPOTHESIS. We investigated whether the reported HLA-DQ/DR restricted male-to-female (M:F) excess in Type I (insulin-dependent) diabetes mellitus also exists in Belgian patients, is specific for immune-mediated diabetes, remains genotype-restricted after adjustment for age at diagnosis, and is associated with sex-dependent environmental factors. METHODS: Autoantibodies, HLA-DQ and 5'INS (5'insulin gene) polymorphisms were assessed in 2,532 diabetic patients (all phenotypes) diagnosed under 40 years of age. Autoantibodies and body mass index (expressed as a standard deviation score by comparison to age-matched and sex-matched control subjects; SDS-BMI) were measured in 1986 siblings or offspring of Type I diabetes patients (0-39 years). RESULTS: In patients aged 15-39 years at diagnosis, the male-to-female ratio was 1.5 or more regardless of their antibody status and significantly higher (p < 0.001) than that in the age-matched Belgian general population. There was no sex bias in patients under 15 years of age. Overall, the male-to-female ratio was significantly higher in patients without HLADQA1*0301-DQB1*0302 (p < or = 0.003) but stratification in age groups and multivariate analysis identified age as the major determinant of male-to-female ratio. The SDS-BMI increased (p < 0.01) in male antibodypositive relatives (n = 103) but not in female antibody-positive (n = 92) or in antibody-negative relatives (n = 1,791). This phenomenon tended to be restricted to male relatives who were positive only for glutamate decarboxylase antibodies (n = 44). CONCLUSIONS/INTERPRETATION: The male-to-female excess in Belgian diabetic patients diagnosed in early adulthood is not specific for immune-mediated Type I diabetes and not HLA-DQ or 5'INS restricted. Our data suggest that, similar to Type II (non-insulin-dependent) diabetes mellitus, the metabolic burden of obesity and insulin resistance could preferentially precipitate postpubertal clinical onset in male subjects with slowly progressive subclinical (immune-mediated) diabetes.

Adolescent↗
PubMed2001

Monocyte chemoattractant protein-1 is expressed in pancreatic islets from prediabetic NOD mice and in interleukin-1 beta-exposed human and rat islet cells.

AIMS/HYPOTHESIS: Monocyte chemoattractant protein-1 (MCP-1) attracts monocytes and T lymphocytes, and could thus contribute to mononuclear cell infiltration in Type I (insulin-dependent) diabetes mellitus. Cytokines induce MCP-1 mRNA expression in pancreatic rat beta cells. To investigate this issue, we analysed the signal transduction for IL-1 beta-induced MCP-1 expression in rat beta cells and in vitro MCP-1 mRNA expression and protein release by human islets as well as in vivo islet MCP-1 mRNA expression in prediabetic non-obese diabetic mice. METHODS: Fluorescence-activated cell sorting-purified rat beta cells were cultured for 6 h with IL-1 beta (30 U/ml) or MAPK inhibitors or both. Human islets were cultured for 6-72 h with the cytokines IL-1 beta, IFN-gamma or the inducible nitric oxide synthase (iNOS) inhibitor NG-methyl-L-arginine or both. We measured MCP-1 mRNA by RT-PCR and protein by ELISA. The MCP-1 mRNA expression in islets from male and female non-obese diabetic mice (2-12 weeks of age) was measured by real time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Interleukin-1 beta induced MCP-1 mRNA expression in rat beta cells, with a maximum induction after 6 h. A combination of p38 and ERK1/2 inhibitors decreased MCP-1 expression by 70%. IL-1 beta induced both MCP-1 mRNA expression and a threefold increase in medium MCP-1 protein accumulation in human islet cells. This effect was not prevented by iNOS blockers. In vivo there was an age-related increase in MCP-1 mRNA expression in islets from male and female non-obese diabetic mice, reaching a peak at 8 weeks. CONCLUSIONS/INTERPRETATION: In rat and human islet cells MCP-1 mRNA is induced by IL-1 beta. Both ERK1/2 and p38 MAPK, but not nitric oxide, contribute to MCP-1 expression. In non-obese diabetic mice MCP-1 mRNA expression increases with age, peaking at the early phases of insulitis. The production of MCP-1 by pancreatic beta cells could contribute to the recruitment of mononuclear cells into pancreatic islets in early Type I diabetes.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Dual role of interferon-gamma signalling pathway in sensitivity of pancreatic beta cells to immune destruction.

AIMS/HYPOTHESIS: Disruption of the interferon-gamma (IFN-gamma) signalling pathway at the level of interferon regulatory factor-1 (IRF-1) protects islets against cytokine-induced nitric oxide production and cell death in vitro. The aim of this study was to investigate the effects of a global disruption of IFN-gamma signalling, or a selective disruption of IRF-1, on beta-cell sensitivity to in vivo immune destruction. METHODS: In a first set of experiments, IFN-gamma receptor knockout mice (IFN-gammaR-/-) and interferon regulatory factor-1 knockout mice (IRF-1-/-) were rendered diabetic by injections of 50 mg streptozotocin i. p. on 5 consecutive days (MLDSTZ). RESULTS: Whereas no difference in sensitivity to MLDSTZ-induced diabetes could be observed between IFN-gammaR-/- mice and their 129/Sv/Ev controls (50% vs 55%, NS), there was an increased incidence of diabetes in IRF-1-/- mice (100% vs 67% in C57B1/6 mice, p < 0.05). A similar increased sensitivity to immune destruction of IRF-1-/- islets was observed when these islets were used as allografts. Islet graft survival rate of IFN-gammaR-/- and 129/Sv/Ev islets, when transplanted in alloxan-diabetic BALB/c recipients, was comparable (12.0 +/- 1.9 days vs 12.9 +/- 2.3 days, NS). Allograft rejection, however, of IRF-1-/- islets by BALB/c recipients occurred more rapidly than following transplantation to their C57B1/6 controls (9.1 +/- 2.0 days vs 13.1 +/- 1.5 days, p < 0.003). CONCLUSIONS/INTERPRETATION: These data indicate that IFN-gamma signal transduction at the beta-cell level is not essential for immune beta-cell destruction in vivo. Moreover, disruption of the IRF-1 gene in pancreatic islets increases susceptibility to beta-cell killing, suggesting that IRF-1 might be necessary for the expression of putative beta-cell "defence and/or repair" genes.

Animals↗
PubMed2001

Gonadotropin level abnormalities in women with cyclic mastalgia.

OBJECTIVES: Women with cyclic mastalgia seem to be at risk of fibrocystic breast disease and/or breast cancer. We studied the relationships between mastalgia and hormone levels throughout the menstrual cycle. STUDY DESIGN: Ostensibly healthy women were monitored during a sum of 326 cycles. A case-control study compared personal and hormonal variables of 30 women experiencing cyclic mastalgia with those of 77 women without this symptom. RESULTS: Except sleeping times, no significant differences were found in personal variables. Cyclic mastalgia and symptoms of fluid retention were slightly associated. Menses and the luteal phase were significantly longer in cases than in controls. Gonadotropin but not ovarian hormone levels were also significantly higher in cases throughout the cycle. CONCLUSION: Cyclic mastalgia is less related to symptoms of fluid retention or to ovarian hormone levels than to regularly high gonadotropin levels, specific inhibitors might thus be used to alleviate the symptom.

Adult↗
PubMed2001

A Medicago truncatula homoglutathione synthetase is derived from glutathione synthetase by gene duplication.

Glutathione (GSH) and homo-GSH (hGSH) are the major low-molecular weight thiols synthesized in Medicago truncatula. Two M. truncatula cDNAs (gshs1 and gshs2) corresponding to a putative GSH synthetase (GSHS) and a putative hGSH synthetase (hGSHS) were characterized. Heterologous expression of gshs1 and gshs2 cDNAs in an Escherichia coli strain deficient in GSHS activity showed that GSHS1 and GSHS2 are a GSHS and an hGSHS, respectively. Leucine-534 and proline-535 present in hGSHS were substituted by alanines that are conserved in plant GSHS. These substitutions resulted in a strongly stimulated GSH accumulation in the transformed E. coli strain showing that these residues play a crucial role in the differential recognition of beta-alanine and glycine by hGSHS. Phylogenetic analysis of GSHS2 and GSHS1 with other eukaryotic GSHS sequences indicated that gshs2 and gshs1 are the result of a gene duplication that occurred after the divergence between Fabales, Solanales, and Brassicales. Analysis of the structure of gshs1 and gshs2 genes shows they are both present in a cluster and in the same orientation in the M. truncatula genome, suggesting that the duplication of gshs1 and gshs2 occurred via a tandem duplication.

Amino Acid Sequence↗
PubMed2001

In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice.

Immune cells carry receptors for 1,25-dihydroxyvitamin D3 [1,25(OH)2D3; vitamin D receptor (VDR)] and individuals with severe vitamin D deficiency have immune abnormalities. The aim of this study was to investigate the role of vitamin D in the immune system by studying VDR-knockout (VDR-KO) mice. VDR-KO mice had the same metabolic phenotype as rachitic animals with severe hypocalcemia. Leukocytosis, lymphocyte subset composition in different immune organs, and splenocyte proliferation to several stimuli were normal, except for a lower response to anti-CD3 stimulation (simulation index [SI] of 13 +/- 4 vs. 24 +/- 9 in wild-type mice; p < 0.01). Macrophage chemotaxis was impaired (41 +/- 19% vs. 60 +/- 18% in wild-type mice; p < 0.01) but phagocytosis and killing were normal. In vivo rejection of allogeneic (31 +/- 12 days vs. 45 +/- 26 days of survival in wild-type mice, NS) or xenogeneic (10 +/- 2 days vs. 16 +/- 9 days of survival in wild-type mice, NS) islet grafts was comparable with wild-type mice. Surprisingly, VDR-KO mice were protected from low-dose streptozotocin-induced diabetes mellitus (LDSDM; 5% vs. 65% in wild-type mice; p < 0.001). Correcting hypocalcemia by use of lactose-rich or polyunsaturated fat-rich diets fully restored the immune abnormalities in vitro and the sensitivity to diabetes in vivo. On the other hand, treatment with 1,25(OH)2D3 protected wild-type mice against diabetes but did not protect normocalcemic VDR-KO mice. We conclude that immune defects observed in VDR-KO mice are an indirect consequence of VDR disruption because they can be restored by calcium homeostasis normalization. This study proves that although 1,25(OH)2D3 is a pharmacologic and probably a physiological immunomodulator, its immune function is redundant. Moreover, we confirm the essential role of calcium in the immune system.

Adjuvants, Immunologic↗
PubMed2000

Conceptually new 20-epi-22-oxa sulfone analogues of the hormone 1alpha,25-dihydroxyvitamin D(3): synthesis and biological evaluation.

New C,D-ring side-chain-modified sulfone 4a, with natural 1alpha, 3beta-hydroxyl groups but lacking the 25-hydroxyl group characteristic of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1), has been prepared and characterized. Novel synthetic features include: (1) chemoselective oxidation of only a primary silyl ether in a primary-secondary bis-silyl ether intermediate and (2) smooth reductive etherification without interference by a neighboring sulfonyl group. Sulfone 4a, but not its 1beta, 3alpha-diastereomer 4b, is powerfully antiproliferative and transcriptionally active in vitro but desirably noncalcemic in vivo. Although sulfone 4a, designed to resemble Leo Pharmaceutical Co.'s KH-1060 (3), is recognized by catabolic enzymes, the selective biological profile of sulfone 4a is likely not due to its metabolites that are formed in only minor amounts.

Animals↗
PubMed2000

Ultrashort microwave pulses generated due to three magnon interactions

Extremely narrow 2 ns wide microwave pulses are generated from nonlinear magnetostatic surface waves in yttrium iron garnet films. The shortest output pulse with the highest amplitude is achieved for input power levels of about 300 mW and a carrier frequency below 3.3 GHz. The results are explained within the model based on dipole exchange spin wave modes involved in three magnon processes. The characteristic time for these processes to develop, as estimated from the smallest fall time of output pulse, is 1 ns. The relevant modes are verified by Brillouin light scattering.

Journal Article↗
PubMed2000

Prevention of experimental colitis in SCID mice reconstituted with CD45RBhigh CD4+ T cells by blocking the CD40-CD154 interactions.

Increased expression of CD40 and CD40 ligand (CD40L or CD154) has been found in inflamed mucosa of human inflammatory bowel disease (IBD), and interactions between these molecules seem to be involved in local cytokine production by macrophages. However, the precise role of CD40 signaling in the pathogenesis of IBD is still poorly understood. The aim of the present study was to investigate the in vivo relevance of CD40 signaling in experimental colitis in SCID mice reconstituted with syngeneic CD45RBhighCD4+ T cells. The results demonstrated that CD40+ and CD40L+ cells as well as their mRNA levels were significantly increased in inflamed mucosa. Administration of anti-CD40L neutralizing mAb over an 8-wk period starting immediately after CD45RBhighCD4+ T cell reconstitution completely prevented symptoms of wasting disease. Intestinal mucosal inflammation was effectively prevented, as revealed by abrogated leukocyte infiltration and decreased CD54 expression and strongly diminished mRNA levels of the proinflammatory cytokines IFN-gamma, TNF, and IL-12. When colitic SCID mice were treated with anti-CD40L starting at 5 wk after T cell transfer up to 8 wk, this delayed treatment still led to significant clinical and histological improvement and down-regulated proinflammatory cytokine secretion. These data suggest that the CD40-CD40L interactions are essential for the Th1 inflammatory responses in the bowel in this experimental model of colitis. Blockade of CD40 signaling may be beneficial to human IBD.

Animals↗