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Biomedical subjects

G G Leroux-Roels

Publications and source records attributed to G G Leroux-Roels.

At least 19 recordsLinked to original sources
PubMed2000

Mouse strain and conditioning regimen determine survival and function of human leucocytes in immunodeficient mice.

The innate immune system of severe combined immunodeficient (SCID) mice represents an important barrier to the successful engraftment of human cells. Different genetic and pharmacological strategies improve the graft survival. Non-obese diabetic (NOD)-SCID mice are better hosts for reconstitution with human peripheral blood leucocytes (Hu-PBL) because of their reduced natural killer cell and macrophage activity next to defective T and B cell functions. We investigated effects of TM-beta1, a rat monoclonal antibody recognizing the mouse IL-2 receptor beta-chain, on Hu-PBL survival and function in NOD-SCID and SCID mice. Relative to untreated littermates, TM-beta1 improved Hu-PBL survival in SCID and NOD-SCID mice. Moreover, TM-beta1-pretreated NOD-SCID mice displayed significantly better Hu-PBL survival and tissue distribution than TM-beta1-pretreated SCID mice. Irradiation of NOD-SCID mice further enhanced the effects of TM-beta1. However, these animals died within 3 weeks post-grafting due to graft-versus-host disease. Secondary immune responses were evaluated with Hu-PBL from a donor immune to hepatitis B surface antigen (HBsAg). In TM-beta1-pretreated NOD-SCID mice, human HBsAg-specific memory B cells produced high titres of anti-HBsAg immunoglobulin irrespective of the administration of a secondary antigen booster dose. This contrasts with secondary immune responses in TM-beta1-pretreated SCID mice where high titred antigen-specific immunoglobulins were produced when the appropriate antigen booster was given. In conclusion, reducing the function of the innate immune system in immunodeficient mice improves survival of the human graft and can result in an activation of the memory B cells without the need for recall antigen exposure.

Animals↗
PubMed1998

Serum creatine kinase activity is not a reliable marker for muscle damage in conditions associated with low extracellular glutathione concentration.

Creatine kinase (CK, EC 2.7.3.2) assays usually contain thiol-reducing compounds to restore the enzyme activity. In this study, we investigated the effect of endogenous extracellular glutathione on serum CK activity. We examined CK activity and glutathione concentrations in serum from 200 healthy subjects (107 males, 93 females) and 38 patients with multiple organ failure, muscle wasting, and low serum CK activity (<50 U/L) (24 males, 14 females). Muscle damage was further evaluated using serum myoglobin concentrations and aldolase activity. In the overall group, serum glutathione concentrations correlated with serum CK activity (r = 0.791) but not with myoglobin concentrations and aldolase activity. In patients with multiple organ failure, low serum CK activities were accompanied by extremely low serum glutathione concentrations (<0.5 ,micromol/L, P <0.001). Endogenous glutathione can be regarded as a CK-preserving agent during the lifetime of the enzyme in the circulation (22 h on average). Serum CK activity should be interpreted with caution in patients with liver disease and multiple organ failure. In these conditions, the loss of CK activity due to extracellular glutathione depletion cannot be restored by the presence of thiol-reducing compounds in the CK assays.

Adult↗
PubMed1996

Genetic polymorphisms and erythrocyte sodium-lithium countertransport in essential hypertension.

Erythrocyte sodium-lithium countertransport (SLC) activity is elevated in essential arterial hypertension. With the growing attention to the genetic substrate of disturbed biochemical tests associated with essential arterial hypertension, we were particularly interested in the involvement of key genes for the regulation of SLC, possibly related to the pathophysiology of essential arterial hypertension. Consequently, the aim of the present study was to investigate SLC and its determining factors in essential hypertension. The influence of haptoglobin (Hp)-polymorphism, insertion/deletion polymorphism of angiotensin converting enzyme (ACE-I/D) and MNS blood group system on the regulation of SLC was studied. SLC activity was studied in a cross-sectional case-control study including 90 Caucasians: 60 patients with essential arterial hypertension who had been treated for at least 1 year and 30 normotensive controls. In essential hypertension, the SLC activity is significantly higher (P = 0.00005) than in controls. In normotensive patients, no differences in SLC are observed for the different polymorphisms studied. However, in the hypertensive group, SLC activity is higher (P = 0.003) in Hp 2-1 phenotype and independent of ACE-I/D genotyping and MNS blood group polymorphism. Multifactor analysis of variance in essential hypertension reveals significant (P = 0.001) differences in SLC activity for the presence or absence of Hp 2-1 phenotype and for body weight (P = 0.0003). Multivariate regression analysis shows the same parameters to be independent determining factors of SLC in essential arterial hypertension. No relation is found between SLC activity and target organ damage which includes coronary artery disease, peripheral arterial occlusive disease, left ventricular hypertrophy and cerebrovascular accident. We conclude that erythrocyte SLC activity is elevated despite pressure-lowering therapy. In essential arterial hypertension, individuals of Hp 2-1 phenotype show higher SLC activity than patients of other Hp-types, suggesting genetic heterogeneity of essential arterial hypertension. The presence or absence of Hp 2-1 phenotype is an independent determining factor of SLC activity whereas body weight codetermines SLC activity in essential hypertension.

Adult↗
PubMed1996

Haptoglobin polymorphism and chronic hepatitis C.

BACKGROUND/AIMS: Haptoglobin (Hp) is a hemoglobin-binding acute phase protein characterized by a genetic polymorphism due to the existence of two different alleles encoding for the alpha chain of the protein. Three phenotypes have been described: Hp 1-1, Hp 2-1 and Hp 2-2. The latter two forms are known to possess immunoglobulin-like properties and play a role in the immune response. Recently, it has been shown that in subjects suffering from hepatitis C, serum Hp concentrations were lower than in the reference population. In the present study we examined whether the haptoglobin phenotype distribution in chronic HCV patients was different from the reference population. We also looked for possible relationships between Hp phenotypes and hepatitis C virus types and response to interferon alpha therapy. Moreover, Hp concentrations were determined. METHODS: The study population consisted of 239 Caucasian patients with proven hepatitis C. Hp phenotypes were determined using starch gel electrophoresis of hemoglobin-supplemented serum, followed by peroxidase staining. Serum Hp concentrations were assayed with an immunonephelometric method. Hepatitis C virus was genotyped and classified according to an internationally accepted system. Two hundred and twenty healthy Caucasian blood-donors served as the reference population. RESULTS: In the reference population, 35 individuals (15.9%) had Hp 1-1, 106 persons (48.2%) had Hp 2-1 and 79 had Hp 2-2 (35.9%), resulting in an Hp 1 allele frequency of 0.400, which is in agreement with the Hardy-Weinberg equilibrium. Hp phenotype distributions and Hp allele frequencies in the chronic hepatitis C virus patient group differed significantly from those obtained in the reference population. In the patient population, 59 individuals (24.7%) had Hp 1-1, 112 persons (46.9%) had Hp 2-1 and 68 had Hp 2-2 (28.5%). This resulted in an Hp 1 allele frequency of 0.481, which is in agreement with the Hardy-Weinberg equilibrium. No statistically significant differences were found between Hp phenotype distribution and hepatitis C virus types or response to interferon alpha therapy. CONCLUSIONS: The observed shift in Hp phenotype distribution in chronic hepatitis C may point to a role of Hp in the natural evolution of hepatitis C.

Adult↗
PubMed1996

Quantitative nephelometric assay for determining alpha-foetoprotein evaluated.

A recently introduced automated nephelometric immunoassay involving shell/core particles for determination of alpha-foetoprotein in serum and amniotic fluid was evaluated with the Behring Nephelometer analyser II. Method stability was good: reconstituted reagents and calibration curve were stable for at least one week. The intra-assay CV varied between 2.3% and 4.0%. The inter-assay CV varied between 3.5% and 4.6%. Samples with alpha-foetoprotein concentrations up to 273000 micrograms/l were analysed without high-dose "hook" effect after automatic dilution. No significant interference from haemoglobin, bilirubin, rheumatoid factors, or human anti-mouse antibodies was detected up to concentrations of 0.15 mmol/l haemoglobin, 268 mumol/l bilirubin, 470 int, units/l rheumatoid factor and a titre of 1/1000 human anti-mouse antibodies. Interference due to triacylglycerols depended on the size of triacylglycerol containing particles: for VLDL, interference did not occur up to triacylglycerol levels of 6.0 mmol/l, for chylomicrons interference was already noted at triacylglycerol levels of 1.0 mmol/l. Correlation with a commercial RIA (Kabi Pharmacia) was excellent both for serum (n = 65) and amniotic fluid (n = 100). The effect of the molecular variation of the carbohydrate moiety of alpha-foetoprotein on the test results was studied using concanavalin A affinity chromatography. The detection of both concanavalin A-reactive and concanavalin A-non-reactive alpha-foetoprotein was equivalent by both methods. Multimeric forms of alpha-foetoprotein were prepared by gel permeation chromatography. The effect of autopolymerization of alpha-foetoprotein on the nephelometric determination of alpha-foetoprotein was negligible. We conclude that latex-enhanced immunonephelometry is a rapid, practical, and reliable method for measuring alpha-foetoprotein in serum and amniotic fluid.

Adult↗
PubMed1995

Refractory hypertension is associated with the haptoglobin 2-2 phenotype.

BACKGROUND: Many cases of refractory hypertension cannot be attributed to specific identifiable factors. Haptoglobin polymorphism has been suggested as a candidate genetic marker in essential hypertension. The aim of this study was to investigate the distribution of haptoglobin types in patients with refractory hypertension. METHODS: Haptoglobin polymorphism was studied in 383 patients with non-refractory and 62 patients with refractory hypertension. Haptoglobin was typed using starch gel electrophoresis of haemoglobin-supplemented serum. RESULTS: In the group of patients with refractory hypertension, the relative allele frequency of haptoglobin 1 (0.266) was lower than in the group with non-refractory hypertension (0.385: P < or = 0.05). The relative frequency of haptoglobin 2-2 was 39% in the non-refractory compared with 56% in the refractory group (P < or = 0.05). In the latter group, the relative frequency of haptoglobin 2-2 was highest (75%) in patients requiring medication with four classes of drug. CONCLUSION: Hypertension patients with the haptoglobin 2-2 phenotype are at higher risk of developing refractory hypertension than those with other haptoglobin phenotypes.

Alleles↗
PubMed1994

Glomerular filtration rate and creatinine production in adult icteric patients.

Various methods for serum creatinine determination were compared and validity of the Cockroft-Gault algorithm for calculating creatinine clearance was tested in adult icteric patients. Using conventional Jaffé assays, negative interference is proportional to the serum bilirubin content. Pretreatment of the serum with bilirubin oxidase was more efficient in eliminating bilirubin than pretreatment with potassium ferricyanide. Due to a continued creatine-poor diet and liver dysfunction, erythrocyte creatine levels and creatinine output rate were decreased. Median effect (creatinine equivalent) of non-specific chromogens in the unmodified Jaffé assay was 21 mumol/l (range: 1-108 mumol/l), vs. 19 mumol/l (range: 16-26 mumol/l) for the reference population. In the absence of multi-organ failure, the Cockroft-Gault algorithm could be used for estimating glomerular filtration rate. In patients with multiple organ failure however, we recommend correction for both bilirubin and non-specific chromogens for measuring the serum creatinine concentration.

Adult↗
PubMed1994

Posttranslational heterogeneity of bone alkaline phosphatase in metabolic bone disease.

Bone alkaline phosphatase is a marker of osteoblast activity. In order to study the posttranscriptional modification (glycosylation) of bone alkaline phosphatase in bone disease, we investigated the relationship between mass and catalytic activity of bone alkaline phosphatase in patients with osteoporosis and hyperthyroidism. Serum bone alkaline phosphatase activity was measured after lectin precipitation using the Iso-ALP test kit. Mass concentration of bone alkaline phosphatase was determined with an immunoradiometric assay (Tandem-R Ostase). In general, serum bone alkaline phosphatase mass and activity concentration correlated well. The activity : mass ratio of bone alkaline phosphatase was low in hyperthyroidism. Activation energy of the reaction catalysed by bone alkaline phosphatase was high in osteoporosis and in hyperthyroidism. Experiments with neuraminidase digestion further demonstrated that the thermodynamic heterogeneity of bone alkaline phosphatase can be explained by a different glycosylation of the enzyme.

Adult↗
PubMed1993

Haptoglobin polymorphism and complications in established essential arterial hypertension.

OBJECTIVE: Salt sensitivity and the magnitude of systolic blood pressure have been linked to haptoglobin (Hp) polymorphism in normotensives. The aim of the present study was to investigate the indices of hypertension, the severity of complications and the occurrence of coronary and peripheral artery disease for the various haptoglobin phenotypes and their relation to the therapeutic needs (number and class of drugs) of established arterial hypertensives. DESIGN: Haptoglobin polymorphism was studied in 302 Caucasians with established essential arterial hypertension who had been treated for at least 1 year. METHODS: Haptoglobin polymorphism was studied using starch-gel electrophoresis of haemoglobin-supplemented serum. RESULTS: The relative allele frequencies of Hp 1 and Hp 2 (0.036 and 0.640, respectively) in established hypertensives were comparable with those of the control population. Logistic regression analysis confirmed that Hp 2-2 contributes to the therapeutic needs in hypertension. The most important factors determining therapeutic needs were coronary artery disease, Hp 2-2 phenotype, body mass index (BMI) and left ventricular hypertrophy. Although no contributive effect of serum haptoglobin concentration could be derived from the logistic regression approach, analysis of serum haptoglobin concentration demonstrated a concentration-related effect on therapeutic needs for the Hp 2-2 phenotype only. CONCLUSIONS: The present study suggests that hypertensives with an Hp 2-2 phenotype need more complex combinations of antihypertensive drugs to reduce blood pressure to the same level. The hypertensive patient carrying Hp 2-2 is more likely to accumulate atherosclerotic lesions of the coronary or peripheral arteries, despite comparable lipid levels, smoking habits and BMI. Hp 1-1 patients are characterized by a younger age at diagnosis and a lower complication rate. In view of the greater therapeutic needs and the higher complication rate, Hp 2-2 hypertensives need more careful follow-up.

Aged↗
PubMed1992

Glycation of human tissue and serum creatine kinase.

Human creatine kinase (CK) was demonstrated to be partly present as a glycated molecule. Sialic acid, galactose and sulfate were also found to be present on the molecule. The glycated forms were characterized by higher activation energies and were thermally unstable. Skeletal muscle CK showed lower relative binding towards the lectin concanavalin A (Con A) in comparison with the heart tissue forms. After skeletal muscle trauma, CK in serum was found to be less glycated than in tissue. After acute myocardial infarction (AMI), no glycated CK could be detected in serum. Following injury, it appears that the transfer from tissue to plasma is accompanied by a loss of glycated isoforms. High-voltage electrophoresis showed no differences in the distribution of CK isoforms between the glycated and non-glycated forms.

Adult↗
PubMed1986

In vivo anti-tumour activity of recombinant human and murine TNF, alone and in combination with murine IFN-gamma, on a syngeneic murine melanoma.

TNF, a protein released by induced macrophages, is believed to mediate, at least in part, the tumoritoxic effects of activated macrophages. In vitro, it has cytotoxic effects on transformed cells but not on normal cells, and in vivo it causes necrosis of tumours. Recently, both human and murine TNF became available as pure recombinant proteins. Subsequent work confirmed its in vitro cytotoxic activity, selective for transformed cells, and revealed other, non-cytotoxic effects on some normal cells. In vitro, the B16BL6 melanoma cells, syngeneic with C57BL6 mice, are resistant to the cytotoxic effects of rTNF but become sensitive when they are also treated with rIFN-gamma. We report that established, s.c. B16BL6 tumours in vivo can be induced to necrotize and regress by a combined systemic treatment with rTNF and murine rIFN-gamma. Although TNF is not species-specific in vitro, the effects of treatment with human and murine rTNF in vivo are different: with murine rTNF, the synergism with rIFN-gamma is relatively less clear, the addition of IFN-gamma is not necessary to induce regression, toxicity is more pronounced and additional mechanisms of tumoritoxicity could be involved. Relapses are frequent but complete cures have been observed. These results give further evidence in favour of a potential clinical use of TNF in combination therapy, e.g. with IFN-gamma. However, there is still a need to develop better regimens, especially for consolidation, and to continue research in order to understand and limit the toxicity, which could be mediated by the activating effects of TNF on some normal cell types.

Animals↗
PubMed1985

Genetic regulation of the immune response to hepatitis B surface antigen (HBsAg). VI. T cell fine specificity.

In the companion paper it was demonstrated that the T cell proliferative response to HBsAg was controlled by I region genes as was previously shown for in vivo anti-HBs production. In this paper, the structural requirements for T cell recognition of HBsAg were compared with B cell (antibody) recognition of HBsAg. Secondly, we attempted to map determinants on HBsAg required for activation of HBsAg-primed T cells, and we examined the influence of I region genotype on the observed T cell antigenic fine specificity. The results of these studies indicate clear differences between T cell and B cell recognition of HBsAg. T cell activation required significantly less native structure as compared with antibody binding to HBsAg. Reduced and alkylated HBsAg, the subunit polypeptide P25, tryptic fragments of P25, and synthetic peptide analogues of HBsAg were all capable of eliciting a T cell proliferative response, whereas these "denatured" forms of the antigen bind anti-HBs marginally or not at all. Furthermore, the results suggest that T cell recognition sites on HBsAg do not necessarily overlap with B cell recognition sites. Examination of T cell fine specificity in a series of H-2 congenic strains, with the use of HBsAg, P25, tryptic fragments of P25, and synthetic peptides, revealed multiple T cell recognition sites on HBsAg, and the particular site(s) recognized is dependent on the H-2 genotype of the responding strain. Finally, preliminary results indicate that the specificity of human, HBsAg-primed T cells appear to be variable among individuals.

Animals↗
PubMed1984

Genetic regulation of the immune response to hepatitis B surface antigen (HBsAg). IV. Distinct H-2-linked Ir genes control antibody responses to different HBsAg determinants on the same molecule and map to the I-A and I-C subregions.

We have previously demonstrated that the murine humoral immune responses to the group-specific a and subtype-specific d/y determinants of hepatitis B surface antigen (HBsAg) are controlled by H-2-linked immune response (Ir) genes. High responder (H-2d,q), intermediate responder (H-2a greater than b greater than k) and nonresponder (H-2f,s) haplotypes have been identified (8, 9). The kinetics and specificity of in vivo antibody production after HBsAg immunization in congeneic, H-2-recombinant strains was analyzed to further define relevant Ir genes and their influence on the immune response to distinct antigenic determinants. These studies indicate that the humoral anti-HBs response is regulated by at least two Ir genes, one in the I-A subregion (Ir-HBs-1) and one in the I-C subregion (Ir-HBs-2) of the murine H-2 complex. Ir-HBs-1 regulates the primary responses to all HBsAg determinants, whereas the influence of Ir-HBs-2 is determinant specific, affecting the responses to the d or y determinants. The anti-a response is regulated exclusively by Ir-HBs-1. Strains possessing only the Ir-HBs-2 gene [B10.S(9R) and B10.HTT] produce no anti-a response and a subtype-specific antibody response is detected only after secondary or tertiary immunization. In contrast, the influence of Ir-HBs-2 in the presence of Ir-HBs-1 is detected upon primary immunization and is additive rather than exclusive. There is also suggestive evidence that the presence of the Ek molecule, at least in the context of I-Ak, may have a suppressive influence on the anti-HBs response. Additionally, HBsAg-specific, T cell proliferative responses were H-2 restricted and the kinetics and specificity of T cell proliferative responses paralleled in vivo antibody production. These data indicate that, although the I-A subregion exerts a dominant influence, distinct Ir-HBs genes, mapping in separate I subregions, control immune responses to alternate HBsAg determinants on the same protein molecule.

Animals↗
PubMed1983

Genetic regulation of the immune response to hepatitis B surface antigen (HBsAg). II. Qualitative characteristics of the humoral immune response to the a, d, and y determinants of HBsAg.

It was previously demonstrated that the murine humoral immune responses to the common a and subtype-specific d determinants of HBsAg are H-2 restricted. The H-2q haplotype confers high responsiveness and the H-2s haplotype low responsiveness to nonresponsiveness to both determinants. We have now demonstrated that the H-2s haplotype also confers nonresponsiveness to the subtype-specific y determinant as well. Studies of H-2 congenic (nonresponder X responder)F1 and backcross mice indicated that responsiveness was inherited as a dominant trait, with no gene dosage effects observed. Qualitative characteristics of the humoral anti-a and anti-d responses were evaluated with respect to strain variation, kinetics, antigen specificity and antibody titer, affinity, and subclass distribution. Unique immune response patterns were observed for each H-2 haplotype studied. On the basis of these patterns, it was possible to construct a hierarchy of responsiveness to HBsAg of the ad subtype as follows: high responders, H-2q and H-2d; intermediate responders, H-2a greater than H-2b greater than H-2k; and nonresponders, H-2s.

Animals↗
PubMed1982

A novel alkaline phosphatase isozyme in 4 patients with acute non-lymphocytic leukemia: its nature, origin and clinical significance.

A novel alkaline phosphatase (AP) isozyme has been observed in the serum of 4 patients suffering from acute non-lymphocytic leukemia (ANLL). It resembled the AP of liver/bone origin in most physico-chemical characteristics, but particular electrophoretic characteristics in agar and starch gel and a distinct molecular weight gave this novel AP isozyme its unique character. Its leukemic origin has been demonstrated by isolation from peripheral blood and bone and bone marrow blasts. The appearance of the novel AP isozyme in the patients' sera appeared to be an ominous sign as, in all four, it shortly preceded death. In patients it may have contributed to the observed resistance towards thioguanine therapy.

Acute Disease↗