[Cardiovascular risk in autoimmune and inflammatory disorders]. / Le risque cardiovasculaire dans les maladies auto-immunes systémiques.

Atherosclerosis (ATS) is characterized by an inflammatory process initiated by oxidized LDL in the vessel wall, where activation of cells of the innate and adaptive immune system takes place. ATS is accelerated with an increased risk of cardiovascular (CV) events in systemic autoimmune disorders (AID) such as systemic lupus erythematosus or rheumatoid arthritis (RA). In addition to the traditional CV risk factors, which are over-represented in AID, the underlying chronic inflammation and dysregulation of the immune system play an amplifying role in ATS. Although certain drugs used in AID can increase the CV risk, the control of the disease as permitted by TNF-blocking agents in RA, reduces this risk. The strategies specific to AID to reduce the CV risk remain to be better defined.

[Variation of amino acids in relation to age in Down syndrome subjects]. / Variation des acides aminés en fonction de l'âge chez des sujets trisomiques 21.

BACKGROUND: A preliminary study of plasma and urinary amino acid concentration in Down's syndrome subjects had shown some impairments. PATIENTS AND METHODS: A comparative study of the variations of amino acid concentration with age in Down's syndrome subjects aged 0 to 60 years and in control subjects aged 0 to 94 years was made in order to determine whether these impairments could be explained by generalized premature aging, or by a specific gene dosage effect. RESULTS: Two major changes (P < 0.001) were found in Down's syndrome: a decrease in plasma concentration of serine at any age, which could be due to a dosage effect of cytathionine-beta-synthase, and an increase in plasma lysine concentration in patients above 10 year's old, probably due to premature aging. Other minor changes were also present in plasma and urine, also possibly explained by premature aging. CONCLUSIONS: Other studies are necessary to evaluate possible consequences of such changes in the amino acid profiles.

Excessive glutamine sensitivity in Alzheimer's disease and Down syndrome lymphocytes.

In addition to clinical and neuropathological similarities between Alzheimer's disease and Down syndrome there are genetic and biochemical data which suggest common disease mechanism. Using an in vitro assay examining variations of the mitotic index in the presence or absence of various inhibitors or metabolites of purine and/or pyrimidine synthesis, we studied 19 Alzheimer disease patients and 16 patients with both Down syndrome and Alzheimer type dementia. A highly significant decrease in mitotic index in the presence of exogenous glutamine was noted in patients presenting an Alzheimer type dementia with or without associated Down syndrome. These findings suggest that glutamine sensitivity or some dysregulation of the glutamine/glutamate pathway may play a role in the pathogenesis of Alzheimer's disease. If these findings are confirmed, they would have important implications in the development of preventive strategies.

In vivo folic acid supplementation partially corrects in vitro methotrexate toxicity in patients with Down syndrome.

Patients with Down syndrome have been found to have characteristic in vivo and in vitro methotrexate toxicity. The in vitro methotrexate toxicity characteristic of Down syndrome can be diminished by the in vivo administration of supplemental high doses of folic acid. A possible explanation for the increased sensitivity to methotrexate which has been documented in patients with Down syndrome may be due to imbalances in nucleotide pools which result from a gene dosage effect and to greater methylation demands. Supplemental folic acid may be beneficial by virtue of a down-regulation of excess gene activity and may also provide needed monocarbons.

[Metabolic anomalies in trisomy 21: a method for analyzing lymphocyte cultures]. / Anomalies métaboliques dans la trisomie 21: méthode d'analyse sur cultures de lymphocytes.

Using a method of analysis which consists in the evaluation of the mitotic index of lymphocyte cultures to which different metabolites and anti-metabolites have been added, we studied various forms of mental retardation due to a chromosomal aberration and observed specific biochemical imbalances. Methotrexate sensitivity is characteristic of trisomy 21. A significant difference in purine synthesis pathway was observed between patients with Down syndrome without complications and those presenting with additional psychotic features. Inspite of a gene dosage effect for genes intervening in purine synthesis, lymphocytes from psychotic trisomy 21 patients seem unable to complete inosine synthesis. Lymphocytes from patients with Alzheimer's disease with or without trisomy 21 are excessively sensitive to exogenous glutamine.

Differences in purine metabolism in patients with Down's syndrome.

Three enzymes intervening in de novo purine synthesis, as well as cystathionine B-synthetase, have been mapped to chromosome 21. In order to gain a better understanding of purine synthesis anomalies in Down's syndrome, the present authors studied the variations in mitotic index of lymphocyte cultures to which various inhibitors or metabolites of purine synthesis had been added. In spite of common gene dosage effects, unexpected and highly significant differences were noted between Down's syndrome patients without complications and those presenting with additional psychotic features. In Down's syndrome patients without complications, a highly significant decrease in mitotic index was noted in the presence of exogenous inosine. A significant decrease in the presence of adenosine and guanosine was also noted. These findings are in keeping with the expected metabolic repercussions of genes mapped to chromosome 21. In Down's syndrome patients with psychotic complications, the in vitro reactions were quite different. A paradoxal increase in mitotic index was noted in the presence of inosine and of adenosine, but the response to guanosine did not differ from that observed in normal controls. These findings were unexpected and seem to indicate that, in spite of the gene dosage effect, psychotic Down's syndrome patients are unable to compensate abnormal purine synthesis and resulting imbalances. Furthermore, a marked difference in purine metabolic reactions was noted between Down's syndrome patients receiving supplemental folic/folinic acid and those on no therapy. This suggests that some modulation of the gene dosage effect may be possible.

Metabolic anomalies in cri du chat syndrome (5p-) lymphocytes and de novo purine synthesis.

Having previously demonstrated that patients with cri du chat, 5p- syndrome, have a highly significant excess of the plasmatic and urinary relative amount of asparagine and aspartate, the authors tested the hypothesis according to which this excess could be in relation with a defect of purine metabolism. Using a previously reported in vitro assay, they found a paradoxal increase in the mitotic index in the presence of L-alanosine in lymphocyte cultures of patients with 5p- who were on no medication. They also observed particularly severe toxicity to HAT medium. This response, apparently characteristic for 5p- syndrome, was highly significant when compared to the one observed in samples of normal controls, of patients with mental retardation of various etiologies, patients with Down syndrome or with Xqfra syndrome. When patients with cri du chat syndrome received inosine with folinic acid, an inversion of their response to alanosine was observed as well as the normalization of their response to HAT medium. These findings suggest that deletion of 5p14-5p15 leads to some impairment of de novo purine synthesis, the implications of these findings are discussed.

Beneficial effect of 6-mercaptopurine on the mitotic index of trisomy 21 lymphocytes. Implications for future research.

Low doses of 6-mercaptopurine were found to significantly increase the mitotic index in lymphocytes of patients with trisomy 21. This finding implies that excess purine synthesis in Down syndrome is responsible for lymphocyte cytotoxicity. We suggest that, in addition to the three steps already known, other genes involved in the "de novo" purine synthesis pathway might be located on chromosome 21 and that they are responsible for increased adenine nucleotides, nucleotide pool imbalance and perhaps relative guanine nucleotide deficiency. This would open new areas of research into the patho-physiology of trisomy 21.

Secondary Hodgkin's disease in childhood acute lymphoblastic leukemia.

Improved survival in childhood acute lymphoblastic leukemia has led to the occurrence of second malignancies in these patients. Hodgkin's disease is very rare as a second malignancy. We report three patients with acute lymphoblastic leukemia in remission who developed Hodgkin's disease. Although all had received low-dose irradiation, none received alkylating agents as part of their chemotherapy. Review of our cases and of 11 reported in the literature revealed unique aspects of this association. There was a short median interval of 19 months to the development of the second malignancy. Over one-third of the patients had uncommon sites of involvement (lung, tonsil, small bowel). The distribution of histologic subtypes was unusual, as 5 of 14 cases had lymphocyte depletion or unclassifiable Hodgkin's disease. The results of therapy were excellent. Our three patients are alive, with both malignancies in continuing remission. Two patients are off all therapy for 4 and 6 years, respectively. The third remains on antileukemic treatment. Secondary Hodgkin's disease in childhood acute lymphoblastic leukemia does not appear to have a poor prognosis and long-term survival and possible cure of both diseases may be achieved.