Biomedical subjects

J Delaunay

Publications and source records attributed to J Delaunay.

At least 19 recordsLinked to original sources

PubMed2006

Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL.

Numerous strategies have been proposed to specifically inhibit telomerase (human telomerase reverse transcriptase (hTERT)) but to date only a few are clinically relevant in anticancer therapy. Recently, we have shown that long-term treatment with all-trans retinoic acid (ATRA), a compound clinically approved for differentiation therapy of acute promyelocytic leukemia (APL), represses hTERT in differentiation-resistant APL cell lines leading to telomere shortening and death. This signaling requires the co-activation of the retinoic acid receptor alpha (RARalpha) and the retinoic X receptor (RXR). In contrast to differentiation-therapy, which is only successful in this subtype of leukemia, the telomerase-targeted pathway could also be of use in non-APL. Here, we demonstrate that repression of hTERT occurs in fresh blasts cells from patients with myeloid leukemias of various subtypes exposed ex vivo to ATRA or synthetic retinoids. These results support the idea that, by hTERT targeting, retinoids can induce telomere shortening and cell death and their integration in therapy protocols for myeloid leukemias refractory to maturation should be considered.

Adult↗

PubMed2006

Mild dehydrated hereditary stomatocytosis revealed by marked hepatosiderosis.

We report a patient in whom hepatosiderosis was diagnosed at the age of 55 years and who has since been treated by regular bleeding. The H63D mutation was found in the heterozygous state in the HFE gene. No mutation was recorded in the SLC11A3 gene (ferroportin). Hepatosiderosis did not seem primary, nevertheless its cause long remained elusive. Only 2 years ago did we find the responsible condition, a very mildly expressed form of dehydrated hereditary stomatocytosis (DHS). This genetic disease is a strongly iron-loading condition. Haemolysis was fully compensated. Kalaemia was slightly elevated, suggesting a pseudohyperkalaemia that may be associated with DHS. Osmotic gradient ektacytometry allowed to assess the diagnosis of DHS. The red cell monovalent Na+ and K+ concentrations were moderately elevated and reduced respectively. The temperature dependence of the ouabain + bumetanide-resistant K+ influx produced a shallow slope, above and parallel to the control curve. These features were consistent with the diagnosis of DHS. The pronounced hepatosiderosis contrasted with the mildly expressed DHS, and with the ferritinaemia that was slightly elevated, if at all, prior to bleeding. Bleeding caused ferritinaemia to decrease and hepatosiderosis to recede. The whole picture accounts for a misleading presentation of DHS, in which the primary condition long remained hidden behind one of its remotest complications, hepatosiderosis.

Aged↗

PubMed2006

NMR metabolite profiling analysis reveals changes in phospholipid metabolism associated with the re-establishment of desiccation tolerance upon osmotic stress in germinated radicles of cucumber.

The adaptation of metabolism is thought to play a role in the acquisition of desiccation tolerance (DT). However, the importance of such a role and whether specific regulatory pathways exist remain to be assessed. Using in vitro 31P and 13C nuclear magnetic resonance (NMR) spectroscopy and biochemical assays, we analysed metabolite profiles of perchloric extracts from germinating radicles of cucumber to identify changes in carbon and phosphate metabolism associated with DT. Emerged radicles measuring 2 mm long can be rendered tolerant to desiccation by incubation in a polyethylene glycol (PEG) solution with a water potential of 1.5 MPa. However, in 4-mm-long emerged radicles, this treatment was ineffective. This manipulable system enabled the discrimination of changes in metabolites associated with DT from those associated with the response to osmotic stress. Independent of radicle length, the PEG treatment resulted in an increase in sucrose (Suc) content, whereas glucose (Glc), fructose (Fru) and the hexose phosphate pool, as well as phosphoenolpyruvate decreased three- to fourfold. In addition, three derivatives arising early during phospholipid catabolism (glycerylphosphorylcholine, glycerylphosphorylethanolamine and glycerylphosphorylinositol) appeared in the PEG-treated radicles. Interestingly, phospholipid degradation was much more pronounced in osmotically challenged radicles that remain sensitive to drying. This was proved by the appearance of catabolites, such as phosphocholine and phosphoethanolamine, solely in 4 mm PEG-treated radicles. Furthermore, glycerol-3-phosphate and its derivative 3-phosphoglycerate increased significantly. Our data suggest that the metabolic response leading to the re-establishment of DT is not entirely identical to that of an osmotic response. It is inferred that membrane remodelling and/or increased phospholipid catabolism is an adaptive response common to osmotic adjustment and DT but is controlled differently in tolerant and sensitive radicles.

Cucumis sativus↗

PubMed2004

A family showing recessively inherited multisystem pathology with aberrant splicing of the erythrocyte Band 7.2b ('stomatin') gene.

The case of a French child, born of consanguineous parents of Tunisian origin, is described. He showed a severe multisystem disease with dyserythropoietic, sideroblastic anaemia, delayed neurological development with hypotonia and convulsions, salt-losing nephropathy, chronic watery diarrhoea, lactic acidosis with mitochondrial dysfunction, brittle hair, hypergammaglobulinaemia, fatty liver with intermittent transaminasaemia, and terminal pulmonary fibrosis. Two siblings, of both sexes, were stillborn; two more lived only a short time. One sister is alive and well. SDS gel analysis of the red cell membranes showed a deficiency within 'Band 7' at 32 kDa. Analysis of the gene encoding 'stomatin', or 'erythrocyte membrane protein 7.2b', the principal protein of 'Band 7', revealed a complex series of aberrant spliceforms centred around exon 3, for which no explanatory genomic lesion could be found. The true underlying molecular cause of this condition remains obscure, but it suggests that the stomatin gene should be studied in other cases.

Alternative Splicing↗

PubMed2004

Different impacts of alleles alphaLEPRA and alphaLELY as assessed versus a novel, virtually null allele of the SPTA1 gene in trans.

The family of two siblings with severe hereditary spherocytosis was investigated. The decrease was evident on both the alpha- and the beta-chains. The parents were haematologically normal. The mother was heterozygous for the low-expression polymorphic allele alphaLEPRA. The father was heterozygous for a novel combination in which one allele showed the alpha-spectrin low expression polymorphic allele alphaLELY, while his other allele showed the alphaLELY polymorphism in cis with a G-->A substitution, named Bicêtre, found at the extreme 3' end of exon 51. This combination was designated alpha(LELY-Bicêtre). The children were compound heterozygotes for alleles alphaLEPRA and alpha(LELY-Bicêtre). Reverse transcription polymerase chain reaction detected only trace amounts of the mRNA coding for alpha(LELY-Bicêtre). Mutation is therefore an essentially null mutation with no functional protein product. The lack of disease in the alphaLELY/(LELY-Bicêtre) father compared with the marked haemolysis in the alphaLEPRA/alpha(LELY-Bicêtre) children showed that expression of allele alphaLELY is not low enough to expose null alpha-spectrin alleles on the other chromosome. Quantitative estimations from these findings suggest that, to evoke spherocytosis, it is necessary that alpha-spectrin expression must be reduced to less than 25% of normal, while a reduction to 8% is sufficient.

Alleles↗

PubMed2003

Dehydrated hereditary stomatocytosis with transient perinatal ascites.

The case is reported of a mother and baby with dehydrated hereditary stomatocytosis and perinatal ascites, an autosomal dominant condition not previously reported in Britain. Recognition is important for the management of pregnancy and for avoidance of splenectomy which, if performed, can predispose the patient to fatal thromboembolic events.

Adult↗

PubMed2001

Novel C60-based building blocks derived from C60(2-) anion.

[reaction: see text]. Reactions of chemically generated C60(2-) dianion with halo derivatives bearing a second functional group (halo, ester, ketone) give rise to new organo C60 derivatives. Thus, the regioselective formation of 1,2- and 1,4-adducts is observed from long-chain halo derivatives, whereas using 1,3-dihaloalkanes leads to 1,2-fused ring C60 adducts. Such adducts may be used as new synthons in C60 chemistry, thus leading to new C60-based dyads, as exemplified by two examples.

Journal Article↗

PubMed2001

Natural history of congenital dyserythropoietic anemia type II.

Congenital dyserythropoietic anemia type II (CDA-II) is an autosomal recessive disease characterized by anemia, jaundice, splenomegaly, and erythroblast multinuclearity. The natural history of the disease is unknown. The frequency, the relevance of complications, and the use of splenectomy are poorly defined. This study examined 98 patients from unrelated families enrolled in the International Registry of CDA-II. Retrospective data were obtained using an appropriate questionnaire. The mean age at presentation was 5.2 +/- 6.1 years. Anemia was present in 66% and jaundice in 53.4% of cases. The mean age at correct diagnosis was 15.9 +/- 11.8 years. Twenty-three percent of patients for whom data were available developed anemia during the neonatal period, and 10 of these individuals required transfusions. Splenectomy produced an increased hemoglobin (P <.001) and a reduced bilirubin level (P =.007) in comparison with values before splenectomy. Preliminary data indicate that iron overload occurs irrespective of the hemochromatosis genotype. (Blood. 2001;98:1258-1260)

Adolescent↗

PubMed2001

Dehydrated hereditary stomatocytosis: a cause of prenatal ascites.

Dehydrated hereditary stomatocytosis (DHS) is a rare congenital hemolytic anemia. We observed that some patients had presented with different prenatal or perinatal forms of edema in some kindreds. Within weeks or months after birth, these exhibited a spontaneous, complete and definitive resorption. We assumed that some DHS patients, who were born without edema before ultrasound was available, might nonetheless have exhibited this during the prenatal period. The present report follows up the first pregnancy in a woman with overt DHS, but not herself having a known history of perinatal effusions. Ultrasound revealed that the fetus displayed ascites that disappeared prior to birth. The neonate had DHS. Prenatal edema must therefore be more frequent in DHS than known until now. DHS is another cause of prenatal edema to be considered in the differential diagnosis.

Adult↗

PubMed2000

Pleiotropic syndrome of dehydrated hereditary stomatocytosis, pseudohyperkalemia, and perinatal edema maps to 16q23-q24.

Dehydrated hereditary stomatocytosis (DHS) is a rare genetic disorder of red cell permeability to cations, leading to a well-compensated hemolytic anemia. DHS was shown previously to be associated in some families with a particular form of perinatal edema, which resolves in the weeks following birth and, in addition, with pseudohyperkalemia in one kindred. The latter condition was hitherto regarded as the separate entity, "familial pseudohyperkalemia." DHS and familial pseudohyperkalemia are thought to stem from the same gene, mapping to 16q23-q24. This study screened 8 French and 2 American families with DHS. DHS appeared to be part of a pleiotropic syndrome in some families: DHS + perinatal edema, DHS + pseudohyperkalemia, or DHS + perinatal edema + pseudohyperkalemia. If adequately attended to, the perinatal edema resolved spontaneously after birth. Logistic regression showed that increased mean corpuscular volume and mean corpuscular hemoglobin concentration were the parameters best related to DHS. In patients in whom cation fluxes were investigated, the temperature dependence of the monovalent cation leak exhibited comparable curves. Specific recombination events consistently suggested that the responsible gene lies between markers D16S402 and D16S3037 (16q23-q24). The 95% confidence limits (Z(max) >/= 3.02) spanned almost the complete 9-cM interval between these 2 markers.

Adolescent↗

PubMed2000

Severe hereditary spherocytosis and distal renal tubular acidosis associated with the total absence of band 3.

Absence of band 3, associated with the mutation Coimbra (V488M) in the homozygous state, caused severe hereditary spherocytosis in a young child. Although prenatal testing was made available to the parents, it was declined. Because the fetus stopped moving near term, an emergency cesarean section was performed and a severely anemic, hydropic female baby was delivered. She was resuscitated and initially kept alive with respiratory assistance and hypertransfusion therapy. Cord blood smears revealed erythroblastosis, poikilocytosis, and red cells with stalk-like elongations. Band 3 and protein 4.2 were absent; spectrin, ankyrin, and glycophorin A were significantly reduced. Renal tubular acidosis was detected by the age of 3 months. Nephrocalcinosis appeared soon thereafter. After 3 years of follow-up the child is doing reasonably well on a regimen that includes regular blood transfusions and daily bicarbonate supplements. The long-term prognosis remains uncertain given the potential for hematologic and renal complications. (Blood. 2000;96:1602-1604)

Acidosis, Renal Tubular↗

PubMed2000

Elliptocytosis in patients with C-terminal domain mutations of protein 4.1 correlates with encoded messenger RNA levels rather than with alterations in primary protein structure.

Early biochemical studies defined 4 functional domains of the erythroid protein 4.1 (4.1R). From amino-terminal to carboxy-terminal, these are 30 kd, 16 kd, 10 kd, and 22/24 kd in size. Although the functional properties of both the 30-kd and the 10-kd domain have been demonstrated in red cells, no functional activities have been assigned to either the 16-kd or the 22/24-kd domain in these cells. We here describe new mutations in the sequence encoding the C-terminal 22/24-kd domain that are associated with hereditary elliptocytosis. An unusually mild phenotype observed in heterozygous and homozygous members of 1 family suggested heterogeneity in the pattern of expression of 4.1R deficiency. Using a variety of protein and messenger RNA (mRNA) quantification strategies, we showed that, regardless of the alteration in the C-terminal primary sequence, when the protein is produced, it assembles at the cell membrane. In addition, we found that alterations in red cell morphologic features and membrane function correlate with the amount of membrane-associated protein-and therefore with the amount of mRNA accumulated-rather than with the primary structure of the variant proteins. These data suggest that an intact sequence at exons 19 through 21 encoding part of the C-terminal 22/24-kd region is not required for proper protein 4.1R assembly in mature red cells. (Blood. 2000;95:1834-1841)

Adult↗

PubMed2000

Natural history of hereditary spherocytosis during the first year of life.

Although hereditary spherocytosis (HS) is a common disorder of the red cell membrane, its clinical and biologic expression at birth and in early infancy has received little attention. In order to obtain insights into the natural history of HS during infancy, we studied 46 neonates, 39 from families in which 1 of the parents had previously been given a diagnosis of HS and 7 presenting with nonimmune hemolytic anemia and no family history of HS. Of these 46 neonates, 23 were subsequently confirmed to have HS and 23 were found to be healthy. The hematologic and biologic analyses carried out in this cohort of 46 newborns enabled us to develop guidelines for early diagnosis of HS. A careful clinical follow-up of 34 HS patients during the first year of life allowed us to define several important clinical features of HS during this period. Hemoglobin values are usually normal at birth but decrease sharply during the subsequent 20 days, which leads, in many cases, to a transient and severe anemia. The anemia is severe enough to warrant blood transfusions in a large number of infants with HS (26 of 34 in our series). The aggravation of anemia appears to be related to the inability of these infants to mount an appropriate erythropoietic response to anemia and to the development of splenic filtering function. These findings indicate that careful monitoring of infants with HS during the first 6 months of life is important for appropriate clinical management. (Blood. 2000;95:393-397)

Blood Transfusion↗

PubMed2000

Recombinant erythropoietin therapy as an alternative to blood transfusions in infants with hereditary spherocytosis.

INTRODUCTION: In hereditary spherocytosis, erythropoiesis has been described as 'sluggish' during the first months of life. The lack of appropriate erythropoietic response to compensate for increased red cell destruction necessitates blood transfusions in 70-80% of hereditary spherocytosis-affected infants during their first year of life. After this period, less than 30% require regular transfusion support. This transient requirement for transfusion led us to wonder whether anemic hereditary spherocytosis infants, like anemic premature infants, could benefit from recombinant erythropoietin therapy (rHu-Epo). MATERIAL AND METHODS: In 16 hereditary spherocytosis infants (age range 16-119 days) with severe anemia, a compassionate open preliminary study was performed. rHu-Epo treatment (1000 IU/kg/week) was instituted together with iron supplementation. Hemoglobin values and reticulocyte counts were repeatedly assessed. RESULTS: In 13 out of 16 infants, prompt increases in reticulocyte counts were noted after the first week of treatment with 1000 IU/kg/week of rHu-Epo. During treatment with Epo these infants maintained clinically acceptable levels of hemoglobin and did not require blood transfusions. As the infants grew and began to mount an adequate erythropoietic response, the rHu-Epo dose could be tapered and the treatment could be discontinued before the age of nine months. CONCLUSION: Epo treatment in most hereditary spherocytosis infants appears to be effective in the management of anemia and could serve as a valuable alternative to packed RBC transfusions.

Blood Transfusion↗

PubMed2000

Severe congenital dyserythropoietic anaemia type I: prenatal management, transfusion support and alpha-interferon therapy.

We report a case of congenital dyserythropoietic anaemia, type I, with severe pre- and postnatal manifestations. Exchange transfusions were required for fetal anaemia (3.5 g/dl) at 28 and 30 weeks of gestation. Transfusions were administered at birth (Caesarean section at week 35) and at regular intervals thereafter. At 14 months, alpha-interferon therapy was initiated (106 units three times a week). This resulted in stabilization of the haemoglobin at or above 11 g/dl and a reduction in the percentage of erythroblasts with ultrastructurally abnormal heterochromatin. After 9 months, the dose of alpha-interferon was decreased to 106 units twice a week. No relapse of anaemia was noted during an additional 4 months of follow-up.

Adult↗

PubMed2000

Heavy transfusions and presence of an anti-protein 4.2 antibody in 4. 2(-) hereditary spherocytosis (949delG).

BACKGROUND AND OBJECTIVE: A patient with hereditary spherocytosis (HS) was found not to have red cell membrane protein 4.2. This rare form of HS, or 4.2 (-) HS, stems from mutations within the ELB42 or the EPB3 genes. The patient had long suffered from a gastric ulcer and impaired liver function. He had had several dramatic episodes of gastrointestinal tract bleeding and had received numerous transfusions. An antibody against a high frequency, undefined antigen was found, creating a transfusional deadlock. We elucidated the responsible mutation and searched for an anti-protein 4.2 antibody. DESIGN AND METHODS: Red cell membranes were analyzed by SDS-PAGE and by Western blotting. Nucleotide sequencing was performed after reverse transcriptase-polymerase chain reaction (RT-PCR) and nested PCR. RESULTS: The not previously described mutation was a single base deletion: 949delG (CGCAECC, exon 7, codon 317) in the homozygous state. It was called protein 4.2 Nancy. The deletion placed a non-sense codon shortly downstream so that no viable polypeptide could be synthesized. The patient carried a strong antibody against protein 4.2 as shown by Western blotting. INTERPRETATION AND CONCLUSIONS: The manifestations resulting from the mutation described were compared with the picture of HS stemming from other ELB42 gene mutations. We discuss the mechanism through which the anti-protein 4.2 antibody developed. There was no way to establish or to rule out whether the antibody participated in the transfusional deadlock found in our patient.

Adult↗

PubMed2000

Geographic distribution of CDA-II: did a founder effect operate in Southern Italy?

BACKGROUND AND OBJECTIVE: Congenital dyserythropoietic anemia type II (CDA-II) is an autosomal recessive condition, whose manifestations range from mild to moderate. Its exact prevalence is unknown. Based on a recently established International Registry of CDA-II (64 unrelated kindreds), a high frequency of CDA II families living in South Italy became evident. DESIGN AND METHODS: The aim of this study was to define the haplotypes of the CDA II kindreds living in Southern Italy based on markers D20S884, D20S863, RPN, D20S841 and D20S908. These markers map to 20q11.2, within the interval of the CDAN2 gene that is responsible for CDA II. Next, we looked at these markers in kindreds from other regions of Italy and from other countries, with special attention to families having ancestors in Southern Italy. RESULTS: Evaluation of the geographic distribution of the ancestry of Italian CDA-II patients clearly demonstrated the unusually high incidence of this condition in Southern Italy. Our statistical calculations and linkage disequilibrium data also clearly demonstrate a strong association of the markers of chromosome 20 with the disease locus in our sample. Almost all the regions defined by the markers here used is in disequilibrium with the disease. Combining the data from the Italian sample together with those obtained from the non-Italian ones, we can restrict the area of highest disequilibrium to that defined by markers D20S863-D20S908. INTERPRETATION AND CONCLUSIONS: Despite the presence of this linkage disequilibrium the search for a common haplotype failed. This could suggest that the mutation was very old or that it occurred more than once on different genetic backgrounds.

Adolescent↗

PubMed2000

Serum sICAM-1 (soluble intercellular adhesion molecule-1) and M-CSF (macrophage colony-stimulating growth factor) throughout monitoring of 34 non-serous ovarian cancers.

PURPOSE: Evaluation of serum ICAM-1 (soluble intercellular adhesion molecule-1) and M-CSF (macrophage colony-stimulating growth factor) determinations for monitoring patients with non-serous ovarian cancers. METHODS: ELISA assay of sICAM-1 (cut-off 235 ng/ml) and M-CSF (cut-off 450 pg/ml) in 190 blood samples from 34 patients. RESULTS: In pre-treatment sera (n=17), sICAM-1 was over the cut-off in 12/17 (70.6%), M-CSF in 14/17 (82.4%) and CA 125 in 12/16 (75%). sICAM-1 was related only to age at diagnosis (p=0.0008). M-CSF was positively correlated to FIGO stage (p=0.04) CA 125 was elevated in 90.9% of adenocarcinomas (p=0.033 vs other). None of the 3 biological markers were related to other clinico-pathological criteria. Among disease-free patients, higher median concentrations of sICAM-1 and M-CSF were recorded under adjuvant treatment than without (p=0.014, and p=0.08, respectively). After relapse, the highest levels of sICAM-1, M-CSF and CA 125 were observed in progressive disease (46/53, 86.8% (p=0.014), 51/53 96.2% (p=0.008) and 46/52 88.5% (p>0.05), respectively). CONCLUSION: In non-serous ovarian cancers, sICAM-1 although elevated in most cases, is not useful for monitoring. Serum M-CSF is a valuable marker when ovarian tumours do not express CA 125.

Adenocarcinoma↗