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Down Syndrome (DS) is the most frequent human chromosomal disorder. Main symptoms include intellectual disability (ID), cardiovascular defects and craniofacial dysmorphisms. Despite ID being measured by a test of symbolic logic skills, it is common for children with DS to arouse a climate of affective intensity greater than the norm. In 1959, Jérôme Lejeune (1926-1994) and coll. described an additional chromosome 21 (Hsa21) in children with DS (trisomy 21), giving origin to the field of medical genetics. Remarkably, the discovery of trisomy 21 had relevant social consequences for the affected children, in that their parents were no longer suspected to be alcoholics or infected with syphilis. Although it is broadly agreed that the DS phenotype originates from the altered expression of the genes located on Hsa21, its molecular pathogenesis is still unknown. To date, no therapy is recognized and recommended by guidelines as being effective in improving the cognitive abilities of persons with DS. The aim of this article is to categorize main therapeutical approaches or pathways to new approaches reported in the biomedical literature, to extract critical methodological points from the works of Lejeune and then to propose a new research project aimed to generate and integrate clinical, biochemical, genetic and bioinformatic data in order to identify novel therapeutic targets for this form of trisomy. We show here that nearly all the current lines of research were pursued, theorized or foreseen by Lejeune, and that central points of his method remain current: positive hypothesis about the existence of a solution, envision of systematic investigation of cell machinery, anchoring of clinical and biochemical finding to the chromosome physical map, and continuing clinical observation of the affected children. We therefore propose a project aimed at producing both experimentally and by meta-analysis state-of the-art maps and databases related to clinical/phenotype, cytogeneti

Congenital amegakaryocytic thrombocytopenia (CAMT) without physical anomalies is a rare disease, presenting isolated thrombocytopenia and megakaryocytopenia in infancy, which can evolve into aplastic anemia and leukemia. Recently, two heterozygous truncating mutations of the thrombopoietin (TPO) receptor MPL, coded by the c-mpl gene, were identified in a 10-year-old Japanese patient with CAMT transmitted in an autosomal recessive manner. Here, we report for the first time two different MPL amino-acid substitutions in a 2-year-old Italian boy with CAMT and compound heterozygosis for two c-mpl point mutations. C-to-T transitions were detected on exons 5 and 12 at the 769 and 1904 cDNA nucleotide positions, reespectively. The mutation in exon 5 substitutes an arginine with a cysteine (R257C) in the extracellular domain, 11 amino acids distant from the WSXWS motif conserved in the cytokine-receptor superfamily. The mutation in exon 12 substitutes a proline with a leucine (P635L) in the last amino acid of the C-terminal intracellular domain, responsible for signal transduction. As in the Japanese family, the mutations were both transmitted from the parents. TPO plasma levels were highly increased in the patient. The patient's 7-year-old brother, who was a candidate donor for allografting, turned out to be an asymptomatic heterozygous carrier of P635L and showed defective megakaryocyte colony formation from bone-marrow progenitor cells. The present study provides important confirmation that CAMT can be associated with c-mpl mutations.

The hematopoietic defect of Diamond-Blackfan anemia (DBA) results in selective failure of erythropoiesis, Thus far, it is not known whether this defect originates from an intrinsic impediment of hematopoietic progenitors to move forward along the erythroid pathway or to the impaired capacity of the bone marrow (BM) microenvironment to support proliferation and differentiation of hematopoietic cells. Reduced longevity of long-term bone marrow cultures, the most physiologic in vitro system to study the interactions of hematopoietic progenitors and hematopoietic microenvironment, is consistent with a defect of an early hematopoietic progenitor in DBA, However, stromal adherent layers from DBA patients generated in a long-term culture system, the in vitro counterpart of BM microenvironment, did not show evidence of any morphologic, phenotypic, or functional abnormality. Our major finding was an impaired capacity of enriched CD34(+) BM cell fraction from DBA patients, cultured in the presence of normal BM stromal cells, to proliferate and differentiate along the erythroid pathway, ii similar impairment was observed in some DBA patients along the granulomacrophage pathway. Our result points to an intrinsic defect of a hematopoietic progenitor with bilineage potential that is earlier than previously suspected as a relevant pathogenetic mechanism of the disease. The finding of impaired granulopoiesis in some DBA patients underlines the heterogeneity of this rare disorder. (C) 1999 International Society for Experimental Hematology. Published by Elsevier Science Inc.

Thrombocytopenia with absent radii (TAR) is a rare autosomal recessive disease characterized by hypomega-karyocytic thrombocytopenia and bilateral radial aplasia. We performed mutational screening of coding and promoter regions of the c-mpl gene, encoding thrombopoietin (TPO) receptor, by sequence analysis in four unrelated patients affected by TAR syndrome. Our results indicate that c-mpl gene mutations are not a common cause of thrombocytopenia in TAR syndrome.

To date, the medical literature suggests that CAPD patients with peritonitis have an increase in the dialysate white cell count (greater than 100 cells mL) with neutrophilia (greater than 50%). In order to explore the differential composition of the peritoneal fluid cells (P.F.C.), we have followed 21 patients (PTS) twice a month over a 30-month period. Nine hundred and fifty samples obtained either from the 24 hours (hrs) drained CAPD fluid, or from the "First Morning Exchange" (F.M.E.) during the same day, when possible, were estimated with the "Millipore Filter" (5-8 Micron (lw) pore size), stained by the Papanicolau method. The results can be so summarized: (1) 13 PTS (62%) showed constantly a low polynuclear count (3-32%); (2) 8 non-infected PTS (38%) showed constantly a higher neutrophilia (40-80%); and (3) from time to time the PTS of the two groups showed a higher neutrophilia and an increased cellularity during clinical infection. In all the samples, the differential P.F.C. count was not affected by the dialysate composition and no difference was observed between the 24 hrs samples and the F.M.E. samples made on the same day. Differential peritoneal cell count may be useful when there are important changes in the stable individual composition.

Catheter obstruction due to fibrin deposits during CAPD can cause poor outflow of peritoneal fluid and recurrent peritonitis. In order to treat this complication, 75,000 IU of diluted Urokinase (UK) were infused into catheters obstructed by fibrin in 10 CAPD patients (4 of which had peritonitis), without adverse reactions. After 60 minutes, a 2 liter exchange of peritoneal fluid was performed. In all the cases a normal outflow was restored. Hemostasis parameters (PT, PTT, TT, Fibrinogen, FDP, Fibrin monomers, BT, AT III) and blood cells count (RBC, HGB, HCT, WBC, PTL), were assayed before and two hours after the UK infusion, and did not show any significant variation, except for a decrease of white blood cells, which remained, however, within the normal range. No peritonitis episode occurred in the follow-up period. UK fibrinolytic therapy is safe and effective in treating fibrin obstruction of CAPD catheters without catheter removal and prevents recurrent peritonitis.

The pharmacokinetics of netilmicin after i.v. administration were studied in 10 adult hemodialyzed patients during and after a dialysis session. The mean interdialysis half-life was 49.6 h, whereas during dialysis this value was reduced to 5.02 h. The mean volume of distribution of netilmicin was about 20% of the total body weight. The dialyzer clearance of netilmicin, measured at 60 and 150 min after the beginning of the session, was about 50 ml/min; this means that 60-65% of the drug may be lost during the 4.5 h standard dialysis. The total body clearance of netilmicin was similar to the dialyzer clearance values, suggesting that the drug is eliminated almost entirely by hemodialysis and that its renal elimination in our patients is negligible. In conclusion, in uremic hemodialyzed patients netilmicin behaves like other aminoglycosides.