Genetic analysis of the 2q33 region containing CD28-CTLA4-ICOS genes: association with non-Hodgkin's lymphoma.

There is strong evidence that altered immunological function entails an increased risk of lymphoma, although the current knowledge of aetiological factors for lymphomas is limited. The CTLA4 gene encodes a receptor that provides a negative signal to the T-cell once an immune response is initiated and completed. We analysed the 2q33 chromosomal region harbouring CD28, CTLA4 and ICOS genes, which are closely linked and have related functions in immune regulation, for association in 100 non-Hodgkin's lymphoma (NHL) patients and in 128 healthy controls; both groups originated from Sardinia. There was a strong association of the CTLA4 49A and the 3'-untranslated region (AT)(82) alleles with NHL [odds ratio (OR) = 2, 95% confidence interval (CI) = 1.2-3.2, and OR = 1.6, 95% CI = 1.1-2.4 respectively]. CTLA4-318C:49A:(AT)(82) was the most represented haplotype in the studied population and was associated with NHL (P = 0.0029, OR = 1.76, 95% CI = 1.2-2.5). Strong linkage disequilibrium was detected between CD28, CTLA4 and ICOS and a 'common' haplotype was found very frequently among NHLs. However, no independent association between CD28, ICOS, D2S72 markers and NHL was observed. Our findings enable CTLA4 from adjacent functionally related genes as the true causative risk gene for NHL susceptibility at least in Sardinian patients.

Serum transferrin receptor levels in patients with thalassemia intermedia during rHuEPO administration.

In this study we determined the levels of circulating soluble transferrin receptor (sTfR) in six untransfused and two transfused patients affected by beta-thalassemia intermedia during low-dose rHuEPO administration. While the majority of the untransfused patients showed a temporary increment during the first month of treatment, a higher and enduring increase in sTfR concentration was observed in the two transfused patients until rHuEPO was discontinued. The transfused patients showed a significant increase in the reticulocyte index together with the rise in sTfR and an improvement of the anemia, as evidenced by the decrease in their transfusional requirement. These data suggest that basal erythropoietic activity is one of the main causes of differences in responsiveness to low doses of rHuEPO given in thalassemia intermedia.

Serum erythropoietin levels in thalassemia intermedia.

Serum concentrations of erythropoietin (EPO) were determined by immunoassay in 45 patients with thalassemia intermedia (TI). The mean serum level of EPO was significantly higher in the thalassemic patients than in the controls, but transfused subjects had lower pretransfusional serum concentrations of EPO than untransfused ones. An inverse relationship between the serum values of EPO and total hemoglobin was observed only in the untransfused thalassemic patients. These data suggest that in TI, even a low transfusional regimen may cause a decrease in serum concentration of EPO, independent of the level of total Hb.

[Differential diagnosis of thalassemia syndromes]. / Diagnosi differenziale delle sindromi talassemiche.

In Sardinia, as in other areas with a high incidence of thalassemia syndromes, a prevention program based on the detection of healthy carriers through mass screening and on prenatal diagnosis in the at-risk couples has been in course for several years. The commonly adopted beta-thalassemia flow-chart consists of a first operative step involving simple and widely standardized tests: the estimation of red cell indices, the measurement of Hb A2 and Hb electrophoresis. These investigations permit the identification of the majority of the at-risk couples for beta-thalassemia. However, the not infrequent evidence of Hb A2 borderline levels, with or without microcytosis, isolated microcytosis or Hb F increased values, causes some problems in differential diagnosis, because these findings can indicate the presence of silent beta-thalassemic traits or other beta-thalassemic like states. A diagnostic definition of these unusual hematological phenotypes is particularly important for the identification of eventual at-risk couples. In this paper we report our data concerning the voluntary screening for beta-thalassemia carried out in North Sardinia. The operative flow-chart is shown. In a population with a high incidence of phenotypically heterogeneous thalassemic syndromes, such as that of Sardinia, differential diagnosis of thalassemic traits can require molecular studies. This molecular characterization, which could be carried out in specialized reference centers, is today absolutely necessary both for exact identification of at-risk couples and eventual prenatal diagnosis.