We studied the molecular bases of beta-thalassemia in Rome, a city centrally located in Latium, which is a region with a low incidence of beta-carriers. People also come to Rome from other regions ...for specific or prenatal diagnostic assessment. Only 11 patients (20%) out of 62 characterized beta-thalassemia subjects were of Latium family origin. They presented five mutations with an uncommonly high frequency of the IVSII-745 allele, that was found in homozygosis in 4 unrelated patients from a southeastern area in the province of Frosinone. These data may indicate a founder effect.
We report the molecular analysis of primary cells from four cases of human B‐cell malignancies each with an 8;14 chromosomal translocation involving the c‐myc proto‐oncogene and the immunoglobulin ...(Ig) gene cluster. In two cases of B‐cell acute lymphocytic leukemia (B‐ALL) the c‐myc is truncated, rearranged into the Ig C alpha 1 locus and over‐expressed in two abnormal mRNAs of approximately 2.0 and 2.8 kb. Conversely, in two cases of B‐cell lymphoma progressed into leukemia the c‐myc locus was translocated intact in its coding and 5′‐flanking region into an Ig region different from C alpha 1, and over‐expressed in two normal mRNA species. Cloning and sequencing of the breakpoint region on chromosome 14q+ from one of the two B‐ALL cases showed that the myc gene is truncated 1077 nucleotides upstream from the translation start site, and rearranged in the opposite transcriptional orientation into an Ig class‐switch segment approximately 4.8 kb upstream from the C alpha 1 gene. The c‐myc anti‐sense strand contains two class‐switch recombination consensus sequences in the immediate boundaries of the breakpoint on chromosome 8: this allows us to postulate that an erroneous, class‐switch‐like recombination between Ig and myc sequences gave rise to the chromosomal translocation. Furthermore, we report 13 point mutations clustered in a region spanning from the first intron to the second exon of the translocated c‐myc gene, five of which cause amino acid changes leading to an abnormal myc protein. This is the first evidence of mutations in a translocated c‐myc in primary tumor cells.
Recently, a new immunometric assay (Cyfra 21-1) was developed to measure serum concentrations of a soluble fragment of cytokeratin subunit 19. With this method, supplied by Boehringer Mannheim (EIA ...Test Cyfra 21-1), an Italian multicenter trial was performed in patients with lung cancer. Cyfra 21-1 serum levels were determined in 568 normal subjects (blood donors), 607 patients with non-malignant diseases (491 respiratory diseases) and 730 patients with malignancies. In the latter group 584 had lung cancer. All these 584 patients had pathologically confirmed disease; 314 were epidermoid tumors, 166 adenocarcinomas, 88 small cell cancers and 16 large cell cancers. In the 568 healthy blood donors the mean Cyfra 21-1 value was 0.91 ng/ml (SD 0.47 ng/ml; range 0.05-2.90 ng/ml). A threshold of 1.9 ng/ml was chosen as the upper limit of normality. High levels of Cyfra 21-1 were observed in patients with chronic hepatitis (positivity rate: 17/51-33.3%) and with pancreatitis (positivity rate 5/16-31.3%). In 114 out of 491 (23.2%) patients with respiratory diseases Cyfra 21-1 showed values greater than 1.9 ng/ml. The overall sensitivity (all stages) of Cyfra 21-1 in lung cancer was 65.6% (383/584). When the histology was considered the highest positivity rates were found in patients with squamous cell tumors (226/314; 72%) followed by adenocarcinomas (105/166; 63%). In patients with SCLC the global sensitivity was 52.3% (46/88). Higher sensitivity of Cyfra 21-1 was observed from stage I to stage IV (53.9% vs 85.7%; Chi square: p < 0.01).
We report a study of four families of Italian origin in which heterocellular HPFH is inherited linked to beta thalassemia over two or three generations. The HPFH + beta thalassemia carriers showed ...thalassemic blood pictures and elevated HbF and F-cell number without increase in the HbF/F-cell content. Association of this gene complex with a second beta thalassemia trait gives rise to a mild clinical picture characterized by 9-12 g/dl of mainly HbF in peripheral blood and no transfusion requirement. In two families, independent segregation of the HPFH or beta-thal trait was observed, and in one case the study of the DNA polymorphisms within the gamma delta beta gene cluster indicated that the HPFH mutation lies outside that DNA region. In one family the coexistence of a polymorphic variant of the A gamma chain (the A gamma T chain) allowed us to demonstrate that the increased gamma chain synthesis caused by the heterocellular HPFH determinant is directed by both chromosomes.
An Italian family in which heterocellular hereditary persistence of fetal haemoglobin (HPFH) interacts with both beta(+)- and delta beta-thalassaemia is described. The index case was an 8 year old ...girl who was presumed to inherit both heterocellular HPFH and beta (+)-thalassaemia from her mother and delta beta-thalassaemia from her father. She was healthy and never needed blood transfusions. The possible contribution of heterocellular HPFH to the less severe expression of the compound delta beta/beta(+)-thalassaemia heterozygosity is discussed. By DNA analysis the specific delta beta-thalassaemia defect on the gamma delta beta globin gene region has been established. In addition, a previously unreported association of a polymorphic restriction site haplotype with a beta (+)-thalassaemia mutation has been observed.
This report is concerned with the evaluation of hematological parameters and the percentage level of the abnormal hemoglobin (Hb) G San Josè as found in 4 heterozygous carriers from a family of ...Sicilian origin. Biosynthetic studies and in vitro recombination experiments strongly indicate that abnormal beta chains are synthesized at lower rate than beta A chains and exhibit a minor affinity (relative to beta A chains) for complementary chains in a condition of relative aA chain deficiency. The possibility that the low affinity of beta G chains for a chains may play a decisive role in controlling the level of the abnormal Hb in the peripheral blood of the present non-a-thalassemic abnormal Hb carriers is therefore discussed.
Vasoactive intestinal peptide (VIP) is released both by neural endings and lymphocytes. Aim of our investigation was to study the effects of immunosuppressive therapy on VIP plasma concentrations. ...The research has been performed on 10 heart transplanted patients assuming cyclosporine (CYCL) and prednisone (PRED). The circulating T lymphocyte subsets, atrial natriuretic peptide (ANP), plasma renin activity (PRA), plasma aldosterone (PA) and plasma cortisol (PC) have been also assayed. Blood pressure (BP) and heart rate (HR) have been monitored over a 24-hour period to detect whether circulating VIP in heart transplanted patients is influenced by pharmacologically-induced interactions. Seriate samplings along the 24-hour span have been performed. Mean values of ANP, PRA and PA were increased, while VIP, PC and T lymphocyte subsets were decreased in heart transplanted patients as compared to clinically healthy subjects. ANOVA and Cosinor analysis showed, respectively, a statistically significant 24-hour variability and circadian rhythm for all the investigated variables only in normal subjects. BP and HR circadian rhythm in heart transplanted patients suggest that the adrenergic activity regulating the cardiovascular system is restored. This finding argues that the reduction in VIP plasma concentrations is likely due to the decreased lymphocyte production secondary to immunosuppressive therapy, or can also be ascribed to the inhibiting action of high circulating levels of ANP.
PDF
