Prevention strategies for severe hemoglobinopathies in endemic and nonendemic immigration countries: the Latium example.

OBJECTIVE: To review prevention data for hemoglobinopathies from Latium, a large Italian region with a considerable immigrant population and with a well-established regional prevention program. METHOD: All data pertaining to population screening for hemoglobinopathies in the Latium region were reviewed for the period 1994-2007. Screening was performed universally in secondary schools and to pregnant couples at the time of prenatal care. We have examined the trends in positive screening results as well as the type of hemoglobinopathies detected during the study period, and we have correlated them to the type of population (immigrant vs indigenous). RESULTS: From 1994 to 2007, 167 235 individuals were examined for carrier status for hemoglobinopathies, and 10 353 of them (6.2%) were immigrants. We have registered a threefold increase in rates of screen-positive subjects who belonged to ethnic minorities during the study period (from 2.7% in 1994 to 9.8% in 2007). Over half of the screen-positive subjects (5397/10 353) presented no hematological anomalies, 24% (n = 2472) had iron deficiency, and 24% (n = 2484) was classified as putative carriers. Among the last group, 22.6% were carriers of beta-thalassemia, 48% were suspected alpha-thalassemia carriers, and the remainder had less common hemoglobinopathies. While the prevention program resulted in nearly zero births of autochthonous newborns affected by severe hemoglobinopathies, a rise in number of affected individuals was noted among immigrants. Screening of secondary school students was accepted by 67% of immigrant parents, resulting in 9737 pupils screened between 2002 and 2006. CONCLUSION: Existing preventive programs for severe hemoglobinopathies should adapt to changes in population ethnicities. Screening for hemoglobinopathies at school age is an efficient strategy.

Treatment of chronic heart failure: an expert system advisor for general practitioners.

Most decision-support systems in medicine have been developed in hospital environments, but only few are designed for being used by general practitioners. The present work aims to design an expert system for practitioners in chronic heart failure (CHF) treatment. It provides assistance in defining the therapy relying on CHF aetiology, gravity, physiopathological conditions, and discriminates if other coexistent diseases and/or drugs taken by the patient could interact with CHF management. It warns the physician about the possible interactions of the considered CHF therapy. In case of contraindications, the system suggests another alternative therapy. It also advices about the control tests to follow-up the prescribed therapy, and about the indicated hygienic-dietetic suggestions. To assess its internal consistency, we examined the behaviour of the system with 20 CHF patients, by comparing the suggested therapy with the prescriptions of cardiologists. In 9 cases the suggested therapeutic schemes contained all the "n" drugs administered by the cardiologists. In 5 cases the concordance was on at least two thirds of the prescribed medications, in 5 between one half and two thirds, while in 1 case there was no concordance at all. In none of the 10 cases with partial concordance, were there major discrepancies (i.e. potentially deleterious for the patient) between the expert system's suggestions and the cardiologists' prescriptions. In conclusion, the advices of the expert system were similar to those of the cardiologists, suggesting the feasibility of such a computer support to CHF management.

Interpreting elevated fetal hemoglobin in pathology and health at the basic laboratory level: new and known γ- gene mutations associated with hereditary persistence of fetal hemoglobin.

Fetal hemoglobin may be slightly or significantly elevated in post-natal life due to a number of causes. We report two novel mutations found on the promoter of the Aγ gene and summarize all common and rare determinants associated with hereditary persistence of fetal hemoglobin (HPFH) described thus far. Hematological and molecular analysis of the Aγ globin gene in two cases of HPFH. Comparison of the novel cases with all those described in the literature. We have found two novel mutations in three Italian patients with HbF values between 5.9% and 6.5% without an elevated HbA(2) and with normal hemoglobin parameters. In two probands (mother and son), a -197 C>T transition was observed, while in a single individual, a -113 A>G transition was present on the distal CCAAT box of the Aγ gene. As no other abnormalities were present in both γ-gene promoters and the changes are located on regulatory sequences, we may conclude that these mutations are responsible for the HPFH phenotype shown by the carriers. The laboratory should be able to discriminate between elevated HbF due to artifacts or to serious causes including bone marrow malignancies, aplastic anemia, and ß-thalassemia major or recessive traits such as ß-thalassemia minor, δß-thalassemia, or nonpathological conditions induced by mutations or polymorphisms of the γ-gene promoters that may even be beneficial when present in patients with thalassemia major or sickle cell disease and, in particular, when these patients are treated with hydroxyurea.

A screening programme for the prospective prevention of Mediterranean anaemia in Latium: results of seven years' work.

Since 1975 the Rome Microcythaemia Centre has carried out every year, under the auspices of the health authorities of the Latium region, a screening of thalassaemics among intermediate schoolchildren of Latium. From these campaigns, knowledge about thalassaemias among the young adult population has grown which, in its turn, has resulted in screening of these young adults. Through screening in schools between 1975 and 1982, of 289 763 students examined, 6838 thalassaemics were identified, 6045 of whom were beta- or delta beta-thalassaemics. The total number of young thalassaemics who are identified at present in the Centre through screenings of schoolchildren and young adults is about 3300 per year. Furthermore, from January 1980 to April 1983, 110 prospective couples of child-bearing age at risk (94 of whom originated from Latium) were identified at the Centre, and five homozygous fetuses (three of which originated from Latium) were diagnosed. These data derive from an area in which the frequency of thalassaemia is only 2.4%, and they show that the programme in Latium for the prevention of Mediterranean anaemia has been successful.

Serial CEA levels in colorectal carcinoma on adjuvant immuno(chemo)therapy--further follow-up. Modulation of adjuvant treatment.

Serial plasma CEA levels have been studied preoperatively (testing A); one day after surgery (B); 10--15 days after surgery (C); 4 (D), 8 (E), 12 (F), 16--18 (G), and 22--24 (H) months after surgery in a series of 45 patients affected by colorectal carcinoma who started soon after surgery a protocol of adjuvant immuno(chemo)therapy with Levamisole and BCG. Postoperative follow-up was from one to 26 months, with 28 patients followed for at least one year. Fourteen patients had recurrences: two of these had false-negative CEA tests, three had persistent high CEA levels after surgery, nine had increasing levels 9--12 months before clinical recurrence; and nine of these 14 patients showed frankly pathologic preoperative plasma CEA levels. Six patients who did not have a recurrence but (both at clinical and instrumental evaluation) who had two consecutive high plasma CEA levels, were put on prophylactic polichemotherapy. The prognostic importance of CEA levels both pre- and postoperatively, the possibility of "modulating" postoperative adjuvant treatments on the basis of CEA levels, and the problem of unexplained fluctuations of plasma CEA levels with the putative metabolic linkages are discussed.

Intensive iron chelation therapy in beta-thalassemia major: some effects on iron metabolism and blood transfusion dependence.

Subcutaneous infusions of Desferal (DF) rarely induce negative iron balance in thalassemia major patients less than 6 years old. In nonsplenectomized patients the requirements for blood transfusions increase slightly. Urinary iron excretion decreases during the first days following a blood transfusion. An average of 5.8 mg/day equivalent to 30% of the total iron excretion is eliminated with the feces after subcutaneous infusions of DF. Serum ferritin does not decrease significantly after 18-24 months of therapy. The effectiveness of long-term therapy progressively increases in the splenectomized patients, while it decreases appreciably in the course of the treatment in the nonsplenectomized ones.

Silent thalassemias: genotypes and phenotypes.

BACKGROUND AND OBJECTIVE: Current application of molecular biology techniques to the study of the DNA of globin genes has confirmed the existence of silent alpha and beta thalassemias; which had already been reported on the basis of red blood cell parameters and family studies. The present work was aimed at analyzing all the aspects of the phenotype of the most common varieties of silent thalassemia. MATERIALS AND METHODS: Groups of heterozygous carriers of these varieties were examined using established techniques that determined all hematologic, hemoglobin (electrophoresis and measurement of Hb A2 and Hb F levels), and globin synthesis (evaluation of the alpha/beta ratio) parameters. Furthermore, all subjects underwent a complete molecular study of the alpha and beta globin genes by means of the ARMS, SSCP, DGGE, PCR and Southern blotting techniques. RESULTS: 1) The -101 C-->T mutation of the promoter of the beta globin gene shows a normal hematological picture with the Hb A2 level often slightly raised and the alpha/beta globin synthesis ratio slightly greater than 1; 2) beta + thalassemia resulting from the IVS II 844 C-->G mutation has a phenotype that is even closer to normal; 3) -alpha 3.7 deletion type I usually has a totally silent phenotype; 4) the alpha Ncol mutation almost always gives rise to a sub-silent phenotype if it is located on gene alpha 2 and to a silent phenotype if it is found on gene alpha 1; 5) alpha + thalassemia due to the alpha 2 Hphl mutation displays a sub-silent phenotype in some cases and a silent one in others; 6) triplication of the alpha genes gives rise to a phenotype that is quite similar to that of the -101 C-->T mutation of the promoter of the beta globin gene, namely one that is very often silent. INTERPRETATION AND CONCLUSIONS: Many of these silent varieties (beta + thalassemia due to the -101 C-->T mutation; alpha + thalassemia from a deletion or point mutation of an alpha gene; alpha alpha alpha triplication) are quite frequent in the overall group of thalassemias. It is therefore important for the operators in the field of thalassemia diagnosis to possess exact knowledge of them especially in order to prevent thalassemia major.

Phenotypes of individuals with a beta thal classical allele associated either with a beta thal silent allele or with alpha globin gene triplication.

BACKGROUND AND OBJECTIVE: beta thalassemia intermedia has its origins in compound heterozygosity for many different beta thal defects or in an interaction of a beta thal defect with altered alpha cluster. Two specific genetic associations (beta thal/beta(+) -101 C-->T and beta thal + alpha alpha alpha or alpha alpha alpha alpha) have been described in recent years as being determining a phenotype similar to that of simple beta thal heterozygote or, alternatively, a clinical picture of thalassemia intermedia. METHODS: A detailed study on this subject was carried out on 55 patients divided into 2 groups. Group I consisted of 20 patients, 17 of whom (Group Ia) had a beta thal/beta(+) -101 C-->T genotype and 3 (Group Ib) had a beta thal/beta IVS II-844 C-->G genotype. Group II consisted of 35 patients with beta thal association + alpha alpha alpha or alpha alpha alpha alpha. The methods of study have already been described in a previous issue. RESULTS: Thirty percent of group Ia and 25% of group II were virtually asymptomatic, while the others presented the thalassemia intermedia phenotype. This second phenotype is generally milder in patients of group I and even less so in those of group II. In the former there is a higher level of HbF; in the second there is more marked alpha/beta + gamma globin synthesis imbalance. The severity of the phenotype has no connection with that of the beta thal defect. The patients of group Ib all presented thalassemia intermedia. INTERPRETATION AND CONCLUSIONS: The definite clinical pictures of groups I and II are quite common in the Italian population and should therefore be well understood, especially for proper application of preventive measures against thalassemia major.