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Objectives: Iron chelation treatment (ICT) in beta-thalassemia major (beta-TM) patients undergoing blood transfusions can cause low satisfaction, low compliance, with possible negative consequences on treatment success, patients' wellbeing, and costs. The purpose was to estimate the societal burden attributable to beta-TM in terms of direct and indirect costs, health-related quality-of-life (HRQoL), satisfaction and compliance with ICT in patients undergoing transfusions and ICT.Research Design and Methods: The naturalistic, multicenter, longitudinal Italian-THAlassemia-Cost-&-Outcomes-Assessment (ITHACA) cost-of-illness study was conducted involving patients of any age, on ICT for at least 3 years, who were enrolled at 8 Italian Thalassemia Care Centers. Costs were estimated from the societal perspective, quantified with tariffs, prices, or net earnings valid in 2006.Results: One-hundred and thirty-seven patients were enrolled (median age = 28.3, 3-48 years, 49.6% male) and retrospectively observed for a median of 11.6 months. Mean direct costs were euro1242/patient/month, 55.5% attributable to ICT, 33.2% attributable to transfusions. Relevant quantity and quality of productivity was lost. Both physical and mental components of HRQoL were compromised. Little difficulties remembering to take ICT and positive satisfaction with the perceived effectiveness of therapy were declared, but not good levels of satisfaction with acceptance, perception of side effects and burden of ICT.Conclusions: The management of beta-TM patients undergoing transfusions and ICT is efficacious, although costly, but overall benefits were not always perceived as optimal by patients. Efforts must be focused to improve patients' acceptance and satisfaction with their therapy; this would contribute to a better compliance and hence an increase in treatment effectiveness and patients' overall wellbeing, with expected improved allocation of human and economic resources. [ABSTRACT FROM AUTHOR]

Objective: Our study was designed to evaluate the effects of 2 dosage schedules of recombinant interferon (IFN)-α (IFNα-2a and IFNα-2b) in reducing serum ALT and eradicating serum hepatitis C virus (HCV) RNA in β-thalassaemic patients with chronic hepatitis C. Design: 38 Sicilian β-thalassaemic patients (22 males and 16 females) received intramuscular IFNα-2a (Roferon-A; Roche) 5 MU/m 3 times weekly for 6 months, followed by 3 MU/m 3 times weekly for a further 6 months. 13 Sardinian β-thalassaemic patients (7 males and 6 females) received intramuscular IFNα-2b (Intron®; Schering-Plough) 3 MU/m 3 times weekly for 12 months. Parallel control groups (n = 20 and n = 8, respectively) did not receive IFNα. All patients received continuous subcutaneous desferoxamine infusion. Results: 24 (63%) Sicilian patients had a positive clinical response to IFNα-2a therapy. Two different patterns of response were apparent: (i) early and progressive decrease in ALT values until stable normalisation; and (ii) slower reduction of ALT values, which fluctuated on the way to normalisation. Five (21%) patients relapsed during the 12-month follow-up period. ALT levels decreased early in 5 (38%) Sardinian patients and one patient (20%) relapsed during the 12-month follow-up period. In the control groups, ALT values spontaneously normalised in 3 (10%) untreated patients. None of the patients treated with IFNα developed anti-IFNα antibodies. Viral clearance was demonstrated in 19 (50%) of 38 patients in the Sicilian group and 4 of 13 patients (31%) in the Sardinian group. Conclusion: Treatment with intramuscular recombinant IFNα-2a 5 MU/m 3 times weekly for 6 months, followed by 3 MU/m 3 times weekly for 6 months, appeared to be more effective than intramuscular IFNα-2b 3 MU/m 3 times weekly for 12 months. [ABSTRACT FROM AUTHOR]

Mean corpuscular volume (MCV) and mean cellular hemoglobin (MCH) were determined by means of a Hemalog 8/90 electronic counter in 51 full-term newborn infants with alpha-thalassemia-2 and 15 with alpha-thalassemia-1, as well as in 150 normal newborn infants. The mean MCV and MCH values were 92 fl +/- 06 and 33.26 pg +/- 2.22 in the normal newborn infants, 82 fl +/- 07 and 29.40 pg +/- 2.60 in the alpha-thalassemia-2 subjects, and 73 fl +/- 06 and 26.7 +/- 2.05 in the alpha-thalassemia-1 subjects. Four of the 150 normal newborn infants had MCV's < 79 fl and MCH's < 29.00 pg whereas 5 of the alpha-thalassemic subjects had MCV's > 90 fl and MCH's > 32.00 pg. We conclude that MCV and MCH determinations are unreliable in the diagnosis of alpha-thalassemia in the neonatal period. [ABSTRACT FROM AUTHOR]

Hb A2 was determined in 50 subjects with erythrocyte G-6-PD deficiency who presented with hyperbilirubinemia in the neonatal period and in 100 non-hyperbilirubinemic G-6-PD deficient newborn infants, at the age of 12 months or more. Six subjects in the first group and 13 in the second were found to be carriers of the beta-thalassemia trait. Statistical analysis of the data did not show any significant difference between the two groups. It seems that the beta-thalassemia trait does not provide any protection against neonatal hyperbilirubinemia associated with G-6-PD deficiency. [ABSTRACT FROM AUTHOR]

We report a case series of four infants with severe autoimmune haemolytic anaemia (AIHA) who responded to treatment with rituximab and cyclosporine after having failed first line therapy with high-dose steroid (prednisolone 4-8 mg/kg/d). Rituximab was started at 11-90 d from onset due to continued haemolysis; three infants also received cyclosporine A. Three of four infants reached complete response, defined as normal haemoglobin, reticulocytes and negative indices of haemolysis, at 7-21 months from diagnosis. In long-term follow-up two infants remained disease-free with normal immunology, one had undefined immunodeficiency and one had autoimmune lymphoproliferative syndrome.

Background: No information is available on the hepatic and extrahepatic pathways of bile acid synthesis in normal children and in pediatric cholestatic liver diseases., Methods: To explore the changes of the two pathways of bile acid synthesis during development, plasma concentrations of 7alpha-hydroxycholesterol and 27-hydroxycholesterol were measured in 50 healthy children (1 month-14 years) and compared to 18 adult controls. We also measured plasma oxysterols in 31 patients with pediatric cholestatic liver disease., Results: A progressive increase of plasma concentrations of both 27-hydroxycholesterol and 7alpha-hydroxycholesterol was found with age. In children with cystic fibrosis-associated liver disease plasma concentrations of 27-hydroxycholesterol were significantly lower compared to age-matched controls (5.6+/-0.5 vs. 12.8+/-1.1 microg/dl; p<0.001) and paralleled significantly lower concentrations of total cholesterol. In infants with biliary atresia plasma concentrations of 27-hydroxycholesterol were significantly higher compared to age-matched controls (8.8+/-0.8 vs. 4.4+/-0.6 microg/dl, p<0.001) paralleling significantly higher concentrations of total cholesterol while 7alpha-hydroxycholesterol resulted significantly lower (1.2+/-0.2 vs. 2.3+/-0.3 microg/100 mg of total cholesterol; p=0.011)., Conclusions: Our data suggest that both pathways of bile acid synthesis reach a state of maturity only after the age of 4 years and are significantly influenced also in children by liver function and intestinal absorption of cholesterol.

Background: The potential risk of acquiring infection by the novel human herpesvirus-8 (HHV-8) through blood derivatives is still debated., Objectives: In the present study, we determined HHV-8 seroprevalence in beta-thalassemic patients living in Italy., Study Design: We have analysed 86 patients from Sardinia, an island characterised by a high diffusion of HHV-8, as well as 33 thalassemics from the area of Rome, where a lower rate of HHV-8 infection has been reported. These data have been compared with HHV-8 seroprevalence found in healthy controls living in the same areas of the assayed patients., Results and Conclusions: A three-fold increase in HHV-8 seroprevalence was found among thalassemic patients when compared to control groups taken from the same regions (17.6% versus 5.1%). This risk factor was statistically significant when considering the Sardinians alone (P = 0.01) and the entire population analysed in the present survey (P = 0.0006). In the Roman area also an increased seroprevalence in thalassemic subjects was found (12.1% versus 4.6%) but it was not statistically significant (P = 0.2). HHV-8 is sporadically present in the blood of healthy individuals and it is unknown whether the virus eventually present in donors' blood is completely cleared by the treatments which blood undergoes before red cells are transfused. Based on these considerations, we hypothesise that multiply transfused subjects living in areas at high HHV-8 prevalence present an increased risk of being infected.

Background and Objectives: Osteonecrosis (ON) is a potentially disabling complication of combination chemotherapy including high doses of steroids. The incidence and main risk factors for symptomatic ON have been investigated in a large group of children treated with high-dose steroids, prednisone and dexamethasone for childhood acute lymphoblastic leukemia (ALL)., Design and Methods: From May 1995 to December 1999, 1421 patients <18 years old, with newly diagnosed non-B ALL, were registered in the AIEOP-ALL 95 study. Their data were reviewed to identify patients who developed symptomatic ON. For those who were positively identified additional data were requested concerning ON-related symptoms, treatment and outcome., Results: Overall, 15 of the 1421 patients developed symptomatic ON (1.1%) in a total of 29 sites. The estimated 5-year cumulative risk for clinically diagnosed ON was 1.6% (SE 0.4). The incidence was significantly higher among females (p=0.01) and older patients, with a peak rate of 7.4% (2.3) among those aged 10 to 17 years (p<0.0001). When the two factors, i.e. age and gender were combined, there was a striking increase in the risk among female patients aged 10 to 17 years. The median time between the diagnosis of ALL and that of ON was 17 months (range 8-45). The hip was the most frequently involved (19/29) site., Interpretation and Conclusions: Symptomatic ON occurred in only 1.1% of patients treated with BFM-type, intensive chemotherapy for childhood ALL. Female adolescents appear to be the subset of patients with the highest risk of ON, especially when categorized as having high risk leukemia and thus administered higher cumulative doses of dexamethasone.

Objective: Our study was designed to evaluate the effects of 2 dosage schedules of recombinant interferon (IFN)-alpha (IFNalpha-2a and IFNalpha-2b) in reducing serum ALT and eradicating serum hepatitis C virus (HCV) RNA in beta-thalassaemic patients with chronic hepatitis C., Design: 38 Sicilian beta-thalassaemic patients (22 males and 16 females) received intramuscular IFNalpha-2a (Roferon-A((R)); Roche) 5 MU/m(2) 3 times weekly for 6 months, followed by 3 MU/m(2) 3 times weekly for a further 6 months. 13 Sardinian beta-thalassaemic patients (7 males and 6 females) received intramuscular IFNalpha-2b (Intron(R); Schering-Plough) 3 MU/m(2) 3 times weekly for 12 months. Parallel control groups (n = 20 and n = 8, respectively) did not receive IFNalpha. All patients received continuous subcutaneous desferoxamine infusion., Results: 24 (63%) Sicilian patients had a positive clinical response to IFNalpha-2a therapy. Two different patterns of response were apparent: (i) early and progressive decrease in ALT values until stable normalisation; and (ii) slower reduction of ALT values, which fluctuated on the way to normalisation. Five (21%) patients relapsed during the 12-month follow-up period. ALT levels decreased early in 5 (38%) Sardinian patients and one patient (20%) relapsed during the 12-month follow-up period. In the control groups, ALT values spontaneously normalised in 3 (10%) untreated patients. None of the patients treated with IFNalpha developed anti-IFNalpha antibodies. Viral clearance was demonstrated in 19 (50%) of 38 patients in the Sicilian group and 4 of 13 patients (31%) in the Sardinian group., Conclusion: Treatment with intramuscular recombinant IFNalpha-2a 5 MU/m(2) 3 times weekly for 6 months, followed by 3 MU/m(2) 3 times weekly for 6 months, appeared to be more effective than intramuscular IFNalpha-2b 3 MU/m(2) 3 times weekly for 12 months.

To evaluate the risk of transmitting blood-borne GB virus C/hepatitis G virus (GBV-C/HGV) and to define the natural course of infection, we performed a prospective study in a cohort of multitransfused beta-thalassemics during a 6-year follow-up period. We analyzed serum samples of 150 patients collected at 3-year intervals from 1990 to 1996. GBV-C/HGV RNA was determined by reverse transcriptase-polymerase chain reaction and antibodies to E2-protein by an enzyme immunoassay. At baseline, 14.5% of patients had viremia and 18.5% anti-E2. None of the patients with anti-E2 in 1990 subsequently became viremic. Of the 100 GBV-C/HGV RNA-, anti-E2- patients, 10 acquired infection during follow-up, as indicated by positivity of GBV-C/HGV RNA (n = 2), anti-E2 (n = 7), or both markers (n = 1) in 1996. The incidence was 1.7 per 100 person-years (95% confidence interval [CI], 0.8 to 3). Since approximately 19,000 blood units were transfused to these patients during follow-up, the risk of infection was 5.3 in 10,000 units (95% CI, 2 to 8.5). Six of 22 viremic patients cleared the virus during follow-up; 4 of them became anti-E2+. Twelve of 28 patients lost anti-E2 reactivity during follow-up. In conclusion, more than 25% of infections resolve within 6 years; the presence of anti-E2 seems to be protective against infection. Anti-E2 reactivity may decrease with time.

We determined prospectively during a 12-month period the incidence, clinical characteristics and outcome of Yersinia enterocolitica infection in 144 thalassemic patients (mean age, 12.8 years) and compared them with 100 controls (mean age, 12.1 years). Symptomatic Y. enterocolitica infection occurred in 14 (10%) of the thalassemic patients and in 2 (2%) controls (P = 0.017). Of the 14 thalassemic patients 5 (36%) had septicemia and 9 (64%) had focal infection (enteritis in 8 and tonsillitis in 1). One control patient had acute enteritis and the other had tonsillitis. All isolates from these patients belonged to pathogenic phenotypes of Y. enterocolitica. Pending culture results symptomatic thalassemic patients discontinued treatment with deferoxamine and were treated with intravenous antibiotic therapy. Patients with the ultimate diagnosis of focal Y. enterocolitica infection continued treatment with intramuscular ceftriaxone or intravenous trimethoprim/sulfamethoxazole (TMP/SMX) for 7 days, whereas those with septicemia continued treatment with intravenous TMP/SMX for 14 days. The outcome was favorable in all 14 thalassemic patients. We conclude that Y. enterocolitica is a significant cause of morbidity in our patients with thalassemia and that prompt antibiotic therapy might prevent life-threatening conditions as well as a complicated course with long term sequelae.

Objective: Data on parathyroid function in patients with homozygous beta-thalassaemia are discordant. Moreover, there is no report on the effects of sexual steroid treatment on bone metabolism in these patients., Methods: Serum parathyroid hormone (PTH), calcitonin (CT) and osteocalcin (GLA protein) levels were measured in 121 patients. Thirty-three prepubertal subjects were treated for six months with sexual steroids., Results and Conclusions: Primary hypoparathyroidism was present in 3.3% of the patients. Osteocalcin levels were found to be lower in thalassaemic subjects than in controls, whereas CT values were similar. No effects of sexual steroid administration on plasmatic levels of osteocalcin were observed.

Objective: Impairment of linear growth is a common clinical feature in patients with beta-thalassaemia major. Although growth hormone secretion appears to be normal in many short thalassaemic patients, it proves to be deficient in some of them. In these cases, administration of biosynthetic growth hormone seems justified. The aim of this study was to evaluate the effect of such treatment in a group of patients with beta-thalassaemia major presenting with growth failure and impairment of growth hormone secretion., Design: Recombinant human growth hormone, 0.6 U/kg body weight per week, given subcutaneously in three divided doses, was administered for 12 months., Patients: Eight prepubertal patients with beta-thalassaemia major, presenting with severe growth retardation and impaired growth hormone secretion in response to provocative stimuli (insulin-induced hypoglycaemia, L-dopa and growth hormone-releasing hormone), were investigated., Measurements: Height and pubertal stage of the patients, as well as plasma levels of insulin-like growth factor I, were determined before, during and after biosynthetic growth hormone treatment., Results: During the first 6 months of therapy, a significant increase of growth velocity was observed, from a mean pretreatment value of 2.1 +/- 0.45 cm/year to a value of 4.8 +/- 0.66 cm/year (P less than 0.002). Mean growth rate at 12 months (4.1 +/- 0.50 cm/year), though slightly decreased in comparison to that recorded at 6 months, was still significantly higher than basal (P less than 0.001). A significant increase in plasma levels of insulin-like growth factor I was recorded during treatment (2.82 +/- 0.47 vs 0.96 +/- 0.22 U/ml, P less than 0.005). No side-effects, adverse reactions or alterations in routine laboratory examinations ensued during or after therapy., Conclusions: It appears from these data that biosynthetic growth hormone administration is worth serious consideration in patients with beta-thalassaemia major presenting growth retardation and impaired growth hormone secretion.

In Sardinia, the beta-39 nonsense mutation is the primary cause of beta 0-thalassaemia. This mutation is found mainly on beta-globin gene cluster haplotypes I and II, which differ in their A gamma globin types (A gamma I and A gamma T, respectively). This report presents data on G gamma, A gamma I and A gamma T levels, and the presence or absence of a 4 base pair (bp) deletion at -225 to -222 of the A gamma globin promoter, in 55 poly-transfused beta 0-thalassaemia major patients. Six patients were homozygotes for the normal (N) A gamma promoter lacking the 4 bp deletion, had no A gamma T globin, and their mean G gamma:A gamma I: A gamma T ratio was 52.9:47.1:0. Twenty-five patients were homozygotes for the mutant (M) A gamma promoter with the 4 bp deletion, had no A gamma I globin, and the mean G gamma:A gamma I: A gamma T ratio was 62.1:0:37.9. For M/M compared to N/N, the lower A gamma T than A gamma I was significant by the t-test (P less than 0.001). Twenty-four N/M cases had mean G gamma:A gamma I:A gamma T of 56:24.4:19.6, and the lower A gamma T than A gamma I was also significant (P less than 0.001). Partial haplotype analysis on these and 17 other beta 0-thalassaemia patients suggested that the 4 bp deletion was strongly associated with haplotype II. Of 33 M/M, 32 were haplotype II/II and one was II/5a; of 31 N/M, 29 were I/II and two were II/IX; of eight N/N, seven were haplotype I/I and one was I/IX. These data show a strong association of the 4 bp promoter deletion with decreased expression of the A gamma T globin gene on haplotype II.

Some uncertainty about deferoxamine ototoxicity is to be found in the literature. Therefore, 100 patients affected by beta-thalassemia were checked audiologically. Twelve of them showed a sensorineural hearing impairment which in most cases was confined to 4 and 8 kHz. If these results are compared with a sample of "normal" population, no significant difference can be observed, therefore excluding that deferoxamine, at least at present dosages, may be considered as a certain cause of cochlear impairment.

12 thalassaemic patients from Northern Sardinia showing the beta + phenotype were examined by isoelectric focusing and high-performance liquid chromatography techniques for the determination of the variant A gamma T globin chain of the foetal haemoglobin. Two patients (16.7%) were homozygotes for the A gamma T gene variant, 2 (16.7%) were heterozygotes and 8 (66.7%) were homozygotes for the normal A gamma I allele. The A gamma T gene frequency was 0.183, much lower than the observed 0.823 in beta zero homozygosity. These data suggest the presence of at least 2 beta +-thalassaemic chromosomes in Sardinians, one associated with the variant A gamma T allele and one associated with the normal A gamma I. The latter is prevalent among adult patients showing the intermediate form of the thalassaemic disease, which is not transfusion-dependent.

Endocrine function was evaluated in 20 prepubertal patients with homozygous beta-thalassemia treated with frequent transfusions and long term iron chelation therapy. FSH, LH, PRL, and TSH secretion were evaluated by LRH and TRH testing and L-dopa and ACTH were used to assess GH and adrenocortical reserve. No statistically significant differences were found between FSH, LH, PRL, GH, and cortisol secretion in the patients and in normal subjects. There was a relatively high incidence (35%) of primary thyroid impairment since 1 patient had primary hypothyroidism and 6 others had evidence of subclinical hypothyroidism as manifested by increased TSH responses to TRH. However, no statistically significant correlations were found between either serum ferritin levels, total blood transfusions received, and thyroid function.

Serum GOT, GPT, gamma-GT and GLDH were determined in 15 G-6-PD-deficient subjects during a hemolytic crisis and hemoglobinuria due to ingestion of fresh fava beans. The same G-6-PD-deficient subjects were studied again 2 months after the crisis, when they were asymptomatic. 15 normal healthy children served as controls. A statistically significant increase, above normal, in serum GOT, GLDH and gamma-GT was observed in the favic subjects during the crisis. All the values reverted to normal in the asymptomatic period.

A study has been performed on the incidence and duration of breast feeding in a group of 103 primiparous women who delivered in the Obstetrics Department of Sassari in 1980. The most important maternal variables that could be related with breast feeding were maternal age, level of school education, maternal feelings concerning the present pregnancy and maternal information concerning the advantages of breast feeding.

Forty-three patients with beta-thalassemia from Northern Sardinia (31 severe and polytransfused, six follow-up babies, five adults with mild thalassemia who were not transfusion dependent, and a young transfused patient was also affected by a disease of intermediate severity) were studied in order to establish the fetal hemoglobin composition, restriction fragment length polymorphism haplotypes at the beta-globin gene cluster, and the type(s) of mutation. Haplotype II was prevalent, [56/86 chromosomes (65%)], haplotype I was also fairly common, [22/86 chromosomes (25%)], while other types were relatively rare. The nonsense mutation at codon 39 was nearly exclusive, [76/80 chromosomes (95%)]. Other beta-thalassemia mutations occurred on chromosomes with haplotypes III, IX, X, and perhaps V, and a new type related to II. The mutated A gamma T gene was associated with type II, X, and the new type. Type IX was linked to a beta(0) gene and to an Xmn I site 5' to the G gamma gene, to a high G gamma globin level, and to a disease of mild severity. Type III was associated with a beta(+)-thalassemic gene. The (0)39 mutation linked to type II was associated with thalassemia intermedia in three patients.