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Aurelio Maggio

Publications and source records attributed to Aurelio Maggio.

At least 19 recordsLinked to original sources
PubMed2007

Standardized T2* map of normal human heart in vivo to correct T2* segmental artefacts.

A segmental, multislice, multi-echo T2* MRI approach could be useful in heart iron-overloaded patients to account for heterogeneous iron distribution, demonstrated by histological studies. However, segmental T2* assessment in heart can be affected by the presence of geometrical and susceptibility artefacts, which can act on different segments in different ways. The aim of this study was to assess T2* value distribution in the left ventricle and to develop a correction procedure to compensate for artefactual variations in segmental analysis. MRI was performed in four groups of 22 subjects each: healthy subjects (I), controls (II) (thalassemia intermedia patients without iron overload), thalassemia major patients with mild (III) and heavy (IV) iron overload. Three short-axis views (basal, median, and apical) of the left ventricle were obtained and analyzed using custom-written, previously validated software. The myocardium was automatically segmented into a 16-segment standardized heart model, and the mean T2* value for each segment was calculated. Punctual distribution of T2* over the myocardium was assessed, and T2* inhomogeneity maps for the three slices were obtained. In group I, no significant variation in the mean T2* among slices was found. T2* showed a characteristic circumferential variation in all three slices. The effect of susceptibility differences induced by cardiac veins was evident, together with low-scale variations induced by geometrical artefacts. Using the mean segmental deviations as correction factors, an artefact correction map was developed and used to normalize segmental data. The correction procedure was validated on group II. Group IV showed no significant presence of segmental artefacts, confirming the hypothesis that susceptibility artefacts are additive in nature and become negligible for high levels of iron overload. Group III showed a greater variability with respect to normal subjects. The correction map failed to compensate for these variations if both additive and percentage-based corrections were applied. This may reinforce the hypothesis that true inhomogeneity in iron deposition exists.

Adult↗
PubMed2006

Multislice multiecho T2* cardiovascular magnetic resonance for detection of the heterogeneous distribution of myocardial iron overload.

PURPOSE: To assess the tissue iron concentration of the left ventricle (LV) using a multislice, multiecho T2* MR technique and a segmental analysis. MATERIALS AND METHODS: T2* multiecho MRI was performed in 53 thalassemia major patients. Three short-axis views of the LV were obtained and analyzed with custom-written software. The myocardium was automatically segmented into 12 segments. The T2* value on each segment as well as the global T2* value were calculated. Cine dynamic images were also obtained to evaluate biventricular function parameters by quantitative analysis. RESULTS: For the T2* global value, the coefficient of variation (CoV) for intra-/interobserver and interstudy reproducibility was 3.9% (r = 0.98), 5.5% (r = 0.98), and 4.7% (r = 0.99) respectively. Three groups were identified based on analysis of myocardial T2*: homogeneous (21%), heterogeneous (38%), and no myocardial iron overload (41%). The mean serum ferritin, liver iron concentration, and urinary iron excretion were significantly different among the groups. We did not find significant differences among groups in biventricular function. There was a correlation between the global T2* value and the T2* value in the mid-ventricular septum (r = 0.95, P < 0.0001). CONCLUSION: Multislice multiecho T2* MRI provides a noninvasive, fast, reproducible means of assessing myocardial iron distribution. The single measurement of mid-septal T2* correlated well with the global T2* value.

Adolescent↗
PubMed2006

A prospective study of hepatocellular carcinoma incidence in thalassemia.

Hepatocellular carcinoma (HCC) is a complication of cirrhosis. Due to blood transfusions, patients with beta-thalassemia (thal) are often infected with either hepatitis C virus (HCV) or hepatitis B virus (HBV). In the past, many patients did not survive long enough to develop HCC. The recent improvements in prognosis have helped in the diagnosis of HCC that has developed. The aim of this study was to evaluate HCC incidence in beta-thal. We performed liver ultrasound (US) on all adults without a previous diagnosis of HCC. Risk factors (iron overload, HCV infection, HBV infection, cirrhosis) were evaluated. One hundred and eight thalassemia patients have been evaluated; of whom three were excluded (two patients as they were under the age of 18 years and one patient because he had a previous history of HCC). Seventy-two patients [31 had thalassemia major (TM), 41 had thalassemia intermedia (TI)] with risk factors (iron overload in 72, HCV infection in 46, HBV infection in two, cirrhosis in 10) and 33 (four with TM and 29 with TI) without risk factors underwent liver US. Overall, two patients were found to have a newly developed HCC. Of these two patients, one was treated with surgery and the other with percutaneous radiofrequency. Further follow-up did not show any evidence of recurrence after 23 and 15 months, respectively. Ultrasound screening can allow early detection and treatment of HCC in thalassemia patients.

Adolescent↗
PubMed2006

Hb Marineo [beta70(E14)Ala-->Val]: a silent hemoglobin variant with a mutation within the heme pocket.

We report a new hemoglobin (Hb) variant, Hb Marineo [beta70(E14)Ala --> Val], found in three generations of a family from West Sicily. The mutation is due to a GCC --> GTC substitution at codon 70 of the beta-globin gene. To date, three mutations at codon 70 of the beta-globin gene have been described, presenting with hemolytic anemia. In our case, no anemia or other alteration of hematological indices were found. Cation exchange high performance liquid chromatography (HPLC) showed a peak in the P2 window (VARIANT I), while a peak was detected by VARIANT II HPLC in the P3 window. Reversed phase HPLC analysis showed an abnormal chain amounting to about 40% of the total beta chains.

Adult↗
PubMed2006

Evaluation of the efficacy of oral deferiprone in beta-thalassemia major by multislice multiecho T2*.

OBJECTIVES: Oral deferiprone (L1) appears to be promising in the treatment of beta-thalassemia major (TM) patients. T2* magnetic resonance imaging (MRI) with a single measurement in the mid-ventricular septum was validated as a quantitative evaluation of myocardial iron overload. Previous studies suggested a marked heterogeneity of iron distribution in the myocardium. We set up a multislice multiecho T2* MRI for the detection of this heterogeneity. The aim of our study was to investigate differences between the L1 vs. the subcutaneous desferrioxamine (DF)-treated patients using this new approach. METHODS: Thirty-six beta-TM patients (age 29 +/- 8 yr) underwent MRI. Eighteen patients received long-term L1, and 18 other patients matched for age and sex received DF. T2* multiecho sequences on three short axis views of the left ventricle were obtained and analyzed by custom-made software. In each slice, the myocardium was automatically segmented into four segments. Cine-dynamic images were also obtained to evaluate biventricular function. RESULTS: For multislice T2* technique, the coefficient of variation for intra- and inter-observer, and inter-study reproducibility was 3.9%, 4.7%, and 5.5%, respectively. The global heart T2* value was significantly higher in the L1 vs. DF group (35 +/- 7 vs. 27 +/- 2 ms; P = 0.02). The number of segments with normal T2* value (>20 ms) was significantly higher in the L1 vs. the DF group (11 +/- 1 vs. 8 +/- 5 segments; P = 0.03). We did not detect significant differences in biventricular function parameters. CONCLUSIONS: This new approach confirms that L1 could be more effective than DF in removal of myocardial iron.

Adult↗
PubMed2006

Analysis of delta-globin gene alleles in the Sicilian population: identification of five new mutations.

Although delta-globin gene (HBD MIM#142000) mutations have no clinical implications, co-inheritance of beta- and delta-thalassemia may lead to misdiagnosis. Among 7,153 samples studied for beta-thalassemia, 205 samples with lower than expected HbA2 levels were selected for our analysis and 183 samples (2.5%) were positive for delta-globin gene mutations. Twelve different mutations were detected, and among these five have not been not previously described (HbA2-Catania HBD c.8A-->T, HbA2-Corleone HBD c.41C-->A, HbA2-Ventimiglia HBD c.212C-->G, HbA2-Montechiaro HBD c.260C-->A, and HbA2-Bagheria HBD c.422C-->T). This study suggests that delta-globin gene defects are very common in Sicily. Thus, these mutations need to be considered during beta-thalassemia screening to avoid false negative results in the detection of at-risk couples.

Alleles↗
PubMed2005

A genetic strategy to treat sickle cell anemia by coregulating globin transgene expression and RNA interference.

The application of RNA interference (RNAi) to stem cell-based therapies will require highly specific and lineage-restricted gene silencing. Here we show the feasibility and therapeutic potential of coregulating transgene expression and RNAi in hematopoietic stem cells. We encoded promoterless small-hairpin RNA (shRNA) within the intron of a recombinant gamma-globin gene. Expression of both gamma-globin and the lariat-embedded small interfering RNA (siRNA) was induced upon erythroid differentiation, specifically downregulating the targeted gene in tissue- and differentiation stage-specific fashion. The position of the shRNA within the intron was critical to concurrently achieve high-level transgene expression, effective siRNA generation and minimal interferon induction. Lentiviral transduction of CD34(+) cells from patients with sickle cell anemia led to erythroid-specific expression of the gamma-globin transgene and concomitant reduction of endogenous beta(S) transcripts, thus providing proof of principle for therapeutic strategies that require synergistic gene addition and gene silencing in stem cell progeny.

Anemia, Sickle Cell↗
PubMed2005

Functional characterization of the sea urchin sns chromatin insulator in erythroid cells.

Chromatin insulators are regulatory elements that determine domains of genetic functions. We have previously described the characterization of a 265 bp insulator element, termed sns, localized at the 3' end of the early histone H2A gene of the sea urchin Paracentrotus lividus. This sequence contains three cis-acting elements (Box A, Box B, and Box C + T) all needed for the enhancer-blocking activity in both sea urchin and human cells. The goal of this study was to further characterize the sea urchin sns insulator in the erythroid environment. We employed colony assays in human (K562) and mouse (MEL) erythroid cell lines. We tested the capability of sns to interfere with the communication between the 5'HS2 enhancer of the human beta-globin LCR and the gamma-globin promoter. We found that the sns sequence displays directional enhancer-blocking activity. By the use of antibodies against known DNA binding proteins, in electrophoretic mobility shift assays, we demonstrated the binding of the erythroid-specific GATA-1 and the ubiquitous Oct-1 and Sp1 transcription factors. These factors bind to Box A, Box B, and Box C + T, respectively, in both K562 and MEL nuclear extracts. These results may have significant implications for the conservation of insulator function in evolutionary distant organisms and may prove to be of practical benefit in gene transfer applications for erythroid disorders such as hemoglobinopathies and thalassemias.

Animals↗
PubMed2005

Analytical evaluation of the Tosoh HLC-723 G7 automated HPLC analyzer for hemoglobin A2 and F determination.

OBJECTIVES: The analytical performance of a new automated HPLC system (Tosoh HLV-723 G7) for Hb A(2) and Hb F quantification in blood was studied. DESIGN AND METHODS: Hb A(2) and Hb F measurements were studied for imprecision, linearity, carry-over, interferences and sample concentration effect. Method comparison study was performed with the Bio-Rad Variant II HPLC system. Hb F results were also compared with those obtained by the alkaline denaturation test. The detection of some common Hb variants was also studied. RESULTS: Hb A(2) within-run and between-run CVs were found between 0.8-2.2% and 2.9-7.2%, respectively, while CVs for Hb F were up to 10.0% in normal and between 1.9-5.3% at more clinically relevant Hb F concentrations (>1.5%). Comparison study with Bio-Rad Variant II for Hb A(2) determination showed good correlation but highlighted calibration differences. The following results were obtained in two different laboratories: y = 1.163x - 0.52, r = 0.9918, n = 144 (Lab A); y = 1.060x - 0.40, r = 0.9920, n = 93 (Lab B). With regard to the determination of Hb F, the measurements performed by the tested method was found to correlate well with the alkaline denaturation test (y = 1.0138x - 0.36, r = 0.9842, n = 20) and with the Variant II HPLC system (y = 0.812x + 0.52, r = 0.9835, n = 110). An excellent linearity (r = 0.999) was found for both Hb A(2) and Hb F in the range 0.8-19%. Hb S, Hb C and Hb D can be presumptively identified by the assigned retention time windows. CONCLUSION: The new analyzer Tosoh HLV-723 G7 was found to be a reliable method for Hb A(2) and Hb F quantification and for the presumptive identification of some common Hb variants.

Automation↗
PubMed2005

Allele-specific transcription of fetal genes in primary erythroid cell cultures from Lepore and deltabeta degrees thalassemia patients.

OBJECTIVE: Autonomous gene silencing and gene competition by globin promoters for locus control region (LCR) function have been proposed as mechanisms in developmental regulation of beta-like genes. deltabeta degrees thalassemias are syndromes presenting an increased production of fetal hemoglobin in adult life; the majority of them are due to various deletions in beta-globin gene cluster. We studied samples from double heterozygotes for beta-thalassemia and for Lepore or Sicilian deltabeta degrees deletions, both lacking beta-promoter sequence. Our goal was to address the question of whether the allele carrying the deltabeta degrees deletion is responsible for high level of fetal hemoglobin (HbF) production. PATIENTS AND METHODS: We analyzed the globin gene transcription in human erythroid cell cultures from peripheral blood stem cells, using primary transcript in situ hybridization. We performed primary erythroid cultures from patients with the following genotypes: Lepore/beta degrees 39, Sicilian deltabeta degrees /beta degrees 39, and, as controls, two thalassemia patients with nondeletional mutations (IVS1,6/IVS1,6; IVS1,6/beta degrees 39), and one normal individual. RESULTS: The cells where it is possible to unambiguously assign gamma genes transcription in cis with the deletion (gamma:beta) are strongly represented with respect to the nine other combinations of gamma and beta hybridization signals. These cells are at least nine times more represented than those expressing the gamma allele in trans to the deletion. CONCLUSION: The allele-specific transcription of fetal genes in cis with the deletion is favored in both deletional genotypes. The absence of the adult promoter may influence LCR recruitment by fetal promoter, supporting the hypothesis that competition mechanism and gene silencing can coexist in regulating human globin gene transcription.

Alleles↗
PubMed2005

Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in Southern Italy.

OBJECTIVE: A defect of gastrointestinal barrier function is considered to represent an important step in the pathogenesis of Crohn's disease (CD) but the mechanisms leading to an increased intestinal permeability (IP) are poorly understood. Since IP is influenced by pro-inflammatory mediators, it seems likely that a genetically determined abnormal immune response may lead to a loss of barrier function. METHODS: In a geographic area in Southern Italy with high incidence of CD we investigated IP (lactulose/mannitol testing) together with the three main mutations of the NOD2/CARD15 and the D299G polymorphism of the toll-like receptor (TLR)-4 gene in 23 families of CD patients (patients and first-degree relatives). RESULTS: Forty-eight percent of CD patients and 40% of their healthy relatives were found to have an abnormal IP compared to 5% of an appropriate control population (p < 0.0001). IP, however, was not associated with the L1007finsC mutation of the NOD2/CARD15 or the D299G variant of the TLR-4 gene. Allele frequency of the only L1007finsC mutation of CARD15 was significantly increased in patients (8.7%, p < 0.003) and in relatives (8.3%, p < 0.024) compared with controls (2.4%), whereas the D299G variant of the TLR-4 gene was found to be increased only in relatives (8.3%, p < 0.022), but not in patients (4.3%) compared with the control population (1.7%). CONCLUSIONS: There was no association between IP and genetic markers. Our findings showed a very high proportion of healthy first-degree relatives to bare alterations suggested to constitute determinants of CD. Mutations of NOD2/CARD15 or TLR-4, however, do not lead to permeability defects emphasizing the importance of additional environmental and/or genetic factors for pathogenesis.

Adult↗
PubMed2004

Hepatocellular carcinoma in the thalassaemia syndromes.

Hepatocellular carcinoma (HCC) frequently complicates hepatic cirrhosis secondary to viral infection or iron overload. Therefore, patients affected by thalassaemia syndromes have a theoretically high risk of developing the tumour. We collected data on patients attending Italian centres for the treatment of thalassaemia. Twenty-two cases of HCC were identified; 15 were male. At diagnosis, the mean age was 45 +/- 11 years and the mean serum ferritin was 1764 +/- 1448 microg/l. Eighty-six percent had been infected by hepatitis C virus. Nineteen of 22 cases were diagnosed after 1993, suggesting that this problem is becoming more frequent with the aging population of thalassaemia patients.

Adult↗