Casa Sollievo della Sofferenza

About: Casa Sollievo della Sofferenza is a healthcare organization based out in San Giovanni Rotondo, Italy. It is known for research contribution in the topics: Population & Cancer. The organization has 2234 authors who have published 6183 publications receiving 239811 citations. The organization is also known as: Home for Relief of the Suffering.

Autosomal dominant reticuloendothelial iron overload (HFE type 4) due to a new missense mutation in the FERROPORTIN 1 gene (SLC11A3) in a large French-Canadian family.

Abstract: Hereditary hemochromatosis (HH) is usually transmitted as an autosomal recessive trait in which excessive iron absorption causes iron overload, primarily in parenchymal cells. It is mainly due to mutations HFE gene (hemochromatosis type 1),1 but a minority of cases are associated with TFR2 gene mutations (hemochromatosis type 3).2 In addition, a severe early onset form (hemochromatosis type 2) has been described and mapped.3 More recently, an autosomal dominant form of HH has been described (HFE type 4) due to mutations in FERROPORTIN 1 (also known as solute carrier family 11, member A3, or SLC11A3).4-6 We have identified a large French-Canadian pedigree affected by an autosomal dominant form of iron overload and characterized by 8 affected and 9 healthy members (Figure 1a). A summary of the most important iron parameters and clinical signs is reported in Table 1. The proband (2055) (now 28 years old) presented with fatigue, diarrhea and tremors. His serum ferritin concentration was 647 μg/L (normal range up to 400 μg/L) and transferrin saturation was 77% (normal range up to 45%). A magnetic resonance imaging (MRI) scan suggested iron accumulation in the liver and steatosis. A liver biopsy revealed iron deposition in both hepatocytes and Kupffer cells without fibrosis but with grade 4 at Perls’ staining (Figure 1b). After one year of venesections (once per week) (450 mL blood per week), the ferritin dropped to 44 μg/L with a transferrin saturation of 31%. The proband's father (2053) (now 59 years old) had a high serum ferritin concentration (1759 μg/L) and a transferrin saturation of 96%. Liver biopsy showed fibrosis and marked iron accumulation in hepatocytes and in macrophages and ferritin concentration fell to 15.5 μg/L after 2 years of phlebotomies. Elevated serum ferritin associated with increased transferrin saturation was found in 6 additional family members. All patients are now undergoing phlebotomies and none of them have any problem tolerating this therapy. Genomic DNA was obtained from all family members. Exclusion of HFE C282Y and H63D mutations was performed as previously described. Linkage to FERROPORTIN 1 locus (Lod score of 4.21 at recombination frequency of τ=0) has been demonstrated using the following markers: D2S2257, D2S350, D2S152, D2S118, D2S315 and D2S280. The following mutational screening of FERROPORTIN 1 gene, carried out by direct sequencing of its coding region and flanking intron-exon boundaries, led to the identification of a T to C change at nucleotide position 190 of the gene. This change corresponds to a substitution of an aromatic and hydrophobic tyrosine residue with a small and polar asparagine one at position 64 of the protein (Y64N). This mutation, which segregates with the disease and was not found in 100 normal controls, can be easily detected by RE digestion since it creates a new HincII restriction site (Figure 1c). According to consensus structural predictions the mutation is located in the first transmembrane domain of ferroportin 1 protein.8 Three other mutations in the human FERROPORTIN 1 gene have been so far reported.4,5,7 Njajou et al. described a Dutch pedigree with a missense mutation (N144H) resulting in autosomal dominant hemochromatosis with significant iron overload treatable by phlebotomy. Montosi et al. reported a missense mutation (A77D) in an autosomal dominant Italian hemochromatosis pedigree, in which transferrin saturation was elevated in 8 of 15 family members. For N144H mutation a gain of function effect was proposed, while for A77D a loss of function and haploinsufficiency was suggested. Finally a common deletion, named V162del was described in cases with increased serum ferritin with either normal or raised transferrin saturation.6,8,9,10 This mutation seems to lead to loss of function and deficiency in the release of iron from phagocytic cells, which becomes apparent on venesection. Serum ferritin concentrah ha em at ol og ic a

Docetaxel as salvage therapy in advanced gastric cancer: a phase II study of the Gruppo Oncologico Italia Meridionale (G.O.I.M.).

Abstract: Background: Docetaxel (DCT), a semisynthetic taxoid, has demonstrated cytotoxic activity against gastric cancer in early phase II studies producing an overall response rate of 17-24%. The Gruppo Oncologico Italia Meridionale (G.O.I.M.) started a confirmatory multicenter phase II trial to evaluate the clinical activity and toxicity of single agent TXT in the treatment of advanced gastric cancer patients who had failed a first-line chemotherapy. Materials and Methods: Thirty patients with advanced gastric carcinoma refractory to first-line ECF or PELF chemotherapy were treated with DCT administered at the dosage of 100 mg/mq given as a 1-hour i.v. infusion every three weeks. All patients received a premedication with dexamethasone 8 mg i.v. 12 hours and 1 hour before, and 12 hours after DCT administration. Granulocyte colony stimulating factor was employed in case of febrile neutropenia as needed. The first evaluation of disease status was planned after three cycles. Results: We observed 5 partial responses without any complete response for an overall response rate of 17% (95% CI=6-36%, intent-to-treat analysis). Nine patients showed stable disease and 14 patients progressed. The duration of objective partial responses were 5, 6, 6, 9 and 12 months, respectively. The median overall survival was 6 months and the 1-year survival rate was 20.6%. No chemotherapy-related toxic death was observed. Haematological grade 3-4 side-effects were respectively: anemia (7%), leucopenia (7%) and neutropenia (18%); in 13 patients (45%) G-CSF was employed to avoid severe leukopenia. Conclusion: This multinstitutional single-step phase II study confirms that single-agent docetaxel is active in advanced gastric cancer progressing after first-line chemotherapy. The most frequent toxicity is neutropenia, which may be managed by G-CSF and/or dose adjustments. Docetaxel is therefore worthy of further study in combination with other active drugs.

Skeletal involvement in female acromegalic subjects: The effects of growth hormone excess in amenorrheal and menstruating patients

Abstract: Bone involvement is a common clinical feature in acromegalic patients, though previous studies gave divergent results possibly because of the different gonadal status of the patients studied. To study the influence of estrogen milieu in these patients, we evaluated 23 acromegalic patients with active disease, subdivided into two groups: menstruating and amenorrheal patients, comparable for duration and activity of disease. Forty-two matched women served as controls. Skeletal involvement was studied by measuring: (a) the main biomarkers of bone turnover: serum alkaline phosphatase total activity (AP), bone GLA protein (BGP), serum carboxy-terminal propeptide of type I collagen (PICP), serum type I cross-linked N-telopeptide (ICTP), and urinary pyridinoline and deoxypyridinoline corrected for creatinine (Pyr/Cr, D-Pyr/Cr) and urinary calcium/creatinine ratio (Ca/Cr); (b) bone mineral density (BMD), as measured by quantitative computed tomography both at lumbar spine and distal radius, and by dual X-ray absorptiometry both at lumbar spine and at three femoral sites (Ward's triangle, femoral neck, and great trochanter). AP, BGP, ICTP, Pyr/Cr, D-Pyr/Cr were significantly higher in patients than in controls, independent of the menstrual pattern. Higher PICP levels were found in the whole group and in menstruating acromegalics when compared with control women; no difference was found in amenorrheal patients, who in turn showed higher urinary Ca/Cr values. When patients were considered all together, BMD at spine, femoral neck, and trochanter was higher than in controls. In contrast, when the gonadal status was taking into account and, menstruating and amenorrheal subjects were considered separately, BMD at spine, but not in other sites, was significantly higher in menstruating patients than in controls. In contrast, no difference of BMD values at any site was observed between amenorrheal patients and controls. The mean BMD Z scores allowed us to detect an unequal involvement of different skeletal sites. Our results show that bone turnover is increased in acromegalic women and suggest that GH anabolic effect on bone is more evident in the presence of estrogens and that different skeletal sites may be affected differently by hormone excess.

Detection of aneuploidies by paralogous sequence quantification

Abstract: BACKGROUND: Chromosomal aneuploidies are a common cause of congenital disorders associated with cognitive impairment and multiple dysmorphic features. Pre-natal diagnosis of aneuploidies is most commonly performed by the karyotyping of fetal cells obtained by amniocentesis or chorionic villus sampling, but this method is labour intensive and requires about 14 days to complete. METHODS: We have developed a PCR based method for the detection of targeted chromosome number abnormalities termed paralogous sequence quantification (PSQ), based on the use of paralogous genes. Paralogous sequences have a high degree of sequence identity, but accumulate nucleotide substitutions in a locus specific manner. These sequence differences, which we term paralogous sequence mismatches (PSMs), can be quantified using pyrosequencing technology, to estimate the relative dosage between different chromosomes. We designed 10 assays for the detection of trisomies of chromosomes 13, 18, and 21 and sex chromosome aneuploidies. RESULTS: We evaluated the performance of this method on 175 DNAs, highly enriched for abnormal samples. A correct and unambiguous diagnosis was given for 119 out of 120 aneuploid samples as well as for all the controls. One sample which gave an intermediate value for the chromosome 13 assays could not be diagnosed. CONCLUSIONS: Our data suggests that PSQ is a robust, easy to interpret, and easy to set up method for the diagnosis of common aneuploidies, and can be performed in less than 48 h, representing a competitive alternative for widespread use in diagnostic laboratories.

Characterizing somatosensory evoked potential sources with dipole models: advantages and limitations.

Abstract: Several methods have been developed to investigate the cerebral generators of scalp somatosensory evoked potentials (SEPs), because simple visual inspection of the electroencephalographic signal does not allow for immediate identification of the active brain regions. When the neurons fired by the afferent inputs are closely grouped, as usually occurs in SEP generation, they can be represented as a dipole, that is, as a linear source with two opposite poles. Several techniques for dipolar source modeling, which use different algorithms, have been employed to build source models of early, middle-latency, and late cognitive SEPs. Modifications of SEP dipolar activities after experimental maneuvers or in pathological conditions have also been observed. Although the effectiveness of dipolar source analysis should not be overestimated due to the intrinsic limitations of the approach, dipole modeling provides a means to assess SEPs in terms of cerebral sources and voltage fields that they produce over the head.