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Biomedical subjects

G Fiorelli

Publications and source records attributed to G Fiorelli.

At least 37 records · Page 2Linked to original sources
PubMed2000

The design of custom orthodontic mechanics.

The straightwire appliance promises prescribed tooth positions within the arches. Unfortunately, such an outcome is not necessarily achieved, especially in the adult patient. Teeth do not always move according to a template. Continuous archwires do not allow for differentiation between active and reactive units; consequently, the correct force system is never developed. These shortcomings could be overcome by custom-designed mechanics. Here we report on the use of Dental Movement Analysis (DMA) software supported by two clinical examples. On the computerized occlusogram, DMA stimulates the desired tooth movements and computes the force vectors and moments necessary to achieve the planned result. These images enable the clinician to fabricate a custom appliance for maximum efficiency. Maximum efficiency results in minimal treatment time.

Journal Article↗
PubMed2000

Non-transferrin-bound iron in myelodysplastic syndromes: a marker of ineffective erythropoiesis?

INTRODUCTION: Iron overload is usually observed in patients (even untransfused) with myelodysplastic syndromes (MDS), and contributes towards the generation of low molecular weight iron complexes or non-transferrin-bound iron (NTBI), which in turn favors oxidative DNA damage and consequent apoptosis. MATERIALS AND METHODS: Levels of NTBI and lipid peroxidation were evaluated by means of free serum malondyaldehyde (MDA) in untransfused MDS patients and we tried to correlate them with ineffective erythropoiesis, apoptosis and the pattern of in vitro growth. RESULTS: NTBI levels were found to be significantly higher in low-risk than in high-risk MDS patients, as well as in patients with a lower myeloid/erythroid ratio. MDA was found to be uniformly higher in the MDS patients as a whole than in normal controls. The bone marrow progenitor cells in the MDS patients with high NTBI levels showed a higher degree of apoptosis, but this difference was not statistically significant. Patients with a leukemic growth pattern had lower NTBI levels than those with a non-leukemic pattern. CONCLUSION: These data suggest that NTBI is related to the degree of ineffective erythropoiesis and that it contributes towards inducing apoptosis in MDS bone marrow precursors. The presence of leukemic growth is associated with low NTBI levels, probably due to increased iron consumption by blast cells.

Apoptosis↗
PubMed2000

Relationship between TNF-alpha and iron metabolism in differentiating human monocytic THP-1 cells.

The human monocytic cell line THP-1 differentiates along the macrophage line after phorbol-12-myristate-13-acetate (PMA) supplementation and can be stimulated to secrete tumour necrosis factor alpha (TNF-alpha) by interferon gamma (IFN-gamma) addition. We found that, in the early stage of differentiation (1-48 h), PMA induction elicited an upregulation of intracellular H ferritin and H ferritin binding sites and a downregulation of transferrin receptor. In addition, we found that iron administration to PMA-differentiating cells induced the expression of TNF-alpha mRNA and TNF-alpha secretion to levels even higher than those induced by IFN-gamma alone. The iron chelator desferrioxamine showed the opposite effect and reduced TNF-alpha release. In contrast, preincubation of the cells with iron before PMA induction resulted in a decrease of the TNF-alpha secretion induced by IFN-gamma, whereas the opposite was true after preincubation with desferrioxamine. The data support a co-ordinate interaction between iron and TNF-alpha in monocyte macrophages, with an iron-mediated upregulation of TNF-alpha in the early phase of differentiation and an iron-mediated inhibition at later stages. This complex relationship has to be considered in evaluating the effects of iron on inflammation.

Binding Sites↗
PubMed2000

Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia.

Thromboembolic phenomena have been described in patients with thalassaemia intermedia and major, although there are relatively few epidemiological data on the overall frequency of these complications. To obtain more insight into the risk and mechanism of venous thromboembolism in thalassaemia, the aims of this study were: (i) to establish retrospectively the prevalence of thromboembolic events in a large group of adults with thalassaemia intermedia and major during a follow up period of 10 years; (ii) to measure in subgroups of these patients sensitive markers of activation of coagulation and fibrinolysis enzymes; and (iii) to look for possible procoagulant mechanisms. A high prevalence of thromboembolic events was found, particularly in splenectomized patients with thalassaemia intermedia (29%). These patients had high plasma levels of markers of coagulation and fibrinolysis activation. Furthermore, thalassaemic red cells and erythroid precursors from splenectomized patients with thalassaemia intermedia had an enhanced capacity to generate thrombin. To evaluate the role of splenectomy per se on procoagulant activity, we evaluated the capacity to form thrombin in healthy individuals who had been splenectomized for trauma. They produced the same amount of thrombin as non-splenectomized controls. In conclusion, the results of this study show the existence of a hypercoagulable state in splenectomized patients with thalassaemia intermedia and that their red and erythroid cells are capable of acting as activated platelets in thrombin generation.

Adult↗
PubMed2000

Chronic non-spherocytic haemolytic disorders associated with glucose-6-phosphate dehydrogenase variants.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, being present in over 400 million people world wide. In a small number of cases, G6PD deficiency can lead to mild-to-severe chronic haemolysis, which is further exacerbated by oxidative stress. Such G6PD variants have been described all over the world and are responsible for chronic non-spherocytic haemolytic anaemia (CNSHA). To date 61 G6PD molecular variants associated with CNSHA have been identified, only some of which can cause the severe reduction in stability of the red blood cell enzyme. The distribution of the different mutations shows a predominance of small mutational events, and many have been found repeatedly in different parts of the world. By revisiting the 61 class I variants described so far, we can observe that a low inhibition constant (Ki) for NADPH, a higher Km for substrates and a reduced thermostability are common.

Anemia, Hemolytic, Congenital Nonspherocytic↗
PubMed2000

Can large cell change and high proliferative activity predict hepatocellular carcinoma in patients with hereditary hemochromatosis?

OBJECTIVE: Patients with hereditary hemochromatosis are at high risk of developing hepatocellular carcinoma. This study was undertaken to define whether large cell change and nucleolar organizer regions proliferative index (marker of high proliferative activity) predict hepatocellular carcinoma development in hereditary hemochromatosis. METHODS: Histological staining for large cell change and high proliferative activity were done on baseline liver biopsies of 74 patients with hereditary hemochromatosis (52 with and 22 without cirrhosis), prospectively followed-up for 83 +/- 53 months (range, 1-230 months). RESULTS: Large cell change and high proliferative activity were found only in cirrhotic patients; 16 of 52 patients (31%) had either the large cell change or high proliferative activity. Large cell change was more frequent in patients with hepatitis B surface antigen than in those positive for hepatitis C virus (57% vs 14%, p = 0.04). Hepatocellular carcinoma developed in 7 of 16 (44%) and in 6 of 36 patients (16%) of the patients positive or negative for these morphological variables. The probability of developing hepatocellular carcinoma at 7 yr of follow-up was significantly higher in patients with large cell change or high proliferative activity than in those without. The length of follow-up from baseline histology to hepatocellular carcinoma occurrence was shorter in patients with large cell change or high proliferative activity than in those without these changes (46 +/- 36 and 109 +/- 34 months, p = 0.01). A multivariate analysis indicated that in patients with cirrhosis, large cell change or high proliferative activity (considered as a single variable), and age >55 yr were the only independent variables significantly associated with the risk of developing hepatocellular carcinoma, with a risk ratio of 4.8 (confidence interval 1.2-18.2) and 4.0 (confidence interval 1.1-15.6), respectively. CONCLUSIONS: In hereditary hemochromatosis, the presence of large cell change or high proliferative activity in patients older than 55 yr with cirrhosis should be considered a strong predictor of hepatocellular carcinoma development, especially if hepatitis B virus infection coexists.

Adult↗
PubMed2000

Iron and liver diseases.

A mild to moderate iron excess is found in patients with liver diseases apparently unrelated to genetic hemochromatosis. Iron appears to affect the natural history of hepatitis C virus-related chronic liver diseases, alcoholic liver disease and nonalcoholic steatohepatitis by leading to a more severe fibrosis and thus aiding the evolution to cirrhosis. A higher frequency of mutations of the HFE gene, the gene responsible for hereditary hemochromatosis, is found in patients with liver diseases and increased liver iron than in normal patients. Patients with excess iron are potentially at a higher risk of developing hepatocellular carcinoma. Iron depletion therapy could interfere with fibrosis development and possibly reduce the risk of liver cancer occurrence.

HLA Antigens↗
PubMed2000

Haemochromatosis in patients with beta-thalassaemia trait.

Severe iron overload has been reported in patients with the beta-thalassaemia trait. Studies performed before the discovery of the haemochromatosis gene (HFE) have yielded conflicting results: some suggest that iron overload might arise from the interaction of the beta-thalassaemia trait with heterozygosity for haemochromatosis, some with homozygosity for haemochromatosis and others that it was unrelated to haemochromatosis. We have studied the clinical phenotype, iron indices and HFE genotypes of 22 unrelated patients with the beta-thalassaemia trait and haemochromatosis, the inheritance of chromosome 6p and 1q haplotypes in families of non-homozygous C282Y probands and serum measures of iron status in relatives heterozygous for C282Y with or without the beta-thalassaemia trait. We demonstrate that the beta-thalassaemia trait aggravates the clinical picture of C282Y homozygotes, favouring higher rates of iron accumulation and the development of severe iron-related complications. We suggest that the coexistence of the beta-thalassaemia trait might also increase the risk of iron overload in patients with HFE genotypes at a mild risk of haemochromatosis. Our findings do not support the hypothesis that the association of the beta-thalassaemia trait with a single C282Y or H63D allele might lead to iron overload and suggest that other non-HFE-related inherited factors are present in haemochromatosis patients with incomplete HFE genotypes.

Adult↗
PubMed1999

Estrogen synthesis in human colon cancer epithelial cells.

Epidemiological and experimental data suggest an involvement of estrogen in the development and progression of colorectal cancer. In order to determine whether local synthesis of estrogen occurred in human colonic cancer cells, two colorectal cancer cell lines, HCT8 and HCT116, were evaluated for gene expression and enzyme activity of cytochrome P450 aromatase. In addition, the effect on aromatase expression of charcoal-stripped fetal calf serum, of quercetin and genistein and of tamoxifen and raloxifene was investigated in both cell lines. RT-PCR analysis revealed that colorectal adenocarcinoma cell lines contain aromatase as a major component. The conversion of [(3)H]-androstenedione to estrone and labeled water was dose-dependently inhibited by 4-hydroxyandrostenedione and obeyed Michaelis-Menten kinetic with apparent Km values of approximately 20 nM and V(max) values of approx. 200 and 500 fmol/mg protein/h for HCT8 and HCT116 cells, respectively. After 24 h incubation, genistein (1 microM) significantly increased aromatase activity in HCT8 cells, with no effect on HCT116 cells. In accord with previous observation in reproductive tissues, quercetin (1 microM) significantly inhibited the enzyme activity in both cell lines. Also tamoxifen (100 nM) acted as inhibitor, while raloxifene (10 nM) decreased the enzyme activity only in HCT116 cells. The aromatase gene expression modulation by these effective agents was consistent with their effects on enzyme activity. These findings demonstrate for the first time that colorectal adenocarcinoma cell lines express aromatase. Interestingly, the enzyme activity was inhibited by quercetin, one major dietary flavonoid, by tamoxifen, a hormonal therapeutic agent for breast cancer, and by raloxifene, used in the prevention of postmenopausal osteoporosis.

Androstenedione↗
PubMed1999

Functional estrogen receptor beta in colon cancer cells.

Evidence exists for expression of estrogen receptor beta (ERbeta) in human colonic mucosa. Here we investigated the expression of the classical ER (ERalpha) and of four isoforms of the human ERbeta in HCT116, HCT8, DLD-1, and LoVo colon adenocarcinoma cell lines. In addition, [(3)H]17beta-estradiol (17betaE(2)) binding to intact colon cancer cells was evaluated. RT-PCR and Western blot analyses showed lack of expression of the classical ERalpha in the four colon cancer cell lines. Conversely, wild-type ERbeta isoform 1 was highly expressed in HCT8, HCT116, DLD-1, and LoVo cells and isoforms ERbeta2-5 were present in HCT8 and HCT116 cells. Scatchard and Hill analysis of [(3)H]17betaE(2) binding to the four different colon cancer cells revealed the presence of two classes of binding sites, one with high affinity (K(d) values of 1-2 nM) and the other with lower affinity (K(d) values of 10-20 nM). Forty-eight hour-pretreatment of cells with 1 and 10 nM 17betaE(2) did not induce an increase of progesterone-specific binding to HCT8 cells, while a significant induction was observed after treatment with 10 nM 17betaE(2) in HCT116 and DLD-1 cells and with both concentrations in LoVo cells. In addition, 1 pM-0.1 nM 17betaE(2) significantly induced cell proliferation of HCT8 cells, while reducing growth of HCT116 and DLD1 cells at 10 nM-1 microM concentrations and of LoVo cells at all tested concentrations (1 pM-1 microM). These in vitro findings pose the basis for in vivo functions of ERbeta and ERbeta-interacting molecules in human colon cancer tissue.

Base Sequence↗
PubMed1999

17beta-estradiol induces apoptosis in the preosteoclastic FLG 29.1 cell line.

Although compelling data have demonstrated the effectiveness of estrogen replacement therapy for the treatment of accelerated bone loss in postmenopausal osteoporosis and ovariectomized animals, the mechanisms by which estrogens reduce bone resorption remain to be elucidated. To address this issue, in the present study we investigated whether estrogens were able to induce programmed cell death or apoptosis in osteoclast precursors. To this purpose, a preosteoclastic cell line (FLG 29.1) was cultured in the absence or presence of nanomolar concentrations of 17beta-estradiol (17betaE2). Using time-lapse videomicroscopy, it was shown that 17betaE2 induced FLG 29.1 cell apoptosis in a dose- and time-dependent manner. Furthermore, a significant increase in the activity of caspase 3 enzyme and in the number of nuclei undergoing DNA fragmentation was observed in FLG 29.1 cells treated with 17betaE2 compared to untreated cells. Finally, transmission electron microscopy of the treated cells showed typical apoptotic morphology. These data indicate that 17betaE2 is able to promote in vitro apoptosis in preosteoclastic cells and suggest that estrogenic molecules may exert in vivo a direct role in negatively modulating the pool of undifferentiated bone marrow cells capable ultimately of maturing into osteoclasts.

Apoptosis↗
PubMed1999

Carbohydrate-deficient transferrin, a sensitive marker of chronic alcohol abuse, is highly influenced by body iron.

Carbohydrate-deficient transferrin (CDT), a microheterogeneous form of serum transferrin (Tf), has been proposed as the most reliable marker of chronic alcohol consumption, although unexplained false-positive and -negative results have been reported. We investigated whether body iron influenced CDT serum levels by studying alcohol abusers with or without iron overload and nonabusers with iron deficiency or iron overload caused by genetic hemochromatosis (GH). In alcohol abusers, CDT was significantly lower in the presence of iron overload than in the absence (24.6 +/- 16.5 U/L vs. 33.3 +/- 11.7 U/L; P <.01), with false-negative results almost exclusively in patients with iron overload. Similarly, in nonabusers with GH, CDT was lower than in normal controls (9.6 +/- 2. 2 U/L vs. 15.7 +/- 3.3 U/L; P <.0001), whereas, patients with iron deficiency anemia had significantly higher levels than controls (28. 1 +/- 5.8 U/L vs. 15.7 +/- 3.3 U/L; P <.0001). In nonabusers, iron supplementation therapy significantly decreased CDT levels in patients with iron deficiency anemia (33.7 +/- 6.6 U/L vs. 21.7 +/- 5.2 U/L; P =.0007), while iron-depletion treatment significantly increased CDT levels in patients with GH (9.7 +/- 2.0 U/L vs. 14.7 +/- 4.0 U/L; P =.001). Alcohol abusers had a significant relationship between liver iron concentration (LIC) and the reciprocal of CDT (r =.65; P <.0001), while in nonabusers, there was a significant correlation between Tf and CDT (r =.72; P <.0001). In conclusion, CDT serum levels are markedly affected by the patient's iron status, with iron overload reducing its sensitivity in alcohol abusers and iron deficiency its specificity in nonabusers. CDT can be considered a reliable marker of alcohol abuse only when iron stores are normal.

Adult↗
PubMed1999

Metabolic indicators of oxidative stress correlate with haemichrome attachment to membrane, band 3 aggregation and erythrophagocytosis in beta-thalassaemia intermedia.

Haematological data, genotype, transfusion requirements, metabolic indicators of oxidative stress (flux via hexose-monophosphate shunt (HMPS); steady state level of GSH and GSSG, NADPH and NADP; activity of anti-oxidant enzymes), parameters of membrane damage (aggregated band 3; membrane-bound haemichromes, autologous immunoglobulins (Igs) and C3 complement fragments) and erythrophagocytosis were measured in erythrocytes (RBC) of 15 beta-thalassaemia intermedia patients (nine splenectomized) with low, if any, transfusion requirements. Patients presented increased aggregated band 3, bound haemichromes, Igs and C3 complement fragments, and increased erythrophagocytosis. Bound haemichromes strongly correlated with aggregated band 3. Anti-band 3 Igs were predominantly associated with aggregated band 3. Erythrophagocytosis positively correlated with aggregated band 3, haemichromes and Igs, suggesting the involvement of haemichrome-induced band 3 aggregation in phagocytic removal of beta-thalassaemic RBC. Splenectomized patients showed higher degrees of membrane damage and phagocytosis, significantly higher numbers of circulating RBC precursors, and tendentially higher numbers of reticulocytes. Basal flux via HMPS was increased twofold, but HMPS stimulation by methylene blue was decreased, as was the glucose flux via HMPS. GSH was remarkably decreased, whereas NADPH was increased. Except for unchanged catalase and glutathione reductase, anti-oxidant enzymes had increased activity. Negative correlation between HMPS stimulation by methylene blue and bound haemichromes indicated that the ability to enhance HMPS may counteract haemichrome precipitation and limit consequent membrane damage leading to erythrophagocytosis.

Adult↗
PubMed1999

Iron overload in porphyria cutanea tarda.

BACKGROUND AND OBJECTIVE: Porphyria cutanea tarda (PCT) is a disorder of porphyrin metabolism associated with decreased activity of uroporphyrinogen decarboxylase (URO-D) in the liver. The relevance of iron in the pathogenesis of PCT is well established: iron overload is one of the factors that trigger the clinical manifestations of the disease and iron depletion remains the cornerstone of therapy for PCT. A role for genetic hemochromatosis in the pathogenesis of iron overload in PCT has been hypothesized in the past but only after the recent identification of the genetic defect causing hemochromatosis has the nature of this association been partially elucidated. This review will outline current concepts of the pathophysiology of iron overload in PCT as well as recent contributions to the molecular epidemiology of hemochromatosis defects in PCT. EVIDENCE AND INFORMATION SOURCES: The authors of the present review have a long-standing interest in the pathogenesis, etiology and epidemiology of iron overload syndromes. Evidence from journal articles covered by the Science Citation Index(R) and Medline(R) has been reviewed and collated with personal data and experience. STATE OF THE ART AND PERPECTIVES: Mild to moderate iron overload plays a key role in the pathogenesis of PCT. The recent identification of genetic mutations of the hemochromatosis gene (HFE) in the majority of patients with PCT confirms previous hypotheses on the association between PCT and hemochromatosis, allows a step forward in the understanding of the pathophysiology of the disturbance of iron metabolism in the liver of PCT patients, and provides an easily detectable genetic marker which could have a useful clinical application. Besides the epidemiological relevance of the association between PCT and hemochromatosis, however, it remains to be fully understood how iron overload, and in particular the cellular modifications of the iron status secondary to hemochromatosis mutations, affect the activity of URO-D, and how the altered iron metabolism interacts with the other two common triggers for PCT and etiological agents for the associated liver disease: alcohol and hepatitis viruses. The availability of a genetic marker for hemochromatosis will allow some of these issues to be addressed by studying aspects of porphyrins and iron metabolism in liver samples obtained from patients with PCT, liver disease of different etiology and different HFE genotypes, and by in vitro studies on genotyped cells and tissues.

DNA Mutational Analysis↗