Severe iron overload usually develops in patients with hereditary hemochromatosis (HHC), but variability in the phenotypic expression of the disease has been reported. This study assessed whether tumor necrosis factor ␣ (TNF-␣) plays a role in phenotypic expression of HHC. Sixty-four patients with HHC and 172 healthy volunteers (controls) were studied. Release of TNF-␣ from stimulated peripheral blood monocytes was measured by enzyme-linked immunosorbent assay, and 308 and 238 TNF-␣ polymorphisms were detected with polymerase chain reaction and restriction fragmentlength polymorphism analysis. The relation between TNF-␣ polymorphisms and clinical expression of HHC was evaluated. Patients with HHC released less TNF-␣ than controls, but the difference was significant only in homozygotes for the C282Y mutation. The prevalence of the 308 TNF-␣ polymorphism was similar in patients and controls, whereas the prevalence of the 238 polymorphic allele was significantly lower in patients (3% versus 16%; P ‫؍‬ .002). A lower prevalence of cirrhosis was observed in patients with TNF-␣ polymorphism than in those without it (4 of 15 [27%] versus 28 of 49 [57%]), but the difference was not significant (P ‫؍‬ .07). In nonhomozygotes for the C282Y mutation, severe liver siderosis was less prevalent in patients with the 308 polymorphism than in those without it (P ‫؍‬ .05). Alanine aminotransferase (ALT) values were significantly lower in patients with TNF-␣ polymorphism (P ‫؍‬ .006), even when patients with other hepatotoxic factors were excluded. Multivariate analysis showed that TNF-␣ polymorphism was independently associated with ALT values (P ‫؍‬ .0008 and P ‫؍‬ .045, respectively, in homozygotes and nonhomozygotes for the C282Y mutation) and siderosis in nonhomozygotes (P ‫؍‬ .047). Thus, TNF-␣ appears to play a role in HHC by modulating the severity of liver damage. (Blood. 2001;97:3707-3712)

Summary. 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 a (TNF-a) by interferon g (IFN-g) 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 PMAdifferentiating cells induced the expression of TNF-a mRNA and TNF-a secretion to levels even higher than those induced by IFN-g alone. The iron chelator desferrioxamine showed the opposite effect and reduced TNF-a release. In contrast, preincubation of the cells with iron before PMA induction resulted in a decrease of the TNF-a secretion induced by IFN-g, whereas the opposite was true after preincubation with desferrioxamine. The data support a coordinate interaction between iron and TNF-a in monocyte macrophages, with an iron-mediated upregulation of TNF-a 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.

This study measures territorial competitiveness at the municipal level in Italy, by proposing a robust composite indicator based on variables not yet used in the literature. The underlying theoretical framework is identified based on the literature on regional competitiveness. The proposed indicator consists of the following seven dimensions of competitiveness: Education, Job, Economic Wellbeing, Territory and Environment, Entrepreneurship, Innovation, and Infrastructures and Mobility. Data are retrieved mainly from administrative sources, for 2014 and 2015. In the building process, three aggregation methods are compared: a compensatory method, the arithmetic mean, and two partially compensatory methods, the geometric mean and the Adjusted Mazziotta-Pareto Index (AMPI). The arithmetic mean turns out to be the most robust method among the three considered, but the AMPI is the most robust method among the two partially compensatory methods. All the methods considered agree in identifying Innovation and Entrepreneurship as the most influential pillars in 2014 and 2015, respectively. The detailed geographical focus provides specific insights into territorial competitiveness in Italy. It emerges a rather heterogeneous picture of municipal competitiveness within the Italian regions. Highly competitive municipalities are present in every region, though with different concentration levels.