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Co-existence of multiple causes of liver injury increases the risk of hepatocellular carcinoma (HCC) development. HCC usually develops in patients with cirrhosis although it may also occur in individuals with no or mild liver disease, in particular in cases with hepatitis B virus (HBV) infection.Here we report the case of a 43year-old man with HFE-haemochromatosis, seronegative for hepatitis B and C infections, who developed HCC in the absence of severe liver damage. Both tumoural and non-tumoural liver DNA extracts were tested by nested-PCR and primers specific for four different HBV genomic regions in order to evaluate the presence of occult HBV infection. Only X gene sequences were detected in tumour (but not in non-tumour) DNA extracts. HBV-Alu PCR showed a HBV integration involving a 5′-deleted X gene with an intact enhancer-II/basal-core promoter region. The viral-host junction sequencing revealed that this integrant was located upstream of the partitioning-defective-6-homolog-gamma gene (PARD6G) and real time-PCR quantification demonstrated that PARD6G was overexpressed in tumour compared to non-tumour liver tissues.In conclusion, the combination of HFE-haemochromatosis and occult HBV infection in this patient might have led to a sequel of cellular events that determined the development of HCC even in the absence of cirrhosis.

In this chapter, the authors review current literature on personal information management to analyze how it is understood with the aim of reviewing the way in which individuals try to manage their personal information and whether libraries observe the information behavior of their community members to learn which is the best way to offer their services. At the end of this process, they show that a role for library professionals could be devised in being information management mediators for their community members in the digital world, helping them make sense out of chaos. This role is clearly linked to the development of information literacy programs in libraries.

Numerous clinical entities have now been identified to cause pathologic iron accumulation in the liver. Some are well described and have a verified hereditary basis; in others the genetic basis is still speculative, while in several cases nongenetic iron-loading factors are apparent. The non- HFE hemochromatosis syndromes identifies a subgroup of hereditary iron loading disorders that share with classic HFE-hemochromatosis, the autosomal recessive trait, the pathogenic basis (i.e., lack of hepcidin synthesis or activity), and key clinical features. Yet, they are caused by pathogenic mutations in other genes, such as transferrin receptor 2 ( TFR2), hepcidin ( HAMP), hemojuvelin ( HJV) , and ferroportin ( FPN), and, unlike HFE-hemochromatosis, are not restricted to Caucasians. Ferroportin disease, the most common non- HFE hereditary iron-loading disorder, is caused by a loss of iron export function of FPN resulting in early and preferential iron accumulation in Kupffer cells and macrophages with high ferritin levels and low-to-normal transferrin saturation. This autosomal dominant disorder has milder expressivity than hemochromatosis. Other much rarer genetic disorders are associated with hepatic iron load, but the clinical picture is usually dominated by symptoms and signs due to failure of other organs (e.g., anemia in atransferrinemia or neurologic defects in aceruloplasminemia). Finally, in the context of various necro-inflammatory or disease processes (i.e., chronic viral or metabolic liver diseases), regional or local iron accumulation may occur that aggravates the clinical course of the underlying disease or limits efficacy of therapy.

Background & Aims HFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression. In murine Hfe and Tfr2 knockout models of hereditary hemochromatosis (HH), signal transduction to hepcidin via the bone morphogenetic protein 6 (Bmp6)/Smad1,5,8 pathway is attenuated. We examined the effect of dietary iron on regulation of hepcidin expression via the Bmp6/Smad1,5,8 pathway using mice with targeted disruption of Tfr2 , Hfe , or both genes. Methods Hepatic iron concentrations and messenger RNA expression of Bmp6 and hepcidin were compared with wild-type mice in each of the HH models on standard or iron-loading diets. Liver phospho-Smad (P-Smad)1,5,8 and Id1 messenger RNA levels were measured as markers of Bmp/Smad signaling. Results Whereas Bmp6 expression was increased, liver hepcidin and Id1 expression were decreased in each of the HH models compared with wild-type mice. Each of the HH models also showed attenuated P-Smad1,5,8 levels relative to liver iron status. Mice with combined Hfe/Tfr2 disruption were most affected. Dietary iron loading increased hepcidin and Id1 expression in each of the HH models. Compared with wild-type mice, HH mice demonstrated attenuated ( Hfe knockout) or no increases in P-Smad1,5,8 levels in response to dietary iron loading. Conclusions These observations show that Tfr2 and Hfe are each required for normal signaling of iron status to hepcidin via the Bmp6/Smad1,5,8 pathway. Mice with combined loss of Hfe and Tfr2 up-regulate hepcidin in response to dietary iron loading without increases in liver Bmp6 messenger RNA or steady-state P-Smad1,5,8 levels.

The liver hormone hepcidin is a main regulator of systemic iron homeostasis (reviewed in 1). Hepcidin binds and induces degradation of ferroportin, an iron exporter expressed on the surface of duodenal enterocytes, reticuloendothelial macrophages, and hepatocytes2. Hepcidin-mediated ferroportin degradation limits iron release from these cells to the bloodstream, thereby reducing iron absorption from the diet and iron mobilization from body stores. Hepcidin deficiency and unregulated ferroportin activity are the common pathogenic mechanism for the iron overload disorder hereditary hemochromatosis due to mutations in the genes encoding hepcidin itself (HAMP), hemojuvelin (HFE2), the hemochromatosis protein HFE, and transferrin receptor 2 (TFR2), while hepcidin excess contributes to the anemia of chronic disease (reviewed in 1). A number of stimuli modulate hepcidin expression to influence systemic iron balance. Erythropoietic demand and hypoxia downregulate hepcidin transcription to increase iron availability, while iron, inflammatory cytokines, and endoplasmic reticulum stress upregulate hepcidin transcription to decrease iron availability.1,3–7 The specific signaling pathways mediating hepcidin transcription in response to these stimuli are increasingly being elucidated. Inflammatory cytokines stimulate hepcidin transcription via the signal transducer and activator of transcription 3 (STAT3) signaling pathway, while iron stimulates hepcidin transcription via the BMP-SMAD signaling pathway (reviewed in 1). BMPs belong to the Transforming Growth Factor-beta (TGF-β) superfamily of ligands and are involved in a myriad of cellular and systemic functions during embryonic and adult life (reviewed in 8). BMPs form a signaling complex with type I and type II serine threonine kinase receptors, leading to phosphorylation of intracellular SMAD1, SMAD5, and SMAD8 proteins. These P-SMAD1/5/8 proteins form a complex with SMAD4 and translocate to the nucleus to modulate transcription of target genes such as ID1 and SMAD7.9–10 Hepcidin is also a target transcript directly upregulated by the BMP signaling pathway (reviewed in 1). The central importance of the BMP-SMAD signaling pathway in hepcidin regulation and iron metabolism in vivo is demonstrated by the fact that mutations in the genes encoding the BMP co-receptor hemojuvelin11–12, the intracellular signaling molecule SMAD413 and the ligand BMP69,14 each result in decreased hepcidin expression and iron overload. Furthermore, pharmacologic modulators of the BMP-SMAD signaling pathway regulate hepcidin expression and systemic iron balance in mice.9,15–16 Notably, the molecular mechanisms by which iron is sensed to induce the BMP-SMAD pathway are not fully understood. Both circulating and tissue iron have been suggested to regulate hepcidin expression. Whether they exert independent effects through the BMP-SMAD pathway and/or involve additional pathways is unclear. For example, although liver iron content (LIC) is correlated with hepatic Bmp6 mRNA levels in mice17–19, suggesting that tissue iron levels regulate BMP-SMAD pathway activity by regulating ligand expression, it is unknown whether circulating iron levels also regulate hepatic BMP6 mRNA, or whether circulating iron sensitizes hepatocytes to increase SMAD1/5/8 phosphorylation in response to tonic BMP6 levels. Additionally, although recent studies suggest that HFE and possibly TFR2 may regulate hepcidin expression through an interaction with the BMP6-SMAD signaling pathway18,20–24, several studies provide indirect evidence suggesting that hepatic MAPK signaling, more specifically the ERK1/2 kinases, may also be involved in hepcidin regulation by iron mediated by TFR2 and/or HFE.21, 25–27 Notably, cross-talk between the canonical SMAD signaling pathway and the MAPK pathway is well-described (reviewed in 28). However the physiologic relevance of the ERK/MAPK signaling pathway in iron homeostasis in vivo is still unknown. Recent studies suggest a role for inhibitory SMAD7 in hepcidin regulation and iron homeostasis10,17,23–24. Inhibitory SMADs function as feedback inhibitors of the BMP/TGF-β pathway by interacting with type I receptors to block their phosphorylation or to promote receptor dephosphorylation or degradation.8 Hepatic Smad7 mRNA is induced by chronic dietary iron loading in mice concordantly with hepcidin and Id1 mRNA17, and SMAD7 was recently shown to be a specific inhibitor of hepcidin transcription in vitro.10 Alterations in hepatic SMAD7 mRNA expression have also been found in hemochromatosis patients23–24. However, the physiologic significance and timing of SMAD7 activation upon iron administration in vivo need further evaluation. Here, we investigated the molecular mechanisms by which iron is sensed to regulate BMP6-SMAD signaling and hepcidin expression. We performed a detailed time course of both acute and chronic enteral iron administration in mice to obtain different conditions of body iron perturbation including isolated increases of either transferrin saturation (Tf sat) or LIC. Then, we dissected the BMP6-SMAD signaling pathway from the induction of tissue specific Bmp6 ligand mRNA expression, to the activation of intracellular signal mediators including P-Smad1/5/8 and Erk1/2 proteins, to the modulation of target transcript expression including hepcidin (Hamp, also known as Hamp1), Id1, and Smad7. Our aim was to determine how tissue and circulating iron stimulate the Bmp6-Smad signaling pathway to regulate hepcidin expression, and whether the Erk1/2 pathway is stimulated by iron.

Mutations in transmembrane protease, serine 6 (TMPRSS6), encoding matriptase-2, are responsible for the familial anemia disorder iron-refractory iron deficiency anemia (IRIDA). Patients with IRIDA have inappropriately elevated levels of the iron regulatory hormone hepcidin, suggesting that TMPRSS6 is involved in negatively regulating hepcidin expression. Hepcidin is positively regulated by iron via the bone morphogenetic protein (BMP)-SMAD signaling pathway. In this study, we investigated whether BMP6 and iron also regulate TMPRSS6 expression. Here we demonstrate that, in vitro, treatment with BMP6 stimulates TMPRSS6 expression at the mRNA and protein levels and leads to an increase in matriptase-2 activity. Moreover, we identify that inhibitor of DNA binding 1 is the key element of the BMP-SMAD pathway to regulate TMPRSS6 expression in response to BMP6 treatment. Finally, we show that, in mice, Tmprss6 mRNA expression is stimulated by chronic iron treatment or BMP6 injection and is blocked by injection of neutralizing antibody against BMP6. Our results indicate that BMP6 and iron not only induce hepcidin expression but also induce TMPRSS6, a negative regulator of hepcidin expression. Modulation of TMPRSS6 expression could serve as a negative feedback inhibitor to avoid excessive hepcidin increases by iron to help maintain tight homeostatic balance of systemic iron levels.

Background & Aims Abnormal hepcidin regulation is central to the pathogenesis of HFE hemochromatosis. Hepatic bone morphogenetic protein 6 (BMP6)–SMAD signaling is a main regulatory mechanism controlling hepcidin expression, and this pathway was recently shown to be impaired in Hfe knockout ( Hfe −/− ) mice. To more definitively determine whether HFE regulates hepcidin expression through an interaction with the BMP6-SMAD signaling pathway, we investigated whether hepatic Hfe overexpression activates the BMP6-SMAD pathway to induce hepcidin expression. We then investigated whether excess exogenous BMP6 administration overcomes the BMP6-SMAD signaling impairment and ameliorates hemochromatosis in Hfe −/− mice. Methods The BMP6-SMAD pathway and the effects of neutralizing BMP6 antibody were examined in Hfe transgenic mice ( Hfe Tg ) compared with wild-type (WT) mice. Hfe −/− and WT mice were treated with exogenous BMP6 and analyzed for hepcidin expression and iron parameters. Results Hfe Tg mice exhibited hepcidin excess and iron deficiency anemia. Hfe Tg mice also exhibited increased hepatic BMP6-SMAD target gene expression compared with WT mice, whereas anti-BMP6 antibody administration to Hfe Tg mice improved the hepcidin excess and iron deficiency. In Hfe −/− mice, supraphysiologic doses of exogenous BMP6 improved hepcidin deficiency, reduced serum iron, and redistributed tissue iron to appropriate storage sites. Conclusions HFE interacts with the BMP6-SMAD signaling pathway to regulate hepcidin expression, but HFE is not necessary for hepcidin induction by BMP6. Exogenous BMP6 treatment in mice compensates for the molecular defect underlying Hfe hemochromatosis, and BMP6-like agonists may have a role as an alternative therapeutic strategy for this disease.

Background & Aims Hemochromatosis is a common hereditary disease caused by mutations in HFE and characterized by increased absorption of iron in the intestine. However, the intestine does not appear to be the site of mutant HFE activity in the disease; we investigated the role of the liver—the source of the iron regulatory hormone hepcidin—in pathogenesis in mice. Methods We exchanged livers between Hfe wild-type ( +/+ ) and Hfe null ( − / − ) mice by orthotopic liver transplantation (OLT) and assessed histopathology, serum and tissue iron parameters, and hepatic hepcidin messenger RNA expression. Results At 6–8 months after OLT, Hfe −/− mice that received Hfe −/− livers maintained the hemochromatosis phenotype: iron accumulation in hepatocytes but not Kupffer cells (KC), increased transferrin levels, and low levels of iron in the spleen. Hfe +/+ mice that received Hfe −/− livers had increased levels of iron in serum and liver and low levels of iron in spleen. However, they did not develop the iron-poor KCs that characterize hemochromatosis: KCs appeared iron rich, although hepatic hepcidin expression was low. Transplantation of Hfe +/+ livers into Hfe −/− mice prevented hepatic iron accumulation but did not return spleen and plasma levels of iron to normal; KCs still appeared to be iron poor, despite normal hepcidin expression. Conclusions In Hfe −/− mice, transplantation of livers from Hfe +/+ mice reversed the iron-loading phenotype associated with hemochromatosis (regardless of Hfe expression in intestine) . However, KCs still had low levels of iron that were not affected by hepatic hepcidin expression. These findings indicate an independent, iron-modifying effect of HFE in KCs.

The BMP signaling pathway controls a number of cell processes during development and in adult tissues. At the cellular level, ligands of the BMP family act by binding a hetero-tetrameric signaling complex, composed of two type I and two type II receptors. BMP ligands make use of a limited number of receptors, which in turn activate a common signal transduction cascade at the intracellular level. A complex regulatory network is required in order to activate the signaling cascade at proper times and locations, and to generate specific downstream effects in the appropriate cellular context. One such regulatory mechanism is the repulsive guidance molecule (RGM) family of BMP co-receptors. This article reviews the current knowledge regarding the structure, regulation, and function of RGMs, focusing on known and potential roles of RGMs in physiology and pathophysiology.

OBJECTIVES: Antiviral treatment in chronic hepatitis C (CHC) involves ribavirin, a hemolytic agent. We planned a prospective study to evaluate whether drug-induced iron perturbation is clinically relevant as it relates to therapeutic outcome. METHODS: Iron variables were sequentially assessed in 206 CHC patients undergoing antiviral therapy and were correlated with pretreatment iron status and histology, hemolysis, and therapeutic outcome. RESULTS: At week 1 of therapy, serum iron (SI), transferrin saturation (TS), and serum ferritin (SF) increased markedly in all patients. All iron parameters correlated with hemolysis up to week 4; this correlation was lost for SF at later time points. SF rise during treatment was inversely related to baseline SF and iron deposits in hepatic mesenchymal/Kupffer cells. Both baseline SF and mesenchymal iron significantly correlated with fibrosis at multivariate analysis (P=0.015 and 0.008, respectively). Interestingly, baseline SF, despite good specificity (89%), had low sensitivity in predicting siderosis (25%). During therapy, SI, TS, and hemolysis parameters did not correlate with sustained virological response (SVR), whereas SF rise became an independent predictor of therapeutic response: a 2.5-fold increase of SF at week 12 associated with higher likelihood of SVR (odds ratio 1.91, P=0.032). Accordingly, lack of mesenchymal iron deposits at the baseline biopsy correlated with SVR (odds ratio 3.02, P=0.043). CONCLUSIONS: In CHC, SF is a useful marker for assessing disease duration and progression before starting treatment and for predicting therapeutic response while on therapy. SF rise during antiviral therapy is largely independent of hemolysis and likely indicates activation of macrophages in response to antivirals.

Background and Aims Mutations in HFE are the most common cause of the iron-overload disorder hereditary hemochromatosis. Levels of the main iron regulatory hormone, hepcidin, are inappropriately low in hereditary hemochromatosis mouse models and patients with HFE mutations, indicating that HFE regulates hepcidin. The bone morphogenetic protein 6 (BMP6)–SMAD signaling pathway is an important endogenous regulator of hepcidin expression. We investigated whether HFE is involved in BMP6–SMAD regulation of hepcidin expression. Methods The BMP6–SMAD pathway was examined in Hfe knockout (KO) mice and in wild-type (WT) mice as controls. Mice were placed on diets of varying iron content. Hepcidin induction by BMP6 was examined in primary hepatocytes from Hfe KO mice; data were compared with those of WT mice. Results Liver levels of Bmp6 messenger RNA (mRNA) were higher in Hfe KO mice; these were appropriate for the increased hepatic levels of iron in these mice, compared with WT mice. However, levels of hepatic phosphorylated Smad 1/5/8 protein (an intracellular mediator of Bmp6 signaling) and Id1 mRNA (a target gene of Bmp6) were inappropriately low for the body iron burden and Bmp6 mRNA levels in Hfe KO, compared with WT mice. BMP6 induction of hepcidin expression was reduced in Hfe KO hepatocytes compared with WT hepatocytes. Conclusions HFE is not involved in regulation of BMP6 by iron, but does regulate the downstream signals of BMP6 that are triggered by iron.

This chapter discusses a project for the implementation of a digital repository in a specific context, namely a small Italian town. The latest developments of Web 2.0, as well as recent concepts of the libraries as places where ‘conversations’ are fostered, can enable new ways of managing library collections, by allowing every member of the community to collaborate in the process of selecting and acquiring sources of information. The author hopes to provide evidence that such a project can represent a valid approach to enhance co-operation among people with different backgrounds who share the common aim to build a community repository that can represent all of them.

Cet article cherche a presenter l'histoire du developpement du systeme bibliothecaire au Trentino depuis les debuts jusqu'a l'etat actuel. Les bases mises en 1981 parle legislateur en vue de la creation d'un catalogue de reseau semble aujourd'hui menacees par des restrictions financieres. On espere que la cooperation durant de longues anneees des collegues puisse accompagner le systeme bibliothecaire âge de 25 ans vers des buts optimistes.

Background & Aims: Hepcidin is a peptide hormone that is central to the regulation of iron homeostasis. In response to interleukin 6 (IL-6), hepatocytes produce hepcidin that decreases iron release/transfer from enterocytes and macrophages and causes hypoferremia. To clarify the molecular pathways involved in hepcidin activation by IL-6, we used different mice strains in which the main IL-6/gp130 signaling pathways have been genetically disrupted. Methods: We generated mice with hepatocyte-specific deletion of the IL-6 signal-transducing gp130 receptor (alfpgp130 LoxP/LoxP), with a gp130 receptor lacking the essential region for STAT1 and -3 activation (alfpCre gp130ΔSTAT/LoxP) or mice expressing a gp130 allele lacking the essential tyrosine for RAS-MAPK activation (alfpCregp130Y757F/LoxP). We studied gp130-dependent pathways and hepcidin mRNA expression by Western blot, reverse-transcription polymerase chain reaction, and Northern blot in vivo and ex vivo. Results: IL-6 stimulated phospho STAT3, serum amyloid A (SAA), and suppressor of cytokine signaling 3 (SOCS3) expression in livers of wild-type and alfpCregp130Y757F/LoxP mice, whereas this response was blocked in alfpCre gp130LoxP/LoxP and alfpCre gp130ΔSTAT/LoxP mice. In wild-type and alfpCregp130Y757F/LoxP animals, significantly higher hepcidin mRNA expression was found 3 to 6 hours after IL-6 stimulation. In contrast, no IL-6-dependent regulation of hepcidin mRNA expression was found in alfpgp130 ΔSTAT/LoxP and AlfpCre gp130 LoxP/LoxP animals. In primary hepatocytes, higher hepcidin mRNA expression after IL-6 stimulation was only observed when gp130-STAT3-dependent signaling was intact. Conclusions: We have demonstrated that both in vivo and in vitro STAT3 is the key transcription factor responsible for IL-6 activation of hepcidin gene expression in the liver.

Ferroportin-associated iron overload (also known as the ferroportin disease) was clinically recognised in 1999,1 and linked in 2001 to the A77D mutation of ferroportin (FPN).2 Owing to the mild clinical expressivity reported in the literature, doubts have been raised on the penetrance of the genetic defect and the rationale for iron-removal therapy.3 However, so far, no prospective data have been collected pertaining to this disorder. We have had the opportunity to study six members of a pedigree carrying the A77D mutation of FPN for 11–24 years in whom the disease was first described.1,2 The proband (subject V13, table 1) was diagnosed at the age 59 years. After being on weekly phlebotomy for 2 years, he was on a maintenance programme for 18 years (one phlebotomy every 3 months). At the age of 79 years, he refused to continue on phlebotomy. In 2006, at the …

Background & Aims: Juvenile hemochromatosis is a severe form of hereditary iron overload that has thus far been linked to pathogenic mutations of the gene coding for hemojuvelin (HJV), on chromosome 1, or, more rarely, that coding for hepcidin ( HAMP ), on chromosome 19. A milder adult-onset form is due to pathogenic mutations of HFE or, rarely, serum transferrin receptor 2. Methods: We studied a pedigree with siblings affected by both juvenile and adult-onset hereditary hemochromatosis. Affected subjects underwent full clinical evaluation, as well as microsatellite and gene sequencing analysis. Results: Two siblings (male and female, aged 24 and 25 years, respectively) were hospitalized for severe endocrinopathy and cardiomyopathy. At age 18 and 17 years, they had presented with impotence and amenorrhea, respectively, and increased serum iron levels. Hypogonadotropic hypogonadism was confirmed in both, and liver biopsy showed marked hepatic iron accumulation and micronodular cirrhosis. Iron levels were normalized after 24 months (female) and 36 months (male) of weekly phlebotomies. Microsatellite analysis showed no linkage with chromosome 1 and 19, and gene sequencing showed no hemojuvelin or hepcidin gene mutations. Instead, combined mutations of HFE (C282Y/H63D compound heterozygosity) and serum transferrin receptor 2 (Q317X homozygosity) were found. A 21-year-old brother with a milder phenotype resembling classic adult-onset hereditary hemochromatosis carried only the Q317X serum transferrin receptor 2 homozygote mutation. Conclusions: Juvenile hereditary hemochromatosis is not a distinct monogenic disorder invariably due to hemojuvelin or hepcidin mutations: it may be genetically linked to the adult-onset form of hereditary hemochromatosis.

Ferroportin-associated iron overload (also known as the ferroportin disease) is a common cause of hereditary hyperferritinemia. It was originally proposed that loss-of-protein function mutations account for iron overload in the FD. This hypothesis is consistent with the phenotype reported in most patients with FD of early iron accumulation in tissues, particularly in macrophages, in spite of relatively normal-low circulatory iron. It was still unclear, however, how FPN mutations would affect iron retention in enterocytes. We studied histologically the intestine of six patients with different FPN mutations as compared to other subjects with various iron disorders. We found that regardless of the underlying FPN mutation, no iron accumulation was found in absorbing enterocytes while, intestinal villi showed marked signs of iron accumulation in the cells of lamina propria. Not surprisingly, in the liver, iron excess was found mainly in Kupffer cells. These results indicate that FPN haploinsufficiency is not limiting for iron export from enterocytes.

The product of the SLC40A1 gene, ferroportin 1, is a main iron export protein. Pathogenic mutations in ferroportin 1 lead to an autosomal dominant hereditary iron overload syndrome characterized by high serum ferritin concentration, normal transferrin saturation, iron accumulation predominantly in macrophages, and marginal anemia. Iron overload occurs in both the African and the African-American populations, but a possible genetic basis has not been established. We analyzed the ferroportin 1 gene in 19 unrelated patients from southern Africa (N = 15) and the United States (N = 4) presenting with primary iron overload. We found a new c. 744 C-->T (Q248H) mutation in the SLC40A1 gene in 4 of these patients (3 Africans and 1 African-American). Among 22 first degree family members, 10 of whom were Q248H heterozygotes, the mutation was associated with a trend to higher serum ferritin to amino aspartate transferase ratios (means of 14.8 versus 4.3 microg/U; P = 0.1) and lower hemoglobin concentrations (means of 11.8 versus 13.2 g/dL; P = 0.1). The ratio corrects serum ferritin concentration for alcohol-induced hepatocellular damage. We also found heterozygosity for the Q248H mutation in 7 of 51 (14%) southern African community control participants selected because they had a serum ferritin concentration below 400 microg/L and in 5 of 100 (5%) anonymous African-Americans, but we did not find the change in 300 Caucasians with normal iron status and 25 Caucasians with non-HFE iron overload. The hemoglobin concentration was significantly lower in the African community controls with the Q248H mutation than in those without it. We conclude that the Q248H mutation is a common polymorphism in the ferroportin 1 gene in African populations that may be associated with mild anemia and a tendency to iron loading.

Summary The Estense Collection of bronzes was gathered in the XV century in Ferrara by the Estense Dukes who were interested in antiquities. This interest was also diffused in the greater Italian and European courts during the Age of Humanism and the Renaissance. During the XVII–XVIII centuries, the collection was housed in the “Galleria dei disegni e delle medaglie” in the Ducal Palace, but it was transferred to Modena when this town became the new capital. The most important acquisition to the collection was the Obizzi Collection, which arrived at Modena thanks to Massimiliano, after the Restoration in 1822. The Estense Collection is very interesting because it shows different types of bronzes from the Bronze Age to the inclusive Roman Age. Our research had the purpose of analysing the alloys of some Etruscan, Italic and Roman bronze statuettes from this collection. The analyses we present in this paper prove that some statuettes are not ancient. We examined the structure of some bronzes under the metallographic microscope and selected a more suitable technique of conservation. Finally, all our analyses were collected in a computer for data processing.

Summary The Museo Lapidario Estense, the first public museum in Modena, was founded by Francesco IV d'Este in 1828. The museum was placed under the arcades in the courtyard of the Albergo del le Arti, now the Palazzo dei Musei. The Roman monuments and remains were first placed in the west side of the courtyard, while the other monuments, of the Middle Age to the 19thcentury where placed at the east side. In 1900 the collection was enlarged to also occupy the north side, the greater part of the monuments come from the ancient Mutina territory, some from Brixellum (now Brescello, Reggio Emilia), and a few from Rome. The principal purpose of this research was to analyze the causes of damage in these monuments in order to select a more suitable technique of conservation. The causes of damage are innumerable: intrinsic causes which derive from the nature of the material employed and extrinsic causes linked to environment. Biological factors of damage where fundamental to the majority of stone in the past: the acidification of the environment is one of the main causes of damage today. The results of the analyses carried out the stones of some monuments are given here.

Anemia of inflammation (AI) is the disturbance of iron homeostasis manifest by a decrease in absorption of dietary iron from the gastrointestinal tract and by iron sequestration by reticuloendothelial macrophages. It is widely recognized that elevated levels of proinflammatory cytokines and other mediators from activated immune cells are the primary causes of AI. More specifically, it is the abnormally decreased rate of iron efflux from macrophages and enterocytes that appear to be the crucial pathophysiology. Increasingly, the central role of the liver-derived factor hepcidin is recognized in mediating the disturbances of iron absorption, sequestration and utilization that characterize AI. Hepcidin decreases iron absorption from the duodenal enterocytes and promotes the sequestration of iron in the reticuloendothelial macrophages by down regulating the transmembrane iron export protein, ferroportin. Thus the regulation of hepatic hepcidin expression becomes of paramount interest in the study of AI. We have shown that bone morphogenetic protein is critical for the regulation of hepcidin expression. The aim of our study is to develop a model to study iron efflux both in vitro and in vivo using magnetic resonance imaging (MRI). This was done by experimentally measuring spin-spin relaxation times (T2 measured in sec-1) through multi-echo, spin-echo technique (16 echoes) on a 4.7 T Bruker pharmacan experimental MRI imager. Iron loaded cells exhibit lower T2 values than normal control cells. In vitro, hepatomas Hep3B and macrophages J774 and Raw 264.7 were loaded with magnetic iron oxide nanoparticles (MION) overnight. The next morning (baseline), the intracellular and extracellular iron content was serially measured for up to 24 hours using MRI. As expected, both J774 and Raw 264.7 cells lines displayed lower intracellular T2 values in comparison to baselines. In addition, both ferroportin and the iron storage protein ferritin were modulated following overnight MION treatment and 24 hours post baseline. In contrast, Hep3B cells did not take up any significant MION following overnight treatment. In vivo, normal mice on a normal diet were given an intravenous MION injection dosed at 10mg/kg iron. MRI was performed at baseline, 24, 48, 72 and 96 hrs post injection. 24 hours post injection, T2 increased in both liver and spleen (liver > spleen). Following the 24 hour spike, the T2 values in the mice decreased for up to 72 hours after injection with a rate in the liver mildly increased relative to the rate of decrease in the spleen.

Iron is an important bio-catalyst of oxidation-reduction reactions in the cell and is essential for life. Paradoxically, it may also be lethal when the fraction of redox-active metal ions exceeds that sequestered in specialized proteins or cellular compartments, and uncontrolled production of free radical species may arise. The liver is the main body site for iron stores and central in the regulation of iron homeostasis. Important iron-proteins, such as hepcidin, the iron regulatory hormone, are specifically produced by the liver. Pathogenic mutations in hepatic iron transporters and regulators lead to hereditary iron overload diseases, including hemochromatosis. Iron toxicity depends on its excessive accumulation and is due to promotion of oxidant stress: free radicals and membrane oxidation by-products cause hepatocellular death by triggering organelle dysfunction, or by activating cells involved in hepatic inflammation and fibrogenesis, such as Kupffer cells and hepatic stellate cells. Xenobiotics and hepatotoxins as well as immunological and host defense mechanisms may cause subtle changes in the pool of redox-active metal ions and in metal compartmentalization that potentially contribute to hepatotoxic, inflammatory and fibrogenic events. The hepatotoxic and profibrogenic potential of metal ions, particularly iron, is dramatic at moderate levels of tissue metal overload in concomitance with other inciting insults, such as alcohol abuse and viral hepatitis. Removal of metal excess from the liver in iron overload diseases is beneficial and prevents progression toward cirrhosis. The development of drugs able to block catalytically active metals, particularly iron, may prove effective in other chronic liver diseases in which inflammatory, degenerative and fibrogenic processes are fueled by redox-active metal ions.

Background & Aims Hepatic gluconeogenesis provides fuel during starvation, and is abnormally induced in obese individuals or those with diabetes. Common metabolic disorders associated with active gluconeogenesis and insulin resistance (obesity, metabolic syndrome, diabetes, and nonalcoholic fatty liver disease) have been associated with alterations in iron homeostasis that disrupt insulin sensitivity and promote disease progression. We investigated whether gluconeogenic signals directly control Hepcidin, an important regulator of iron homeostasis, in starving mice (a model of persistently activated gluconeogenesis and insulin resistance). Methods We investigated hepatic regulation of Hepcidin expression in C57BL/6Crl, 129S2/SvPas, BALB/c, and Creb3l3 –/– null mice. Mice were fed a standard, iron-balanced chow diet or an iron-deficient diet for 9 days before death, or for 7 days before a 24- to 48-hour starvation period; liver and spleen tissues then were collected and analyzed by quantitative reverse-transcription polymerase chain reaction and immunoblot analyses. Serum levels of iron, hemoglobin, Hepcidin, and glucose also were measured. We analyzed human hepatoma (HepG2) cells and mouse primary hepatocytes to study transcriptional control of Hamp (the gene that encodes Hepcidin) in response to gluconeogenic stimuli using small interfering RNA, luciferase promoter, and chromatin immunoprecipitation analyses. Results Starvation led to increased transcription of the gene that encodes phosphoenolpyruvate carboxykinase 1 (a protein involved in gluconeogenesis) in livers of mice, increased levels of Hepcidin, and degradation of Ferroportin, compared with nonstarved mice. These changes resulted in hypoferremia and iron retention in liver tissue. Livers of starved mice also had increased levels of Ppargc1a mRNA and Creb3l3 mRNA, which encode a transcriptional co-activator involved in energy metabolism and a liver-specific transcription factor, respectively. Glucagon and a cyclic adenosine monophosphate analog increased promoter activity and transcription of Hamp in cultured liver cells; levels of Hamp were reduced after administration of small interfering RNAs against Ppargc1a and Creb3l3 . PPARGC1A and CREB3L3 bound the Hamp promoter to activate its transcription in response to a cyclic adenosine monophosphate analog. Creb3l3 –/– mice did not up-regulate Hamp or become hypoferremic during starvation. Conclusions We identified a link between glucose and iron homeostasis, showing that Hepcidin is a gluconeogenic sensor in mice during starvation. This response is involved in hepatic metabolic adaptation to increased energy demands; it preserves tissue iron for vital activities during food withdrawal, but can cause excessive iron retention and hypoferremia in disorders with persistently activated gluconeogenesis and insulin resistance.