L’anziano attivo. Proposte e riflessioni per la terza e la quarta età

Il problema della senilità si pone ormai in Italia, come in tutte le società avanzate, in termini assai diversi dal passato. I saggi compresi nel presente volume intervengono su tutti gli aspetti della senilità - da quelli psicologici, sanitari e affettivi a quelli assistenziali, economici e giuridici - per suggerire indicazioni operative e possibili soluzioni.- Indice #4- Prefazione, Marcello Pacini #10- Introduzione, Giuliano Urbani #12- Prima parte Per una nuova concezione della condizione anziana #20- L’età del tempo libero, Norberto Bobbio #22- L’anziano protagonista in una società che cambia, Gian Maria Capuani e Giannino Piana #26- La piccola immortalità, Nando dalla Chiesa #36- L’anziano come risorsa sociale: il volontariato dopo la pensione, Fausto Melloni #44- Seconda Parte Aspetti sociali della condizione anziana #62- Psicogerontologia: attualità e nuove prospettive, Maria Antonietta Aveni Casucci #64- L’invecchiamento della popolazione italiana in un contesto internazionale, Antonio Golini e Agostino Lori #82- L’anziano e l’innovazione tecnologica, Francesco Jovane e Roberto Groppetti #114- La tutela giuridica dell’anziano, Luigi Mengoni #128- La salute dell’anziano: valutazione dei meccanismi di plasticità, Renzo Rozzini, Angelo Bianchetti e Marco Trabucchi #140- Lavoratori anziani: ambivalenza e interventi, Harris T. Schrank e Joan M. Waring #156- Il medico e l’anziano, Carlo Vergani #176- La normalità incerta, Virginio Oddone e Fabrizio Fabris #188- Il quadro organizzativo per una corretta assistenza socio-sanitaria alla popolazione anziana, Gaetano Maria Fara #200- Terza Parte Le tendenze della riflessione #216- La condizione degli anziani in Italia, Claudio Calvaruso #218- Anziani attivi: un possibile esempio di nuova centralità del sociale, Vincenzo Cesareo #228- Appendice Un contributo di ricerca #246- Figli adulti e genitori anziani: una nuova relazione tra le generazioni, Giovanna Rossi #24

Genome-wide expression profiling and functional characterization of SCA28 lymphoblastoid cell lines reveal impairment in cell growth and activation of apoptotic pathways

BACKGROUND: SCA28 is an autosomal dominant ataxia associated with AFG3L2 gene mutations. We performed a whole genome expression profiling using lymphoblastoid cell lines (LCLs) from four SCA28 patients and six unrelated healthy controls matched for sex and age. METHODS: Gene expression was evaluated with the Affymetrix GeneChip Human Genome U133A 2.0 Arrays and data were validated by real-time PCR. RESULTS: We found 66 genes whose expression was statistically different in SCA28 LCLs, 35 of which were up-regulated and 31 down-regulated. The differentially expressed genes were clustered in five functional categories: (1) regulation of cell proliferation; (2) regulation of programmed cell death; (3) response to oxidative stress; (4) cell adhesion, and (5) chemical homeostasis. To validate these data, we performed functional experiments that proved an impaired SCA28 LCLs growth compared to controls (p\u2009<\u20090.005), an increased number of cells in the G0/G1 phase (p\u2009<\u20090.001), and an increased mortality because of apoptosis (p\u2009<\u20090.05). We also showed that respiratory chain activity and reactive oxygen species levels was not altered, although lipid peroxidation in SCA28 LCLs was increased in basal conditions (p\u2009<\u20090.05). We did not detect mitochondrial DNA large deletions. An increase of TFAM, a crucial protein for mtDNA maintenance, and of DRP1, a key regulator of mitochondrial dynamic mechanism, suggested an alteration of fission/fusion pathways. CONCLUSIONS: Whole genome expression profiling, performed on SCA28 LCLs, allowed us to identify five altered functional categories that characterize the SCA28 LCLs phenotype, the first reported in human cells to our knowledge. \ua9 2013 Mancini et al.; licensee BioMed Central Ltd

A unique combination of rare mitochondrial ribosomal RNA variants affects the kinetics of complex I assembly

Mitochondrial DNA (mtDNA) mutations in respiratory complexes subunits contribute to a large spectrum of human diseases. Nonetheless, ribosomal RNA variants remain largely under-investigated from a functional point of view. We here report a unique combination of two rare mitochondrial rRNA variants detected by serendipity in a subject with chronic granulomatous disease and never reported to co-occur within the same mitochondrial haplotype. In silico prediction of the mitochondrial ribosomal structure showed a dramatic rearrangement of the rRNA secondary structure. Functional investigation of cybrids carrying this unique haplotype demonstrated that the co-occurrence of the two rRNA variants determines a slow-down of the mitochondrial protein synthesis, especially in cells with an elevated metabolic rate, which impairs the assembly kinetics of Complex I, induces a bioenergetic defect and stimulates reactive oxygen species production. In conclusion, our results point to a sub-pathogenic role for these two rare mitochondrial rRNA variants, when found in the unique combination here reported in a single individual

Analysis of Mitochondrial Proteome of Cybrid Cells Harbouring a Truncative Mitochondrial DNA Mutation in Respiratory Complex I

none9Transmitochondrial cytoplasmic hybrids (cybrids) are a well established model system to reveal the effects of mitochondrial DNA (mtDNA) mutations on cell metabolism excluding the interferences of a different nuclear background. The m.3571insC mutation in MTND1 gene of respiratory complex I (CI) is commonly detected in oncocytic tumors, in which it causes a severe CI dysfunction leading to an energetic impairment when present above 83% mutant load. To assess whether the energetic deficit may alter the mitochondrial proteome, OS-78 and OS-93 cybrid cell lines bearing two different degrees of the m.3571insC mutation (78% and 92.8%, respectively) and control cybrids bearing wild-type mtDNA (CC) were analyzed. Two-dimensional electrophoresis and mass spectrometry revealed significant alterations only in cybrids above the threshold (OS-93). All differentially expressed proteins are decreased. In particular, the level of pyruvate dehydrogenase E1 chain B subunit (E1b), of lipoamide dehydrogenase (E3), the enzyme component of pyruvate and 2-oxoglutarate dehydrogenase complexes and of lactate dehydrogenase B (LDHB) was reduced. Moreover, a significant decrease of the pyruvate dehydrogenase complex activity was found when OS-93 cybrid cells were grown in galactose medium, a metabolic condition that forces cells to use respiration. These results demonstrate that the energetic impairment caused by the almost homoplasmic m.3571insC mutation perturbs cellular metabolism leading to a decreased steady state level of components of very important mitochondrial NAD-dependent dehydrogenases.noneClara Musicco;Antonella Cormio;Maria Antonietta Calvaruso;Luisa Iommarini;Giuseppe Gasparre;Anna Maria Porcelli;Anna Maria Timperio;Lello Zolla;Maria Nicola GadaletaClara Musicco;Antonella Cormio;Maria Antonietta Calvaruso;Luisa Iommarini;Giuseppe Gasparre;Anna Maria Porcelli;Anna Maria Timperio;Lello Zolla;Maria Nicola Gadalet

The hepatic expression of vitamin D receptor is inversely associated with the severity of liver damage in genotype 1 chronic hepatitis C patients

BACKGROUND/AIMS: Low 25-hydroxyvitamin D serum levels have been associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients (G1CHC), and experimental evidence suggested a hepatoprotective role of vitamin D via interaction with hepatic vitamin D receptor (VDR). We assessed the hepatic expression of VDR protein and its association with liver disease severity. METHODS: Ninety-one consecutive patients with biopsy-proven G1CHC and available frozen liver tissue were evaluated. Ten subjects without chronic liver diseases and nine patients with autoimmune hepatitis served as controls. The hepatic expression of VDR protein was assessed by Western blot for quantification and by immunohistochemistry for morphological distribution. RESULTS: Liver VDR protein was mainly localized in hepatocytes and cholangiocytes, and its expression by a Western blot was similar in chronic hepatitis C (CHC) and controls (1.83 +/- 0.97 vs 2.18 +/- 0.62, P = .14) but was lower in autoimmune hepatitis (0.84 +/- 0.14, P < .001). The expression was lower in CHC with severe necroinflammatory activity (1.44 +/- 0.87) vs both controls and CHC with grade 1-2 inflammation (1.94 +/- 0.97, P = .01 and P = .03, respectively) but higher compared with autoimmune hepatitis (P = .007). A similar difference was observed in CHC patients with F3-F4 fibrosis whose VDR expression (1.51 +/- 1.07) was also lower compared with controls and CHC with F0-F2 fibrosis (1.98 +/- 0.89, P = .02 and P = .04, respectively) but higher vs autoimmune hepatitis (P = .003). At multivariate logistic regression analysis, low VDR protein expression remained associated with severe necroinflammatory activity and severe fibrosis (odds ratio 0.543,95% confidence interval 0.288-0.989, P = .04; and odds ratio 0.484,95% confidence interval 0.268-0.877, P = .01, respectively) in CHC after correction for clinical, biochemical, and histological features. CONCLUSION: In a cohort of G1CHC patients, the hepatic expression of VDR protein is associated with the severity of both liver fibrosis and inflammation

The cytochrome b p.278Y&gt;C mutation causative of a multisystem disorder enhances superoxide production and alters supramolecular interactions of respiratory chain complexes

Cytochrome b is the only mtDNA-encoded subunit of the mitochondrial complex III (CIII), the functional bottleneck of the respiratory chain. Previously, the human cytochrome b missense mutation m.15579A>G, which substitutes the Tyr 278 with Cys (p.278Y>C), was identified in a patient with severe exercise intolerance and multisystem manifestations. In this study, we characterized the biochemical properties of cybrids carrying this mutation and report that the homoplasmic p.278Y>C mutation caused a dramatic reduction in the CIII activity and in CIII-driven mitochondrial ATP synthesis. However, the CI, CI + CIII and CII + CIII activities and the rate of ATP synthesis driven by the CI or CII substrate were only partially reduced or unaffected. Consistent with these findings, mutated cybrids maintained the mitochondrial membrane potential in the presence of oligomycin, indicating that it originated from the respiratory electron transport chain. The p.278Y>C mutation enhanced superoxide production, as indicated by direct measurements in mitochondria and by the imbalance of glutathione homeostasis in intact cybrids. Remarkably, although the assembly of CI or CIII was not affected, the examination of respiratory supercomplexes revealed that the amounts of CIII dimer and III(2)IV(1) were reduced, whereas those of I(1)III(2)IV(n) slightly increased. We therefore suggest that the deleterious effects of p.278Y>C mutation on cytochrome b are palliated when CIII is assembled into the supercomplexes I(1)III(2)IV(n), in contrast to when it is found alone. These findings underline the importance of supramolecular interactions between complexes for maintaining a basal respiratory chain activity and shed light to the molecular basis of disease manifestations associated with this mutation

IL28B polymorphisms influence stage of fibrosis and spontaneous or interferon-induced viral clearance in thalassemia patients with hepatitis C virus infection

Polymorphisms in the interleukin-28B are important determinants in the spontaneous and drug-induced control of hepatitis C virus infection