Zinc-bound metallothioneins and immune plasticity: lessons from very old mice and humans

The capacity of the remodelling immune responses during stress (named immune plasticity) is fundamental to reach successful ageing. We herein report two pivotal experimental models in order to demonstrate the relevance of the immune plasticity in ageing and successful ageing. These two experimental models will be compared with the capacity in remodelling the immune response in human centenarians. With regard to experimental models, one model is represented by the circadian rhythms of immune responses, the other one is the immune responses during partial hepatectomy/liver regeneration (pHx). The latter is suggestive because it mimics the immunosenescence and chronic inflammation 48 h after partial hepatectomy in the young through the continuous production of IL-6, which is the main cause of immune plasticity lack in ageing. The constant production of IL-6 leads to abnormal increments of zinc-bound Metallothionein (MT), which is in turn unable in zinc release in ageing. As a consequence, low zinc ion bioavailability appears for thymic and extrathymic immune efficiency, in particular of liver NKT cells bearing TCR γδ. The remodelling during the circadian cycle and during pHx of zinc-bound MT confers the immune plasticity of liver NKT γδ cells and NK cells in young and very old mice, not in old mice. With regard to human centenarians and their capacity in remodelling the immune response with respect to elderly, these exceptional individuals display low zinc-bound MT associated with: a) satisfactory intracellular zinc ion availability, b) more capacity in zinc release by MT, c) less inflammation due to low gene expression of IL-6 receptor (gp130), d) increased levels of IFN-gamma and number of NKT cell bearing TCR γδ. Moreover, some polymorphisms for MT tested in PBMCs from human donors are related to successful ageing. In conclusion, zinc-bound MT homeostasis is fundamental to confer the immune plasticity that is a condition "sine qua non" to achieve healthy ageing and longevity

Zinc, oxidative stress, genetic background and immunosenescence: implications for healthy ageing

The relevance of zinc for proper functioning of the entire immune system is already well documented. However, the identification of individuals who really need zinc supplementation is still debated in view of the fact that excessive zinc may also be toxic. The risk of developing zinc deficiency in people from industrialized countries is relatively low, except for elderly subjects where zinc intake may be suboptimal and inflammation is chronic. Thus, the role of zinc on the immune system and on the health of European elderly people is becoming of paramount importance, considering also that the elderly population is rapidly increasing. In particular, the factors contributing to and the biochemical markers of zinc deficiency in the elderly are still remain to be established. Epidemiological, functional, and genetic studies aimed at formulating a rationale for the promotion of healthy ageing through zinc supplementation was the subject of an International Conference held in Madrid from 11–13 February 2006 (3(rd )ZincAge Meeting) at the CNIO Institute (local organizer: Maria Blasco, partner of ZincAge

Judicial power and expert knowledge: for an evolutionary interpretation of art. 101 of the Constitution

La presente trattazione si propone l’obiettivo di indagare le trasformazioni cui il ruolo del giudice è esposto per effetto dell’ingresso nel processo delle cosiddette conoscenze esperte. Assumendo l’art. 101 Cost. quale punto di partenza e di arrivo dell’intera ricerca, l’intenzione di chi scrive è quella di ricostruire il complesso rapporto tra il potere giudiziario e il sapere tecnico-scientifico adottando una prospettiva di analisi che consenta di osservare il fenomeno nel suo concreto atteggiarsi nel perimetro elettivo di azione del giudice: il processo. Si è dunque scelto di suddividere il lavoro in due parti: la prima, dedicata allo studio della funzione giudiziaria nel suo dover essere secondo una duplice direttrice di matrice storico-costituzionalistica e dogmatico-processualistica; la seconda, rivolta all’indagine dell’essere e dunque all’osservazione empirica delle più emblematiche e dibattute manifestazioni dell’interazione tra il giudice e il dato tecnico-scientifico nelle singole realtà processuali del nostro ordinamento giuridico, ossia il processo penale, il processo civile, il processo amministrativo e il processo costituzionale. Tale opzione ha imposto l’adozione di un metodo di analisi di tipo induttivo, atto ad approdare a conclusioni di carattere sistematico sulla base di un’attenta osservazione empirica delle peculiarità proprie di ciascuno dei contesti processuali di volta in volta esaminati. Nelle conclusioni, ci spingeremo a proporre un’interpretazione evolutiva dell’art. 101 Cost. e del brocardo – iudex peritus peritorum – che ne rappresenta il precipitato per misurare i principi fondamentali ivi consacrati sulle istanze del progresso tecnico-scientifico e attualizzarne il significato in un’epoca storica in cui la scienza e la tecnica permeano e condizionano le relazioni intersoggettive in modo senz’altro più incisivo che non in passato.The present dissertation aims to investigate if and how the role of the judge is transformed due to the entry into the process of the expert knowledge. Assuming the art. 101 of the Constitution as the point of departure and arrival of the whole research, the intention of the writer is to reconstruct the complex relationship between judicial power and technical-scientific knowledge by adopting a perspective of analysis that allows to observe the phenomenon in the elective perimeter of the judge's action: the process. We have therefore chosen to divide the work into two parts: the first, dedicated to the study of the judicial function in its “sollen” according to a double directrix of historical-constitutionalist and dogmatic-proceduralist matrix; the second, addressed to the investigation of the “sein” and therefore to the empirical observation of the most emblematic and controversial manifestations of the interaction between the judge and the technical-scientific data in the single procedural contexts of our legal system, ie the criminal trial, the civil trial, the administrative trial and the constitutional trial. By adopting an inductive analysis method, we will try to propose a systematic reconstruction that allows us to identify the outcomes and the trends of our interdisciplinary research, and therefore to collect the distortions to which the role of the judge is exposed in the era of scientific-technological progress. Aware of the risk of yielding to simplifying temptations or to scientistic illusions, as well as to surrender to technocratic drifts, we will try to propose some solutions in order to preserve the most authentic meaning of art. 101 of the Constitution, which requires the judge both to administer justice "in the name of the people" and to be subjected "only to the law", in the tireless pursuit of truth and justice

Are zinc-bound metallothionein isoforms (I+II and III) involved in impaired thymulin production and thymic involution during ageing?

BACKGROUND: With advancing age, thymic efficiency shows progressive decline due to thymic involution allowing impaired cell-mediated immunity and the appearance of age-related diseases. The intrinsic cause of thymic involution is still undefined. Chronic inflammation and high glucocorticoids (GCs) may be involved. However, transgenic mice, with increased GC sensitivity and over expression of GC receptors, display delayed age-associated thymic involution. This fact suggests that other substances may affect thymic involution. Among them, both isoforms of metallothioneins (MTs) I+II and III are the major candidates because their increments leads to organ atrophy in constant stress and are induced by IL-6, which increases in ageing. Enhanced MTs in ageing allows constant sequester of zinc ions and no subsequent zinc release leading to low zinc ion bioavailability for thymic efficiency. This sequester is very limited in very old age. Thus, we have investigated the MTmRNA (I+II and III) in the thymus from young, old and very old mice. METHODS: MTmRNA and IL-6mRNA (RT-PCR) in the thymus from different donors were tested. Concomitantly, TECs proliferation, zinc ion bioavailability (ratio total thymulin/active thymulin), thymulin activity and corticosterone were tested from different donors. RESULTS: Both isoforms of MTmRNA and IL-6mRNA increase in old thymus coupled with low zinc ion bioavailability, reduced TECs proliferation, impaired thymulin activity and enhanced plasma corticosterone in comparison with young. Conversely, although the thymus is involuted in very old mice because of no changes in thymus weight in comparison to old mice, reduced MTmRNA, especially MT-I+II isoforms, and low IL6mRNA occur. Concomitantly, good zinc ion bioavailability, maintained TECs proliferation, satisfactory thymulin activity and reduced corticosterone are observed in very old mice. CONCLUSIONS: The concomitant increments by high IL-6 of both MT isoforms in the thymus from old mice may be involved in thymic involution because provoking low zinc ion bioavailability, which is relevant for thymic efficiency. By contrast, the limited increments of MTs by low IL-6 induce good zinc ion bioavailability and satisfactory thymic efficiency in very old mice. Therefore, abnormal increased MTs may provoke complete thymic involution during ageing and the possible appearance of age-related diseases. If their increments are instead limited by low inflammation, healthy ageing and longevity may be reached

ЗАСТОСУВАННЯ В СХЕМАХ ЗБАГАЧЕННЯ ТОНКОПОДРІБНЕНОЇ СИРОВИНИ УДОСКОНАЛЕНОГО МАГНІТНОГО ГІДРОЦИКЛОНУ

Проблема та її зв'язок з науковими і практичними задачами. Необхідна ступінь подрібнення руди перед її переробленням визначається характером вкраплення рудних мінералів, використанням різних методів збагачення сиро-вини, вимогами до якості концентратів, послідовністю технологічних процесів, що застосовуються у схемах переробки корисних копалин. Чим тонше кінцева крупність подрібнення руди, тим менше залишається мінеральних зростків і тим більше вірогідність отримання якісних концентратів

Speciation of trace elements in human serum by micro anion exchange chromatography coupled with inductively coupled plasma mass spectrometry

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Quinupristin/dalfopristin Bonding in Combination with Intraperitoneal Antibiotics Prevent Infection of Knitted Polyester Graft Material in a Subcutaneous Rat Pouch Model Infected with Resistant Staphylococcus epidermidis

AbstractObjective: to investigate the efficacy of quinupristin/dalfopristin in the prevention of prosthetic graft infection in a rat subcutaneous pouch model.Methods: graft infections were established in the subcutaneous tissue of 140 male Wistar rats by implantation of Dacron prostheses followed by topical inoculation withStaphylococcus epidermidis with intermediate resistance to glycopeptides. The study included one group without contamination, one contaminated group without prophylaxis, one contaminated group that received 50mg/l quinupristin/dalfopristin-soaked graft, one contaminated group that received 10mg/kg intraperitoneal levofloxacin, one contaminated group that received 3mg/kg intraperitoneal doxycycline, and two contaminated groups that received 50mg/l quinupristin/dalfopristin-soaked plus 10mg/kg intraperitoneal levofloxacin or 3mg/kg intraperitoneal doxycycline. Each group included 20 animals. The grafts were removed after 7 days and evaluated by quantitative culture.Results: quinupristin/dalfopristin showed a significantly higher efficacy than levofloxacin and doxycycline, even though quantitative graft cultures for rats that received only quinupristin/dalfopristin-soaked graft showed bacterial growth. Otherwise, the efficacy of levofloxacin was similar to that of doxycycline. Only the group treated with quinupristin/dalfopristin combined with levofloxacin or doxycycline showed no evidence of staphylococcal infection.Conclusions: quinupristin/dalfopristin as adjunctive topical antibiotic prophylaxis can be useful for the prevention of vascular graft infections caused by staphylococcal strains with high levels of resistance

Effects of the Infusion of 4% or 20% Human Serum Albumin on the Skeletal Muscle Microcirculation in Endotoxemic Rats

Sepsis-induced microcirculatory alterations contribute to tissue hypoxia and organ dysfunction. In addition to its plasma volume expanding activity, human serum albumin (HSA) has anti-oxidant and anti-inflammatory properties and may have a protective role in the microcirculation during sepsis. The concentration of HSA infused may influence these effects. We compared the microcirculatory effects of the infusion of 4% and 20% HSA in an experimental model of sepsis

RNAIII-inhibiting Peptide and/or Nisin Inhibit Experimental Vascular Graft Infection with Methicillin-susceptible and Methicillin-resistant Staphylococcus epidermidis

AbstractObjective. To investigate the efficacy of RNAIII-inhibiting peptide (RIP) and nisin as prophylactic agents in a rat model of vascular graft infection.Design. Prospective, randomized, controlled animal study.Materials. Two hundred and twenty adult male Wistar rats. Staphylococcus epidermidis ATCC 12228 and one clinical isolate of methicillin-resistant S. epidermidis. Drugs: RIP, nisin and rifampin.Methods. Graft infections were established in the dorsal subcutaneous tissue by implantation of 1 cm2 sterile Dacron grafts, followed by topical bacterial inoculation: grafts were retrieved at 7 days. The study included a control group (without inoculation) and two series composed of five groups for each staphylococcal strain: one contaminated group that did not receive any antibiotic prophylaxis, three contaminated groups that received grafts soaked with 10 mg/l RIP, 10 mg/l nisin, 10 mg/l rifampin, or RIP+nisin. The main outcome measure was the extent of bacterial at graft harvest.Results. The bacterial counts for methicillin-resistant S. epidermidis on explanted grafts were 6.1±2.8×102, 7.8±3.0×103 and 5.5±2.9×104 for RIP, nisin and rifampin, respectively. RIP and nisin used in combination reduced the bacterial count to <10. The results for S. epidermidis were similar.Conclusions. RIP and nisin could be used in combination to coat medical devices to prevent drug resistant S. epidermidis infections

Zinc and ageing: third Zincage conference

The importance of Zn for optimal functioning of the immune system and antioxidant stress response is well documented. Zn homeostasis influences development and function of immune cells, activity of stress-related and antioxidant proteins [metallothioneins (MT), chaperones, ApoJ, Poly(ADP-Ribose) polymerase-1 (PARP-1) and Methionione Sulfoxide Reductase (Msr), Superoxide Dismutase (SOD)], and helps to maintain genomic integrity and stability. During ageing, the intake of Zn decreases due to inadequate diet and/or intestinal malabsorption, contributing to frailty, general disability and increased incidence of age-related degenerative diseases (cancer, infections and atherosclerosis). Although many factors contributing to Zn deficiency have been identified, the biochemical markers of Zn deficiency as well as the possibility to achieve relevant health benefits through Zn supplementation in the elderly are still a matter for evaluation. Taking into account that Zn homeostasis is regulated by proteins and enzymes for which polymorphisms have been previously found to be associated with successful/unsuccessful ageing, genetic screening might be of added value in evaluating the individual response to Zn supplementation. Biochemical, immunological, dietary and genetic studies aimed at understanding the impact of Zn in healthy ageing, the effect of Zn supplementation in the elderly and finally formulating a rationale for the promotion of correct Zn supplementation were discussed at the international Zincage conference held in Ancona in January 2007