Besides the well-known reciprocal influences of skeletal muscle and heart during and after physical exercise, a new perspective is emerging on the short- and long-term effects of exercise-induced damage, in particular the pathogenic role of inappropriate apoptosis in skeletal and cardiac muscle. Cells from multicellular organisms self-destruct when they are no longer needed, or have become damaged; they do this by activating a genetically controlled cell suicide machinery that leads to programmed cell death (PCD), or apoptosis. Apoptosis is a specific form of programmed cell death that plays an important role in development, growth regulation and disease. Skeletal muscles in adult animals are fully differentiated syncytial cells. Apoptosis, which is known to be present in tissues that modulate their cellular homeostasis under the influence of growth and/or hormonal factors, has been recently described in early stages of myocardial infarct, and in dystrophic skeletal muscle. The role and the cellular and molecular aspects of muscle cell death and apoptosis are far from clear, particularly following several types of muscle damage (genetic defects, exercise-induced damage, oxidative stress, etc.). It can be predicted that apoptosis plays a major role in regulating myoblast proliferation during muscle regeneration, and in the progression of dystrophinopathies. A particularly important area has recently developed concerning cardiac muscle and reperfusion injury after ischemia; in this case as well, a major role of apoptosis is emerging.

Adult↗

PubMedDate not supplied

Effect of zinc ions on apoptosis in PBMCs from healthy aged subjects.

Immunosenescence features, such as thymic involution, alteration of T-cell repertoire, autoimmunity and accumulation of memory/effector T cells, may be the result, at least in part, of a zinc deficiency, which is often observed during ageing. Zinc, as essential trace element, affects the immune system function and it is an important regulator of apoptosis of immune cells. In this study we addressed the question whether zinc supplementation in vitro at physiological doses can affect spontaneous and oxidative stress-induced apoptosis in peripheral blood mononuclear cells from subjects of three different age groups: young (mean age 28 years), old (mean age 72 years) and nonagenarians. We studied different parameters related to apoptosis (phosphatydilserine exposure, mitochondrial membrane potential, caspase 3 cleavage) and we found that zinc, while decreasing spontaneous apoptosis, can increase oxidative stress-induced apoptosis in an age-related fashion, being this effect more evident in nonagenarians than in old or young subjects. In particular, zinc can increase late apoptosis/necrosis, a phenomenon that could trigger unnecessary inflammation in vivo. We surmise that these age-associated alterations in susceptibility to apoptosis may be due to a different effect of zinc on T cell subsets, that are altered in very old people, and finally that the zinc deficiency, which is often observed in aged subjects, could be a compensatory mechanism to counteract the inflammatory status of the elderly.

Adult↗

PubMedDate not supplied

The neuroimmunology of stress from invertebrates to man.

Stress can be seen as the body's most important and complex reaction to ensure survival involving the neuroendocrine systems and a variety of other organs. The investigation of the evolutionary bases of stress argues that the basic mechanisms and molecules involved in stress (CRH, ACTH, glucocorticoids, biogenic amines and cytokines) are fundamentally similar and well preserved throughout evolution in different species and taxa. A review of available data highlights that the involvement of immunity during stress response has a strong evolutionary basis and is not a mere consequence of glucocorticoid hormone release. We propose that the evolutive cellular bases of stress are to be identified in immune cells, such as invertebrate hemocytes, producing a variety of cytokine-like molecules, capable at the same time of producing a variety of hormone- and neuropeptide-like molecules and of performing a proto-stress response (release of biogenic amines). We conclude that stress, a highly conserved reaction remarkably similar in different species and taxa, is a fundamentally positive type of adaptive reaction.

Animals↗

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Age-related increase of mitomycin C-induced micronuclei in lymphocytes from Down's syndrome subjects.

Peripheral blood lymphocytes from 7 patients with Down's syndrome (DS; trisomy 21) and 14 healthy age-matched controls were studied for the induction of micronuclei (MN) by the cytokinesis-block method. The spontaneous incidence of MN in lymphocytes from DS subjects was lower than that of control cultures. When lymphocytes were treated with mitomycin C (MMC) at the beginning of the culture period, an increase in MN formation was found in cells from both DS and control subjects. In DS subjects this increase was much more marked than in control donors. This effect had to be ascribed to cells from older DS subjects (37-55 years old), which showed an MMC-induced MN formation that was markedly and significantly higher than that observed in cells from younger (9-16 years old) DS subjects. These data indicate that age has to be considered a major variable when studies on the genetic instability of DS subjects are performed.

Adolescent↗

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Apoptosis by 2-chloro-2'-deoxy-adenosine and 2-chloro-adenosine in human peripheral blood mononuclear cells.

Adenosine has profound effects on immune cells and has been implicated in the intrathymic apoptotic deletion of T-cells during development. In order to characterize adenosine effects on quiescent peripheral blood mononuclear cells (PBMC), we have evaluated the ability of the previously characterized adenosine receptor agonist 2-chloro-adenosine (2CA; Ceruti, Barbieri et al., 1997) and of the antineoplastic drug 2-chloro-2'-deoxy-adenosine (2CdA, cladribine) to trigger apoptosis of PBMC. Apoptosis was assessed by morphological changes, DNA fragmentation by agarose gel electrophoresis and appearance of hypodiploid DNA peak by flow cytometry. 2CA (10 microM) and 2CdA (1 microM) induced apoptosis in human PBMC, which are relatively insensitive to apoptosis. For both agents, the effect was concentration- and time-dependent, although 2CdA induced apoptosis more potently than 2CA. Evaluation of mitochondrial function in parallel samples using the mitochondrial membrane-potential-specific dye JC-1 showed that mitochondrial damage followed the same kinetics as apoptosis, hence an early damage of mitochondria is likely not responsible for adenosine-induced death of PBMC. The effect of 2CA was partially prevented by addition of dipyridamole (DP), a nucleoside transport inhibitor, hence some of the apoptotic effect of this nucleoside is, at least in part, due to intracellular action. Alternatively, DP did not affect 2CdA-induced apoptosis, suggesting that 2CdA may enter cells via a DP-insensitive transporter. 5-Iodotubercidin (5-Itu), a nucleoside kinase inhibitor, was also able to partially prevent the action of 2CA and was not able to affect 2CdA-induced apoptosis, suggesting a different role for phosphorylation in 2CA- vs 2CdA-induced apoptosis. To test the role of P1 receptors, agonists and antagonists selective at various P1 receptor subtypes were used. Data suggest that, for 2CA, apoptosis is partially sustained by activation of the A2A receptor subtype, whereas no role is exerted by P1 receptors in 2CdA-dependent apoptosis. Moreover, in these cells, apoptosis could also be triggered through intense activation of the A3 receptor via selective agonists such as 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA), but this mechanism plays no role in either 2CA- or 2CdA-induced apoptosis. On the whole, our results suggest that 2CA and 2CdA follow different pathways in inducing apoptosis of immune cells. Moreover, our data also suggest that there are at least three different ways by which adenosine derivatives may induce apoptosis of human PBMC: (i) through an A2A-like extracellular membrane receptor; (ii) through entry of nucleosides into cells and direct activation of intracellular events involved in the apoptotic process; or (iii) through activation of the A3 receptor.

2-Chloroadenosine↗

PubMedDate not supplied

Age dependent impact of LMP polymorphisms on TNFalpha-induced apoptosis in human peripheral blood mononuclear cells.

As a consequence of inflammatory stimuli (such as TNFalpha and IFNgamma), some constitutive subunits of the proteasome, the principal mediator of nonlysosomal protein degradation, are replaced with other subunits, the large multifunctional proteases LMP2 and LMP7, thus originating the immunoproteasome. An age-related alteration of proteasome activity and susceptibility to TNFalpha-induced apoptosis, in which LMP2 and the nuclear factor (NF)-kappaB activation play an important role has been recently reported. In this paper, we investigated the possible influence of two LMP2 and LMP7 polymorphisms on susceptibility to TNFalpha-induced apoptosis. Our data show that an increase in susceptibility to TNFalpha-induced apoptosis is evident in long-lived people (aged >88 years) in comparison to young individuals. Moreover, the modulation of LMP2 codon 60 polymorphism on TNFalpha-induced apoptosis is evident in long-lived subjects. Genotyping of 311 young people and 157 nonagenarians and centenarians revealed no changes in LMP2 codon 60 genotype frequency distribution. No correlation with TNFalpha-induced apoptosis and no difference in frequency between young people and nonagenarians/centenarians was observed when the LMP7 nucleotide 145 polymorphism was studied.

Adult↗

PubMedDate not supplied

Male/female ratio in centenarians: a possible role played by population genetic structure.

All the demographic surveys on the centenarians have highlighted that females outnumber males. The centenarians' male/female (M/F) ratio reported by most studies ranges between 1:4 and 1:7. A puzzling 1:2 ratio was observed in Calabria, a Southern Italian region. To our knowledge only in Sardinia a similar phenomenon had been previously observed. We have therefore used the data of the Italian Institute of Statistics to figure out the centenarians' M/F ratio in the Italian regions. We found that this ratio gradually decreases from South to North. Such a result is certainly due to many factors. Thus, we have explored the possibility, it is also influenced by the genetic structure of the Italian population. In fact, the distribution of the centenarians' M/F ratio turned out to be significantly correlated with the genetic structure of the Italian population as outlined by the principal component analysis.

Aged↗

PubMedDate not supplied

Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2).

The possibility that four loci (REN, THO, PARP, SOD2) are associated with longevity was explored by comparing the genotypic pools of subjects older than 100 years with those of younger subjects matched for sex and geographic area (northern and southern Italy). The markers (all located within the respective gene) were HUMREN4; HUMTHO1; HUMPARP (gt)845nt; SOD2(C/T)401nt. In order to reduce the number of genotypes, multiallelic polymorphisms were recoded as diallelic according to allele size and frequency patterns (small: S, and large: L, alleles). A significant loss of LL homozygous genotypes was found at the THO locus in male but not in female centenarians with respect to matched controls. On the other hand no significant difference was found between case/control genotypic frequencies at REN, PARP, SOD2 loci. The latter loci therefore do not affect inter-individual variability in life expectancy (at least in terms of qualitative variants associated with the tested markers). However, the data is consistent with an association between the THO locus and longevity.

Adolescent↗

PubMedDate not supplied

Metabolic gene polymorphisms and p53 mutations in healthy centenarians and younger controls.

To obtain insights into the genetic mechanisms of ageing, we studied the frequency of the simultaneous presence of polymorphisms in phase I and phase II genes and of several p53 germline mutations in a group of 66 nonagenarians and centenarians in good health, selected from a larger sample of a multicentre Italian study in Northern Italy, and in a sample of 150 young healthy volunteers of the same ethnic group. We found a statistically significant difference in the frequency of 1the GSTT1 deletion and the p53 genotypes: the absence of any p53 polymorphisms and of GSTT1 deletion, and the simultaneous presence of the three p53 polymorphisms and of GSTT1 deletion, were much more frequent in young subjects than in centenarians (41.5% versus 26.9% and 8.8% versus 3.8%, respectively). One hypothesis to explain this difference is that subjects with both GSTT1 deletion and p53 polymorphisms may accumulate carcinogens and may have reduced DNA repair ability, and thus are more at risk for cancer. Another possible explanation is that both metabolic genes and p53 act on pathways related to cell ageing and death, and therefore certain composite genetic patterns could represent a generic mechanism of protection against ageing, not just against the development of chronic diseases. It is likely that longevity is related to a complex genetic trait as well as to certain environmental exposures.

Adult↗

PubMedDate not supplied

Role of TLR4 receptor polymorphisms in Boutonneuse fever.

The genetics of the interaction between host and microbes plays an essential role in the survival of the individual and attainment of longevity. The activation of toll-like receptor (TLR)4 plays a key role in natural and clonotypic immune responses. We evaluated whether TLR4 genotype is a component of genetic background protective versus rickettsiosis and whether this background influences longevity. We genotyped for +896A/G TLR4 polymorphism 78 patients affected with Boutonneuse fever, 78 age-matched controls and 78 advanced age individuals from Sicily. The +869G allele, that attenuates receptor signalling, was significantly overrepresented in patients in comparison with age-matched controls. By analyzing data according to gender, this allele was significantly higher in female patients when compared to advanced age women. Pro-inflammatory responses are programmed to resist fatal infections. So, it is not surprising that the genetic background of people that survive to an advanced age may be protective against infections. However, this seems to occur in women but not in men. In a previous study, the +896G TLR4 allele was overrepresented in advanced age men and underrepresented in men affected by myocardial infarction. Thus, previous and present results tend to agree with the suggestion that men and women may follow different trajectories to reach longevity. For men it might be more important to control atherogenesis, whereas for women it might be more important to control infectious diseases.

Adult↗

PubMedDate not supplied

A mathematical model for the immunosenescence.

We propose a model for the dynamics of the immune system by considering the subpopulations of virgin and memory T lymphocytes on a time scale corresponding to the human life span. In the deterministic balance equation we introduce a fluctuating term in order to take into account the chronic antigenic stress. Starting from the hypothesis that the depletion of virgin cells with cytotoxic properties (CD8+) is a mortality marker, the model provides survival curves quite similar to the demographic curves.

Aging↗

PubMedDate not supplied

[The conservative and hemodynamic treatment of ambulatory venous insufficiency].

Explore the source record for details and available documents.

Humans↗

PubMedDate not supplied

[Reimplantation of the subclavian artery into the common carotid artery].

Since 1973, transposition of the subclavian artery into the common carotid artery has been the technique of choice to treat prevertebral occlusive subclavian lesions. However, the haemodynamic results in the vertebral artery were far from perfect, as shown by immediate post-operative ultrasonic examinations. This has been corrected by a technical modification: the subclavian artery is severed flush with the vertebral artery lying obliquely downward and medially, which is equivalent to reimplanting a "double-barrelled" vessel (the vertebral and subclavian arteries) into the common carotid artery.

Arterial Occlusive Diseases↗