bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of the Helmeted Athlete with Suspected Cervical Spine Injury
Authors: Waninger Kevin N.
Published: July 2004

Improper handling of an unstable neck injury may result in iatrogenic neurologic injury. A review of published evidence on cervical management in the helmeted athlete with a suspected spinal injury is discussed. The approach to the neck-injured helmeted athlete and the algorithms for on-field and emergency department evaluations are reviewed. The characteristics of the fitted foot-ball helmet allow safe access for airway management, and helmets and shoulder pads should not be initially removed unless absolutely necessary. Prehospital and emergency personnel should be trained in the indications for removal and in proper helmet, shoulder pad, and facemask removal techniques. If required, both helmet and shoulder pads should be removed simultaneously. Radiographs with equipment in place may be inadequate, and the value of computed tomography and magnetic resonance imaging in these helmeted patients has been studied. If adequate films cannot be obtained with equipment in place, helmet and shoulder pads may need to be removed before radiographic clearance. A plan should be formulated to prepare for such unexpected clinical scenarios as cervical spine injuries, and skills should be practiced. Airway and cervical spine management in these helmeted athletes is an area of ongoing research.
Missing the Mark: Nationalist Politics and Student Apathy
Authors: Fox Jon E.
Published: July 2004

Nationalist politics is widely recognized as a key site for the articulation, legitimation, and propagation of a national view of the world. But the effectiveness of nationalist politics in advancing this view ultimately rests upon the uses ordinary people make of it. Popular reception, however, is more often assumed than specified in the literature on nationalism. In this article, I identify the ways in which Romanian and Hungarian university students in the ethnically mixed town of Cluj, Romania, consume and engage—and deflect and ignore—nationalist politics. I examine the ways the students talk (and do not talk) about three hotly contested political matters: the debate over an independent Hungarian university in Cluj, the politics of the city’s ultranationalist Romanian mayor, and the Romanian presidential elections of 2000. I show that the students can reproduce the nationally polarized terms of debate in response to survey questions. In the course of their everyday lives, however, there are few occasions in which they engage such issues. Instead, the students’ apathy and disdain for politics in general precludes meaningful engagement of the issues in national or other terms. Nationalist politics misses its mark.
Explaining Labor Weakness in Post-Communist Europe: Historical Legacies and Comparative Perspective
Authors: Crowley Stephen
Published: July 2004

With expansion of the European Union (EU), the transformation of industrial relations in Eastern Europe becomes increasingly important. Studies on labor relations in post-communist countries have flourished in recent years, yet these studies have not reached a consensus on what they seek to explain. Is labor in post-communist societies weak or (in some countries) strong? And strong or weak compared to what? To the extent labor is weak, what would explain this weakness? This study demonstrates that labor is indeed a weak social and political actor in post-communist societies, especially when compared to labor in Western Europe. The article examines a number of hypotheses that have been proposed to explain labor’s weakness, concluding that the institutional and ideological legacies of the communist period best explain this overall weakness. Because labor in post-communist societies more resembles American-style flexibility than the European “social model,” the ability to extend the European model to new EU entrants is questioned.
Ghosts in the machine
Authors: Hutchings Stephen
Published: July 2004

• This article examines how Russian television's recent assimilation of western genres to its own cultural paradigms has influenced the development of a post-Soviet identity. Informed by W.J.T. Mitchell's theory of the importance of word—image thresholds, and by Iurii Lotman's conception of intercultural dialogue, it is based on light entertainment broadcasts recorded over the period 1999—2001 on the NTV channel. It argues that Russia's traditionally dominant literary culture provides a `translation code' for its reception of western televisual texts and shapes its conceptions of `western-ness' and `New Russian-ness'. The article shows how the globalized imagery of the quiz-show and the talk-show are transformed into generic hybrids reliant on the narrativity and distancing capacities of verbal discourse, whose related capacity for reconciling mutually antagonistic meanings enables Russian television to negotiate between Soviet, pre-Soviet and western identities. •
The `tabloid effect' in the O.J. Simpson case
Authors: Grochowski Tom
Published: July 2004

• This article considers the `tabloid effect' of the O.J. Simpson case in terms of the production of crime knowledge. Summarizing important literature on crime and the media, it suggests that unusual circumstances must occur for news media to offer information in conflict with law enforcement agencies (as in the Rodney King incident, where an independent videotape existed). The Simpson case is an excellent example of how the debate on criticism of the blurring of the distinction between `mainstream' and `tabloid' media helps to illustrate the economic and cultural mechanisms that produce crime knowledge. This is done through careful discussion of two crucial `mainstream' assessments of the notorious `tabloid' weekly the National Enquirer. •
Human fetal, cord blood, and adult lymphocyte progenitors have similar potential for generating B cells with a diverse immunoglobulin repertoire
Authors: Kolar Grant R. , Yokota Takafumi , Rossi Maria Isabel D. , Nath Swapan K. , Capra J. Donald
Published: July 2004

Several characteristics of the immunoglobulin (Ig) repertoire in fetuses and adults set them apart from each other. Functionally, this translates into differences in the affinity and effectiveness of the humoral immune response between adults and the very young. At least 2 possibilities could explain these differences: (1) fetal and adult lymphocyte progenitors differ significantly in their potential to form a diverse repertoire, and (2) factors extrinsic to the immunoglobulin locus are more influential to the character of the repertoire. To address this we used nonobese diabetic-severe combined immunodeficient-β2 microglobulin knockout (NOD/SCID/β2m-/-) mice reconstituted with human B-cell progenitors to compare the immunoglobulin repertoire potential of human fetal, cord blood, and adult sources. We found nearly identical VH and JH gene segment use and only modest differences in the third complementarity determining region of the immunoglobulin heavy chain (HCDR3). We conclude that the repertoire potential is remarkably similar regardless of the age of the individual from which progenitors are derived. Age-related differences in the immunoglobulin repertoire and variance of B-cell responses to immunization appear to arise from selection rather than from changes in recombination of the immunoglobulin locus itself. From the standpoint of the Ig repertoire, an immune system reconstituted from fetal or neonatal stem cells would likely be as diverse as one generated from adult bone marrow.
The Fanconi anemia core complex associates with chromatin during S phase
Authors: Mi Jun , Kupfer Gary M.
Published: July 2004

Fanconi anemia (FA) is an autosomal recessive disease marked by bone marrow failure, birth defects, and cancer. The FA proteins FANCA, FANCC, FANCE, FANCF, FANCG, and FANCL participate in a core complex. We previously have shown that several members of this complex bind to chromatin until mitosis and that this binding increases after DNA damage. The purpose of the present study was to determine the dynamics of complex movement between cytoplasm and nuclear compartments. Fluorescent-tagged versions of FANCA, FANCC, and FANCG colocalize in cytoplasm and nucleus, chiefly in chromatin. At the G1-S border, the FA core complex exists as foci on chromatin, progressively diffusing and migrating to the nuclear periphery and becoming completely excluded from condensed chromosomes by mitosis. Chromatin fiber analysis shows FA proteins diffusely staining along chromatin fibers during G1-S and S phase. Treatment with the DNA cross-linker mitomycin C results in a diffusion of foci and increased binding of complex proteins to chromatin, as well as diffuse and increased complex binding to chromatin fibers. These data are consistent with the idea that the FA proteins function at the level of chromatin during S phase to regulate and maintain genomic stability.
A spectrum of biophysical interaction modes between T cells and different antigen-presenting cells during priming in 3-D collagen and in vivo
Authors: Gunzer Matthias , Weishaupt Carsten , Hillmer Anja , Basoglu Yasmin , Friedl Peter , Dittmar Kurt E. , Kolanus Waldemar , Varga Georg , Grabbe Stephan
Published: July 2004

For activation T cells engage antigen-presenting cells (APCs) in lymphatic tissues. The contact duration and kinetics (static versus dynamic) vary considerably in different model systems; however, it is unclear whether T cells, APCs, or the environment are responsible for the observed discrepancies. Using 3-D collagen matrices as structural scaffold, we directly compared the kinetics of T-cell engagement and activation by functionally major APC types, ie, dendritic cells (DCs) and resting or activated B cells. Resting B cells engaged T cells in long-lived (several hours), adhesive, and leukocyte function-associated antigen-1 (LFA-1)-dependent conjugates in 3-D collagen as well as in intact lymph nodes in vivo. DCs and preactivated B cells, however, supported predominantly dynamic, short-lived (minutes), and sequential contacts to T cells that were dependent on high cytoskeletal activity of the APCs but could not be inhibited by anti-LFA-1 treatment. Naive T cells were most strongly activated by DCs and activated B cells, whereas resting B cells were 100-fold less efficient to induce T-cell proliferation. Thus, in the same 3-D environment, naive T cells respond with a spectrum of different interaction modes dependent on the type and activation state of the APCs. Thereby, more dynamic interaction kinetics is positively correlated with higher T-cell priming efficiency. (Blood. 2004;104: 2801-2809)
Combining Growth Factors, Stem Cells, and Gene Therapy for the Aging Brain
Authors: BEHRSTOCK SOSHANA , SVENDSEN CLIVE N.
Published: July 2004

Abstract: Stem cells have been suggested as a possible “fountain of youth” for replacing tissues lost during aging. In the brain, replacing lost neurons is a challenge, as they have to then be reconnected with their appropriate targets. Perhaps a more realistic and practical strategy for affecting the aging process would be to prevent the loss of neurons from occurring, thus retaining intact circuitry. Glial cell line‐derived neurotrophic factor (GDNF) can reverse some aspects of aging in the monkey. Additionally, we have recently shown that GDNF directly infused into the human brain has significant effects on the symptoms of Parkinson disease. Human neural stem cells can be cultured, genetically modified, and transplanted. As such, these cells are ideal for ex vivo gene therapy, and may be used in the future as “minipumps” to release GDNF in vivo to protect aging neurons. Using such an approach could delay the effects of aging in the brain, giving a better quality of life. Stem cells might not be the fountain of youth, but provide a fountain of youth through the release of growth factors such as GDNF.
Metabolic Substrates of Neuronal Aging
Authors: TOESCU E C , XIONG J
Published: July 2004

Abstract: One mechanism proposed to explain age‐dependent changes has been the “Ca2+ hypothesis” of aging. Data indicate that most changes in the Ca2+ homeostasis of the cerebellar granule neurons appear only when the aged neurons are exposed to higher levels of stimulation and that these changes are secondary to metabolic limitations imposed by altered mitochondrial function.
The Biphasic Relationship between Regional Brain Senile Plaque and Neurofibrillary Tangle Distributions: Modification by Age, Sex, and APOE Polymorphism
Authors: CORDER ELIZABETH H. , GHEBREMEDHIN ESTIFANOS , TAYLOR MILES G. , THAL DIETMAR R. , OHM THOMAS G. , BRAAK HEIKO
Published: July 2004

Abstract: Epidemiologic studies indicate that elderly women are at higher risk for Alzheimer disease compared to men. In order to pathologically verify this result, the extent of AD brain lesions (NFT and SP) was compared for men and women at each age, that is, at each decade from 25 years to 95 years, in a large sample of > 5000 routine autopsy cases. Women had more affected brain regions beginning in late middle age. They also had more extensive SP depositions throughout the brain compared to men at each early NFT stage I, II, and III. At later NFT stages IV, V, and VI both men and women had extensive SP deposits. The gender gap in SPs at early NFT stages was large and specific to women who carried the APOE4 allele (P < .001) and in addition to the acceleration in NFT stage also found for APOE4+ women.
Chronic Treatment with a Precursor of Cellular Phosphatidylcholine Ameliorates Morphological and Behavioral Effects of Aging in the Rat Hippocampus
Authors: CRESPO D , MEGIAS M , FERNANDEZ‐VIADERO C , VERDUGA R
Published: July 2004

Abstract: Normal aging is commonly associated with a decline in memory, mainly for that related with newly acquired information. The hippocampal formation (HF) is a brain region that has been implicated in this dysfunction. Within the HF there are several cellular types, such as pyramidal cells, granule neurons of the dentate gyrus, and astrocytes. CDP‐choline is a well‐known intermediate in the biosynthesis of phosphatidylcholine, a phospholipid essential for neuronal membrane preservation and function; thus, this compound would attenuate the process of neuronal aging. To test this, three groups of male mice were used in this study. An adult 12‐month‐old group (ACG), a 24‐month‐old (OCG), and an old experimental group (OEG) were administered orally a solution of CDP‐choline (150 mg/kg per day) from 12 up to 24 months. Experimental observations suggest that CDP‐choline has a positive effect on memory (reference errors were attenuated), and hippocampal morphology resembled that of younger animals.
Chronic Aluminum Administration to Old Rats Results in Increased Levels of Brain Metal Ions and Enlarged Hippocampal Mossy Fibers
Authors: FATTORETTI PATRIZIA , BERTONI‐FREDDARI CARLO , BALIETTI MARTA , GIORGETTI BELINDA , SOLAZZI MORENO , ZATTA PAOLO
Published: July 2004

Abstract: The effect of chronic aluminium administration (2 g/L/6 months) was investigated in the central nervous system (CNS) of old rats. The content of Al3+, Cu2+, Zn2+, and Mn2+ was measured in prosencephalon + mesencephalon, pons‐medulla, and cerebellum. The area occupied by the mossy fibers in the hippocampal CA3 zone was also measured. In Al‐treated rats the contents of Al3+, Cu2+, Zn2+, and Mn2+ were significantly increased in prosencephalon + mesencephalon and pons‐medulla, while no change was observed in the cerebellum except a Cu2+ decrease. The area occupied by the mossy fibers in the CA3 field was significantly increased (+32%) in Al‐treated rats. Taken together, the present findings document that the aging CNS is particularly susceptible to aluminum toxic effects that may be responsible for a consistent rise in the cell load of oxidative stress. This may contribute, as an aggravating factor, to the development of neurodegenerative events, as observed in Alzheimer disease.
Environmental Enrichment‐Behavior‐Oxidative Stress Interactions in the Aged Rat: Issues for a Therapeutic Approach in Human Aging
Authors: FERNÁNDEZ C I , COLLAZO J , BAUZA Y , CASTELLANOS M R , LÓPEZ O
Published: July 2004

Abstract: The effects of environment enrichment on motor activity, exploration, and cognitive performances were studied in aged rats. Both nonimpaired (NI) and impaired (I) rats were submitted to daily training in a complex‐enriched environment (cEE) for 60 days. Animals were examined at spatial water maze task, passive avoidance test, open‐field test, and sensorimotor coordination tasks (bridges test and Marshall scales). At the end of experiments, animals were killed for brain biochemical determinations (gluthatione content and specific‐ChAT activity). Results after the first evaluation (before training) corroborate that the aged rat population showed a heterogeneity in behavioral patterns like that observed in humans. Also, cEE modified exploration activity, cognition, motor functions, and biochemical markers in both NI and I groups, but changes reached significant relevance for the last group. It is significant that neurotrophins, “novo” synthesis of neurotransmitters, and oxidative stress levels may mediate the observed changes, indicating that the aged brain still has appreciable plasticity in response to well‐manipulated environmental stimulation. Finally, our results also support the novel concepts and programs in prevention/reduction both in incidence/severity and outcome of age‐associated neurodegenerative conditions.
Digital Transcriptome Analysis in the Aging Cerebellum
Authors: POPESCO MAGDALENA C. , FROSTHOLM ADRIENNE , REJNIAK KATARZYNA , ROTTER ANDREJ
Published: July 2004

Abstract: Serial analysis of gene expression (SAGE) was used to identify and quantify all expressed cerebellar genes in the adult (P92) and aged (P810) C57BL/6J mouse cerebellum. A “closest‐neighbor” algorithm was used to differentiate low abundance tags from possible sequencing errors in both libraries. Unique tags were categorized into four groups: (1) novel genes; (2) ESTs; (3) RIKEN, KIA, and hypothetical genes; and (4) known genes. Known genes were further subdivided into functional categories based on the gene ontology classification, using a web‐based program developed in this laboratory (MmSAGEClass). Comparison of adult and aged cerebellar libraries revealed several genes that were differentially expressed, including growth hormone and prolactin, both of which were markedly decreased in the aged cerebellum. In addition, several tags showing differential expression were not identified in the Unigene database and are likely to represent novel genes. The present SAGE data on the aged cerebellar transcriptome may reveal candidate genes involved in the aging process.
Antiaging Treatments Have Been Legally Prescribed for Approximately Thirty Years
Authors: UKRAINTSEVA SVETLANA V. , ARBEEV KONSTANTIN G. , MICHALSKY ANATOLY I. , YASHIN ANATOLY I.
Published: July 2004

Abstract: There is an interesting divergence between the achievements of geriatrics and gerontology. On the one hand, during the last 30 years physicians in many developed countries have successfully prescribed several medicines to cure various symptoms of senescence. On the other hand, the influence of such medicines on human life span practically has not been studied. The most common of the relevant medicines are nootropic piracetam, gamma‐aminobutyric acid (GABA), selegiline, Ginkgo biloba, pentoxifylline, cerebrolysin, solcoseryl, ergoloid, vinpocetin, sertraline, and estrogens, among others. Available data from human clinical practices and experimental animal studies indicate that treatments with these drugs improve learning, memory, brain metabolism, and capacity. Some of these drugs increase tolerance to various stresses such as oxygen deficit and exercise, stimulate the regeneration of neurons in the old brain, and speed up the performance of mental and physical tasks. This means that modern medicine already has “antiaging” treatments at its disposal. However, the influence of such treatments on the mean and maximal life span of humans, and on the age trajectory of a human survival curve has been poorly studied. The increase in human life expectancy at birth in the second half of the last century was mostly caused by the better survival at the old and oldest old rather than at the young ages. In parallel, the consumption of brain protective and regenerative drugs has been expanding in the elderly population. We provide evidence in support of the idea that the consumption of medicines exerting antiaging properties may contribute to the increase in human longevity.
Aging of Cardiac Myocytes in Culture: Oxidative Stress, Lipofuscin Accumulation, and Mitochondrial Turnover
Authors: TERMAN ALEXEI , DALEN HELGE , EATON JOHN W. , NEUZIL JIRI , BRUNK ULF T.
Published: July 2004

Abstract: Oxidative stress is believed to be an important contributor to aging, mainly affecting long‐lived postmitotic cells such as cardiac myocytes and neurons. Aging cells accumulate functionally effete, often mutant and enlarged mitochondria, as well as an intralysosomal undegradable pigment, lipofuscin. To provide better insight into the role of oxidative stress, mitochondrial damage, and lipofuscinogenesis in postmitotic aging, we studied the relationship between these parameters in cultured neonatal rat cardiac myocytes. It was found that the content of lipofuscin, which varied drastically between cells, positively correlated with mitochondrial damage (evaluated by decreased innermembrane potential), as well as with the production of reactive oxygen species. These results suggest that both lipofuscin accumulation and mitochondrial damage have common underlying mechanisms, likely including imperfect autophagy and ensuing lysosomal degradation of oxidatively damaged mitochondria and other organelles. Increased size of mitochondria (possibly resulting from impaired fission due to oxidative damage to mitochondrial DNA, membranes, and proteins) also may interfere with mitochondrial turnover, leading to the appearance of so‐called “giant” mitochondria. This assumption is based on our observation that pharmacological inhibition of autophagy with 3‐methyladenine induced only moderate accumulation of large (senescent‐like) mitochondria but drastically increased numbers of small, apparently normal mitochondria, reflecting their rapid turnover and suggesting that enlarged mitochondria are poorly autophagocytosed. Overall, our findings emphasize the importance of mitochondrial turnover in postmitotic aging and provide further support for the mitochondrial‐lysosomal axis theory of aging.
Impairment of the Transcriptional Responses to Oxidative Stress in the Heart of Aged C57BL/6 Mice
Authors: EDWARDS MICHAEL G. , SARKAR DEEPAYAN , KLOPP ROGER , MORROW JASON D. , WEINDRUCH RICHARD , PROLLA TOMAS A.
Published: July 2004

Abstract: To investigate the transcriptional response to oxidative stress in the heart and how it changes with age, we examined the cardiac gene expression profiles of young (5 months old), middle‐aged (15 months old), and old (25 months old) C57BL/6 mice treated with a single intraperitoneal injection of paraquat (50 mg/kg). Mice were killed at 0, 1, 3, 5, and 7 hours after paraquat treatment, and the gene expression profile was obtained with high‐density oligonucleotide microarrays. Of 9,977 genes represented on the microarray, 249 transcripts in the young mice, 298 transcripts in the middle‐aged mice, and 256 transcripts in the old mice displayed a significant change in mRNA levels (ANOVA, P < .01). Among these, a total of 55 transcripts were determined to be paraquat responsive for all age groups. Genes commonly induced in all age groups include those associated with stress, inflammatory, immune, and growth factor responses. Interestingly, only young mice displayed a significant increase in expression of all three isoforms of GADD45, a DNA damage‐responsive gene. Additionally, the number of immediate early genes found to be induced by paraquat was considerably higher in the younger animals. These results demonstrate that, at the transcriptional level, there is an age‐related impairment of specific inducible pathways in the response to oxidative stress in the mouse heart.
Effects of Age and Caloric Restriction on Brain Neuronal Cell Death/Survival
Authors: HIONA ASIMINA , LEEUWENBURGH CHRISTIAAN
Published: July 2004

Abstract: Aging may pose a challenge to the central nervous system, increasing its susceptibility to apoptotic events. Recent findings indicate that caloric restriction (CR) may have a profound effect on brain function and vulnerability to injury and diseases, by enhancing neuroprotection, stimulating the production of new neurons, and increasing synaptic plasticity. Apoptosis and apoptotic regulatory proteins in the brain frontal cortex of 6‐month‐old ad libitum fed (6AD), 26‐month‐old ad libitum fed (26AD), and 26‐month‐old caloric‐restricted (26CR) male Fischer 344 rats (40% restriction compared to ad libitum fed) were investigated. Levels of Poly‐ADP ribose polymerase (PARP‐DNA repair enzyme; its cleaved 89 kDA fragment is a marker of apoptosis), cytoplasmic histone‐associated DNA fragments, and X chromosome‐linked inhibitor of apoptosis (XIAP—an endogenous apoptosis inhibitor) were determined. A significant age‐associated increase in PARP was found, which was ameliorated in the frontal cortices of the CR rats. No significant differences in cytoplasmic histone‐associated DNA fragments with age or with CR were observed. XIAP levels significantly increased with age in the brains of the ad libitum animals, while CR animals exhibited the highest levels of this inhibitor compared to all groups. Our findings suggest that caloric restriction may provide neuroprotection to the aging brain by preserving DNA repair enzymes in their intact form, and/or upregulating specific antiapoptotic proteins involved in neuronal cell death.
Differential Regulation of Telomerase in Endothelial Cells by Fibroblast Growth Factor‐2 and Vascular Endothelial Growth Factor‐A: Association with Replicative Life Span
Authors: TRIVIER ELISABETH , KURZ DAVID J. , HONG YING , HUANG HSIU‐LIN , ERUSALIMSKY JORGE D.
Published: July 2004

Abstract: In cultured human umbilical vein endothelial cells (HUVECs), fibroblast growth factor‐2 (FGF‐2), but not vascular endothelial growth factor‐A (VEGF‐A), upregulates telomerase activity. Here, we examined the functional significance of this differential regulation on the replicative life span of HUVECs. HUVECs were serially passaged until senescence under four different conditions: (1) EGM‐2, a medium containing both VEGF‐A and FGF‐2; (2) basal medium (BM), consisting of EGM‐2 devoid of FGF‐2 and VEGF‐A; (3) BM supplemented with FGF‐2; and (4) BM supplemented with VEGF‐A. Cells cultured in BM demonstrated decreased growth rate and ceased to proliferate at ∼15 population doublings (PDs), whereas those cultured with VEGF‐A alone initially proliferated vigorously but arrested growth abruptly at a PD level comparable with cultures grown in BM. In contrast, cells maintained in EGM‐2 or in BM/FGF‐2 attained a normal replicative life span (∼40 PDs). These differences in replicative behavior were reflected by the early appearance of a senescent phenotype in cultures grown in BM or BM/VEGF‐A. HUVECs grown in the presence of VEGF‐A alone have a decreased life span compared with cultures maintained with FGF‐2. This suggests that the upregulation of telomerase activity by FGF‐2, an effect not achieved with VEGF‐A, plays a functional role in preventing the early onset of senescence.
Interleukin‐7: An Interleukin for Rejuvenating the Immune System
Authors: ASPINALL RICHARD , HENSON SIAN , PIDO‐LOPEZ JEFFREY , NGOM PA TAMBA
Published: July 2004

Abstract: Infection of an individual (aged 20‐30 years) by a virus will cause a response from the T (thymus derived) lymphocytes of which there are approximately 3 × 1011. If the individual has not met the virus before, the response will come from the naive T cell subset (50 ± 10% of the total T cell pool at this age) containing recent thymic emigrants produced from the thymus at approximately 108 per day. Their antigen‐specific receptor has a defined specificity governed by the conformation of its two chains (α and β), and the repertoire of specificities is somewhere in the region of 2 × 107 to 108. A successful response leads to clonal expansion and the generation of memory T cells to the infecting agent.
T Cell Replicative Senescence Pleiotropic Effects on Human Aging
Authors: EFFROS RITA B.
Published: July 2004

Abstract: Long‐term culture studies using CD8 T cells, the immune cells responsible for control of viral infection, have identified the major features of replicative senescence. Aging is associated with increased proportions of CD8 T cells with similar characteristics, such as absence of expression of the CD28 costimulatory molecule and reduced antiviral effector functions. Proinflammatory cytokines produced by senescent CD8 T cells also may exert pleiotropic suppressive effects on overall immune function and bone homeostasis. Thus, modulation of T cell replicative senescence may provide a comprehensive therapeutic strategy to prevent multiple age‐associated pathologies.
Zinc, Immune Plasticity, Aging, and Successful Aging: Role of Metallothionein
Authors: MOCCHEGIANI EUGENIO , GIACCONI ROBERTINA , MUTI ELISA , ROGO CINZIA , BRACCI MASSIMO , MUZZIOLI MARIO , CIPRIANO CATIA , MALAVOLTA MARCO
Published: July 2004

Abstract: The capacity of the remodeling immune responses during stress (immune plasticity) is fundamental to reach successful aging. We herein report two pivotal models to demonstrate the relevance of the immune plasticity in aging and successful aging. 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 hours after partial hepatectomy in the young through the continuous production of IL‐6, which is the main cause of immune plasticity lack in aging. The constant production of IL‐6 leads to abnormal increments of zinc‐bound metallothionein (MT), which is, in turn, unable in zinc release in aging. As a consequence, low zinc ion bioavailability appears for thymic and extrathymic immune efficiency, in particular, of liver NKT cells bearing TCR gd. The remodeling 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 age, not in old age. Therefore, zinc‐bound MT homeostasis is crucial in conferring liver immune plasticity with subsequent successful aging.
Looking for Immunological Risk Genotypes
Authors: CARUSO CALOGERO , AQUINO ALESSANDRA , CANDORE GIUSEPPINA , SCOLA LETIZIA , COLONNA‐ROMANO GIUSEPPINA , LIO DOMENICO
Published: July 2004

Abstract: Several functional markers of the immune system may be used either as markers of successful aging or conversely as markers of unsuccessful aging. Particularly, a combination of high CD8 and low CD4 and poor T cell proliferation has been associated with a higher two‐year mortality in very old subjects. Therefore, genetic determinants of longevity should reside in those polymorphisms for the immune system genes that regulate immune responses. Concerning these changes in T cell subpopulations, how much they depend on the immunogenetic background and how much they depend on individual antigenic load, such as chronic infections, should be assessed. As previously demonstrated in our population, the interleukin (IL)‐2 high‐producer genotype is less frequent in old men than in young people; conversely, the IL‐10 high‐producer genotype is increased in old men. In this study, we tried to assess the role of low‐ and high‐producer genotypes for IL‐10 and IL‐2 in the CD4 and CD8 absolute values, taking into account gender and age. The results suggest that old men carrying an anti‐inflammatory IL‐10 high‐producer genotype or a proinflammatory IL‐2 low‐producer genotype show the lowest values of CD8 cells. Although in our study we were not able to show any correlation with CD4 values and no functional assessment of T cell was performed, these results suggest that cytokine genotypes may be involved in the subpopulation dynamics in old age.
Engineering Anticancer T Cells for Extended Functional Longevity
Authors: PAWELEC GRAHAM , MARIANI ERMINIA , McLEOD JULIE , BEN‐YEHUDA ARIE , FÜLÖP TAMAS , ARINGER MARTIN , BARNETT YVONNE
Published: July 2004

Abstract: Like other somatic cells, human T lymphocytes have a finite replicative capacity in vitro, and, by implication and consistent with the limited data available, in vivo as well. An accumulation of dysfunctional T cells may be detrimental under conditions of chronic antigenic stress (chronic infection, cancer, autoimmunity). Using T cells from young donors to model the process of T cell clonal expansion in vitro under these conditions reveals age‐associated increasing levels of oxidative DNA damage and microsatellite instability (MSI), coupled with decreasing DNA repair capacity, telomerase induction and telomere length, decreased levels of expression of the T cell costimulator CD28 and consequently reduced secretion of the T cell growth factor interleukin‐2 (IL‐2). However, data from similar experiments using T cell clones (TCCs) derived from extremely healthy very elderly donors (“successfully aged”) indicate that DNA repair is better maintained, MSI less prevalent, and (already short) telomere lengths are maintained. Nonetheless, oxidative DNA damage is seen to the same extent, and clonal longevity is also similar in these clones. DNA damage levels are reduced by culture in 5% oxygen, but longevity is not improved. This may be because of the requirement for intermittent reactivation via receptor pathways dependent on free radical production in T cells. These recent findings from our international immunosenescence research consortium suggest that strategies other than telomere maintenance, better protection against free radicals, or improved DNA repair will be required for functional longevity extension of human TCCs. To obtain sufficient cells for adoptive immunotherapy of cancer, alternative avenues need exploration; currently, these include enforced expression of certain heat shock proteins and proteasome components, and interference with the expression of negative regulatory receptors expressed by T cells.
Telomerase Expression Is Differentially Regulated in Birds of Differing Life Span
Authors: HAUSSMANN MARK F. , WINKLER DAVID W. , HUNTINGTON CHARLES E. , NISBET IAN C. T. , VLECK CAROL M.
Published: July 2004

Abstract: Cellular senescence caused by telomere shortening has been suggested as one potential causal agent of aging. In some tissues, telomeres are maintained by telomerase; however, telomerase promotes tumor formation, suggesting a trade‐off between aging and cancer. We predicted that telomerase activity should vary directly with life span. We determined telomerase activity in bone marrow in cross‐sectional samples from two short‐lived bird species and two long‐lived bird species. The two short‐lived species had high telomerase activity as hatchlings but showed a sharp downregulation in both the young and old adults, whereas the two long‐lived species had relatively high telomerase activity in bone marrow that did not decrease with age. In zebra finches, the age‐related change in telomerase activity varied in different tissues. Telomerase activity increased late in life in skeletal muscle, liver, and gonad, but not in blood or bone marrow.
The Role of Cellular Senescence May Be to Prevent Proliferation of Neighboring Cells within Stem Cell Niches
Authors: LYNCH M D
Published: July 2004

Abstract: It has long been suspected that cellular senescence is an anticancer mechanism; however, it has been difficult to understand the advantage for the organism of retaining mutant cells in a postmitotic state rather than simply deleting them by apoptosis. It is proposed that in certain circumstances apoptosis promotes neoplasia by causing cells adjacent to the deleted cell to divide and that the role of cellular senescence is to prevent this. This may be particularly important in mammalian stem cell niches. After loss of a stem cell from a niche, another stem cell within the same niche divides symmetrically to restore the original number. The most important human malignancies arise from tissues maintained by stem cells, and there is increasing evidence that stem cells are the targets for at least the initial genetic changes that occur during carcinogenesis. If a subset of stem cells within a niche arises containing an oncogenic mutation, then tumor suppressor mechanisms promote apoptosis of these cells, and the niche restores the original number of stem cells by replication of both normal and mutated stem cells. Thus, paradoxically apoptosis increases turnover of mutant cells with associated risk of further genetic changes. However, if in addition mutant cells can become senescent, then the niche is progressively filled by senescent cells until either the mutant cells are eliminated or the niche is completely occupied by postmitotic cells, thereby preventing further evolution of the neoplastic clone. The consequences of this hypothesis are explored by computer modeling.
The Aging/Precancerous Gastric Mucosa: A Pilot Nutraceutical Trial
Authors: MAROTTA F , BARRETO R , TAJIRI H , BERTUCCELLI J , SAFRAN P , YOSHIDA C , FESCE E
Published: July 2004

Abstract: The aim of this study was to test the effect of antioxidant supplementation on enzymatic abnormalities and free radical‐modified DNA adducts associated with premalignant changes in the gastric mucosa of elderly patients with HP‐negative atrophic gastritis (CAG). Sixty patients with atrophic gastritis and intestinal metaplasia underwent a nutritional interview and a gastroscopy with multiple biopsy samples in the antrum that were processed for histology and for assaying: alpha‐tocopherol, MDA, xanthine oxidase (XO), ornithine decarboxylase (ODC), and 8‐OHdG. Patients were randomly allocated into three matched groups and supplemented for 6 months with (1) vitamin E, 300 mg/day; (2) multivitamin, two tablets t.i.d.; and (3) Immun‐Age 6 g/day nocte (ORI, Gifu, Japan), a certified fermented papaya preparation with basic science‐validated antioxidant/immunomodulant properties. Ten dyspeptic patients served as controls. Histology and biochemistry were blindly repeated at 3 and 6 months. CAG patients showed a significantly (P < .05) increased level of mucosal MDA and XO concentration that were reverted to normal by each supplementation (P < .05). All supplements caused a significant decrease of ODC (P < .01), but Immun‐Age yielded the most effective (P < 0.05) and was the only one significantly decreasing 8‐OhdG (P < 0.05). These data suggest that antioxidant supplementation, and, namely, Immun‐Age, might be potential chemopreventive agents in HP‐eradicated CAG patients and especially in the elderly population.
Functional Analysis of Clusterin/Apolipoprotein J in Cellular Death Induced by Severe Genotoxic Stress
Authors: TROUGAKOS IOANNIS P. , GONOS EFSTATHIOS S.
Published: July 2004

Abstract: Clusterin/apolipoprotein J (CLU) is a secreted heterodimeric glycoprotein that is reportedly upregulated during tumorigenesis, as well as during cell injury or death. Despite extensive efforts, CLU function during cellular death remains largely elusive. We are using as a model system to study CLU function three human osteosarcoma (OS) cell lines, namely, Sa OS, KH OS, and U‐2 OS cells, induced to die after exposure to severe genotoxic stress mediated by the chemotherapeutic drug doxorubicin (DXR). We initially applied small interfering RNA (siRNA)‐mediated specific knockdown of the CLU protein in OS cells. In all three cell lines, CLU knockdown resulted in increased sensitization to DXR‐induced apoptosis. Supportively, moderate levels of forced transgene‐mediated CLU stable overexpression in KH OS cells could rescue them from DXR‐mediated apoptosis. In contrast, stable overexpression of high CLU levels in Sa OS and U‐2 OS cells augmented apoptosis induced by cell exposure to severe DXR‐mediated genotoxic stress. In summary, our data provide evidence that, although CLU is essential for cellular homeostasis, it may become highly cytotoxic in certain cellular contexts when it accumulates in high amounts intracellularly either by direct synthesis or by uptake from the extracellular milieu.
Evidence of Preferential Protein Targets for Age‐Related Modifications in Peripheral Blood Lymphocytes
Authors: POGGIOLI SYLVIE , MARY JEAN , BAKALA HILAIRE , FRIGUET BERTRAND
Published: July 2004

Abstract: Oxidatively modified proteins have been analyzed in aging human peripheral blood lymphocytes since protein modification by oxidation and other related pathways are believed to contribute to the intracellular age‐related accumulation of damaged proteins, a process that has been associated with the cellular functional deficits that occur with age. Advanced glycation end products (AGE) were quantified and the pattern of glycated proteins analyzed by two‐dimensional gel electrophoresis followed by Western blotting using an anti‐AGE antibody raised against glycated RNAse. The protein silver stain and the immunoblot patterns were not superimposable, indicating that glycoxidative modifications are targeting only a restricted set of proteins. Modification of proteins with the lipid peroxidation product 4‐hydroxy‐2‐nonenal has also been studied. The patterns of modified proteins have been analyzed using two‐ dimensional gel electrophoresis followed by Western blotting with an antibody recognizing 4‐hydroxy‐2‐nonenal protein adducts using the same proteomic approach as for glycoxidative modifications. Specific protein targets for these modifications, that might serve as biomarkers of aging lymphocytes, are currently characterized and identified by mass spectrometry.
Protective Effects of Mutant Ubiquitin in Transgenic Mice
Authors: GRAY D A , TSIRIGOTIS M , BRUN J , TANG M , ZHANG M , BEYERS M , WOULFE J
Published: July 2004

Abstract: The K48R mutant ubiquitin can exert profound in vivo protective effects against a variety of insults, including agents of direct clinical relevance. The manipulation of the ubiquitin/proteasome pathway has enormous potential for clinical benefit, and it is not unreasonable to expect that such benefits will include diseases of aging.
Algae Extract Protection Effect on Oxidized Protein Level in Human Stratum Corneum
Authors: NIZARD CARINE , POGGIOLI SYLVIE , HEUSÈLE CATHERINE , BULTEAU ANNE‐LAURE , MOREAU MARIELLE , SAUNOIS ALEX , SCHNEBERT SYLVIANNE , MAHÉ CHRISTIAN , FRIGUET BERTRAND
Published: July 2004

Abstract: Modification of proteins by reactive oxygen species is implicated in different disorders. The proteasome is a multicatalytic proteinase in charge of intracellular protein turnover and of oxidized proteins degradation. Consequently, proteasome function is very important in controlling the level of altered proteins in eukaryotic cells. Evidence for a decline in proteasome activity during skin photo‐aging has been provided in Bulteau et al. in 2002. The ability of a lipid algae extract (Phaeodactylum tricornutum) to stimulate 20S proteasome peptidase activities was described by Nizard et al. in 2001. Furthermore, keratinocytes treated with Phaeodactylum tricornutum extract and then UVA and UVB irradiated, exhibited a sustained level of proteasome activitiy comparable to the one of nonirradiated cells. The level of modified proteins can be quantified by measurement of protein carbonyl content (Oxyblot technique), which has been shown to increase with aging and other disorders. In this paper, it is described that, in the presence of this lipid algae extract, the level of oxidized proteins is reduced, as assessed by the Oxyblot technique. These results are obtained both with culture of human keratinocytes and stratum corneum skin cells (obtained by stripping) from human volunteers. Altogether, these results argue for the presence of compounds in this algae extract that have a stimulating and/or protective effect on proteasome activity, resulting in a decreased level of protein oxidation.
RAGE: A New Pleiotropic Antagonistic Gene?
Authors: SIMM A , BARTLING B , SILBER R‐E
Published: July 2004

Abstract: Advanced glycation end products (AGEs) are the result of a nonenzymatic reaction of reducing sugars with primary amino groups of proteins (Maillard reaction). They accumulate in various tissues in the course of aging. Because AGEs induce protein cross‐links and oxidative stress (radicals) within cells and tissues, they have been implicated in the development of many degenerative diseases. Binding of AGEs to receptors like RAGE induces the release of profibrotic cytokines, such as TGF‐β or proinflammatory cytokines, such as TNF‐α or IL‐6. AGE inhibitors or breakers, such as aminoguanidine or ALT‐711, inhibit the age‐induced heart hypertrophy or stiffness of the large arteries. On the other hand, little is known about the physiological role of RAGE as the receptor of AGEs. Investigations about the expression of RAGE in lung tissue and lung tumors may give a hint for such a role.
Genomic Instability, Aging, and Cellular Senescence
Authors: BUSUTTIL RITA A. , DOLLÉ MARTIJN , CAMPISI JUDITH , VIJGA JAN
Published: July 2004

Abstract: Aging can be defined in practical terms as a series of time‐related processes that ultimately bring life to a close. Genomic instability has been implicated as a major causal factor in aging. Here, we describe the use of a transgenic mouse model, harboring lacZ reporter genes as part of a plasmid construct integrated at one or more chromosomal locations, to study genomic instability during aging of different mouse organs and tissues as well as in mouse embryonic fibroblasts during primary culture.
Camptothecin Sensitivity in Werner Syndrome Fibroblasts as Assessed by the COMET Technique
Authors: LOWE J , SHEERIN A , JENNERT‐BURSTON K , BURTON D , OSTLER E L , BIRD J , GREEN M H L , FARAGHER R G A
Published: July 2004

Abstract: Werner syndrome (WS) is an inherited genetic disease in which individuals display the premature aging of a selected subset of tissues. The disorder results from the loss of function mutations in the wrn gene. Wrn codes for a member of the RecQ helicase family with a unique nuclease domain. There is significant evidence that the role of wrn is to assist in the repair and reinitiation of DNA replication forks that have stalled. Loss of the wrn helicase imposes a distinct set of phenotypes at the cellular level. These include premature replicative senescence (in a subset of cell types), chromosomal instability, a distinct mutator phenotype, and hypersensitivity to a limited number of DNA damaging agents. Unfortunately, most of these phenotypes are not suitable for the rapid assessment of loss of function of the wrn gene product. However, WS cells have been reported to show abnormal sensitivity to the drug camptothecin (an inhibitor of topoisomerase type I). A rapid assay for this sensitivity would be a useful marker of loss of wrn function. The COMET (single‐cell gel electrophoresis) assay is a rapid, sensitive, versatile, and robust technique for the quantitative assessment of DNA damage in eukaryotic cells. Using this assay, we have found that a significantly increased level of strand breaks can be demonstrated in WS cells treated with camptothecin compared with normal controls.
Mitochondrial Dysfunction Is a Common Phenotype in Aging and Cancer
Authors: SINGH KESHAV K.
Published: July 2004

Abstract: An interesting clue with regard to molecular mechanisms underlying age‐associated cancers is the apparent defect in mitochondrial function. Recent studies demonstrate a progressive decline in mitochondrial function during aging. Studies have established that the decline in mitochondrial function is due to the accumulation of mutations in mitochondrial DNA. These observations suggest that the mitochondrial dysfunction that accompanies aging may exert a major influence on carcinogenesis.