bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrastructural effects of lead acetate on brain of rats
Authors: Deveci Engin
Published: April 2007

Lead is a metal that has been implicated in toxic processes, which affect several organ systems in humans and other animals. The purpose of this study was to investigate the ultrastructural effects of lead on the brain of rats.Wistar Albino rats (180-200 g body weight) were divided into a controlled and lead acetate-exposed group. Rats received lead acetate at 500 ppm in their drinking water for 60 days. Both groups were fed with the same standard food, but lead acetate was added to the drinking water. During the experimental period, blood samples were drawn from the abdominal aorta of the anesthetised animals. At the end of exposure, body weight and blood lead levels were measured. The brain tissue samples were preapared and analysed by light and transmission electron microscopy. In the brain cortex, degeneration in some of the neuron cells, in the lumens of the blood vessels, dilation, hemorhagia and free floating erytrocytes were observed. Ultrastructural changes were revealed in the form of vacularisation of cell cytoplasm and degeneration in mitochondria, in the perinuclear cytoplasm, electron-dense inclusion bodies were detected, and dilation were in the endopasmic reticulum. Toxicology and Industrial Health 2006; 22: 419-422.
Evaluation of toxic metals in biological samples (scalp hair, blood and urine) of steel mill workers by electrothermal atomic absorption spectrometry
Authors: Afridi Hassan I , Kazi Tasneem G , Jamali Mohammad K , Kazi Gul H , Arain Mohammad B , Jalbani Nusrat , Shar Ghulam Q , Sarfaraz Raja A
Published: April 2007

The determination of toxic metals in the biological samples of human beings is an important clinical screening procedure. This study aimed to assess the possible influence of environmental exposure on production workers (PW) and quality control workers (QCW) of a steel mill, all male subjects aged 25-55 years. In this investigation, the concentrations of Pb, Cd, Ni and Cr were determined in biological samples (blood, urine and scalp hair samples) from these steel mill workers in relation to controlled unexposed healthy subjects of the same age group. After pre-treatment with nitric acid-hydrogen peroxide, the samples were digested via a microwave oven, and for comparison purposes, the same samples were digested by the conventional wet acid digestion method. The samples digested were subjected to graphite furnace atomic absorption spectrometry (GFAAS).

To assess the reliability of these methods, critical factors, such as detection limit(s), calibration range(s), accuracy and precision, were studied. Quality control for these procedures was established with certified sample of human hair, urine and whole blood. The results indicate that the level of lead, cadmium and nickel in scalp hair, blood and urine samples were significantly higher in both groups of exposed workers (QW and PW) than those of the controls. The possible connection of these elements with the etiology of disease is discussed. The results also show the need for immediate improvements in workplace ventilation and industrial hygiene practices. Toxicology and Industrial Health 2006; 22: 381-393.
Self-Efficacy as a Predictor to PFMT Adherence in a Prevention of Urinary Incontinence Clinical Trial
Authors: Messer Kassandra L. , Hines Sandra H. , Raghunathan T.E. , Seng Julia S. , Diokno Ananias C. , Sampselle Carolyn M.
Published: April 2007

Past research suggests a positive correlation between self-efficacy (SE) and adherence to behavioral interventions. Less is known about SE and adherence in behavioral programs that are preventive in nature and specific to urinary incontinence (UI). Using treatment-group data from a previously reported randomized controlled trial, the authors assess the role of SE in predicting adherence to pelvic-floor muscle training (PFMT) for UI prevention in a sample of postmenopausal women. Results indicate that at 12 months follow-up, nearly 70% of participants reported medium or high adherence, performing the recommended PFMT regimen 2 to 3 times per week or more. Summary scores of both Task SE, β = .25, SE (β) = .08, p < .01, and Regulatory SE, β = .43, SE (β) = .06, p < .0001, predict adherence. Also, the authors found a modest decline in self-efficacy scores over time. These findings highlight the importance of SE in sustained behavioral change.
Diffusion of Clean Indoor Air Ordinances in the Southwestern United States
Authors: Rogers Everett M. , Peterson Jeffery C.
Published: April 2007

The authors investigate the process through which clean indoor air ordinances were considered in 10 communities in the southwestern United States and key factors that influenced diffusion and adoption. Clean indoor air ordinances, which ban smoking in public places, were adopted in approximately 1,409 U.S. communities from 1986 to April 2004. The authors gathered data from 10 communities in New Mexico and Texas by means of face-to-face interview, e-mail, and telephone interviews and by analyzing archival materials. Important influences on the adoption or rejection of clean indoor air ordinances were (a) personal experiences of policy champions, (b) local framing of the ordinance as a public health issue versus as an economic/ business or an individual rights issue, and (c) interpersonal networks connecting a community to previously adopting communities. The policies that were adopted ranged in comprehensiveness, with each community of study reinventing model policies obtained from other communities.
The Pragmatics of Passion: A Sociology of Attachment to Mathematics
Authors: Landri Paolo
Published: April 2007

This paper addresses the question of the intertwining of practice and passion in scientific work, considering passion as a collective attachment to the subjects and objects of knowledge in an epistemic community. The paper draws on a research program on Renato Caccioppoli (1904—59), the famous Italian mathematician, and the group of mathematicians he used to work with, showing the use of sociology of attachment in the description of the link between practice, passion and knowledge. The research followed a qualitative methodology and focused on interviews and documents (letters, books, movies analysis, newspapers' articles) on historical and contemporary accounts of schools of mathematics and epistemic communities. This paper unfolds in three parts: a brief focus on the theoretical framework of the research; the analyses of the practices for mobilizing passion used by the mathematicians emerging from the research program; the discussion of the relevance of our first findings and the indication of future directions for the research.
Pleasure and Pedagogy
Authors: Brereton Pat , O'Connor Barbara
Published: April 2007

This article addresses the issue of young people and media use in the digital age, more specifically the interconnection between new media pleasures and pedagogy as they relate to the consumption of DVD add-ons. Arguing against the view of new media as having predominantly detrimental effects on young people, the authors claim that new media can enable young people to develop media literacy skills and are of the view that media literacy strategies must be based on an understanding and legitimating of young people's use patterns and pleasures. The discussion is based on a pilot research project on the use patterns and pleasures of use with a sample of Irish teenagers. They found that DVDs were used predominantly in the home context, and that, while there was variability in use between the groups, overall they developed critical literacy skills and competences which were interwoven into their social life and projects of identity construction. The authors suggest that these findings could be used to develop DVDs and their add-on features as a learning resource in the more formal educational setting and they go on to outline the potential teaching benefits of their use across a range of pedagogical areas.
FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia
Authors: Mead Adam J. , Linch David C. , Hills Robert K. , Wheatley Keith , Burnett Alan K. , Gale Rosemary E.
Published: April 2007

The prognostic impact of tyrosine kinase domain (TKD) mutations of the fms-like tyrosine kinase-3 (FLT3) gene in acute myeloid leukemia (AML) is currently uncertain. To resolve this issue we screened 1107 young adult nonacute promyelocytic leukemia AML patients with known FLT3 internal tandem duplication (ITD) status for FLT3/TKDs; they were detected in 127 (11%) cases. Mutations were associated with a high white cell count (P =.006) and patients with inv(16) (P = .005) but were infrequent in patients with adverse cytogenetics and secondary AML. Overall survival (OS) at 5 years was 53% and 37% for FLT3/TKD mutant and wild-type patients respectively (odds ratio, 0.72; 95% confidence interval, 0.58 to 0.89; P = .002). For both the cumulative incidence of relapse and OS the difference in outcome between FLT3/ITDs and FLT3/TKDs was highly significant (P < .001). In multivariate analysis, impact of FLT3/TKDs on OS when including all mutant-positive patients was not significant, but patients with high-level mutations (more than 25% mutant) had a significantly improved outcome (P = .004). The novel finding that biologically distinct activating mutations of the same gene can be associated with markedly different clinical outcomes has implications for risk stratification and therapy and is significant to the understanding of chemoresistance in AML.
Effects of age-dependent membrane transport changes on the homeostasis of senescent human red blood cells
Authors: Lew Virgilio L. , Daw Nuala , Etzion Zipora , Tiffert Teresa , Muoma Adaeze , Vanagas Laura , Bookchin Robert M.
Published: April 2007

Little is known about age-related changes in red blood cell (RBC) membrane transport and homeostasis. We investigated first whether the known large variation in plasma membrane Ca2+ (PMCA) pump activity was correlated with RBC age. Glycated hemoglobin, Hb A1c, was used as a reliable age marker for normal RBCs. We found an inverse correlation between PMCA strength and Hb A1c content, indicating that PMCA activity declines monotonically with RBC age. The previously described subpopulation of high-Na+, low-density RBCs had the highest Hb A1c levels, suggesting it represents a late homeostatic condition of senescent RBCs. Thus, the normal densification process of RBCs with age must undergo late reversal, requiring a membrane permeability increase with net NaCl gain exceeding KCl loss. Activation of a nonselective cation channel, Pcat, was considered the key link in this density reversal. Investigation of Pcat properties showed that its most powerful activator was increased intracellular Ca2+. Pcat was comparably selective to Na+, K+, choline, and N-methyl-D-glucamine, indicating a fairly large, poorly selective cation permeability pathway. Based on these observations, a working hypothesis is proposed to explain the mechanism of progressive RBC densification with age and of the late reversal to a low-density condition with altered ionic gradients.
A set of genes that regulate cell proliferation predicts treatment outcome in childhood acute lymphoblastic leukemia
Authors: Flotho Christian , Coustan-Smith Elaine , Pei Deqing , Cheng Cheng , Song Guangchun , Pui Ching-Hon , Downing James R. , Campana Dario
Published: April 2007

To identify novel predictors of outcome in childhood acute lymphoblastic leukemia (ALL), we analyzed gene expression in the leukemic cells of 187 children with newly diagnosed ALL and compared the findings with minimal residual disease (MRD) results obtained on day 19 of remission induction treatment. Genes that showed a significant relationship to MRD were then tested for their capacity to predict leukemic relapse in an independent cohort of 99 patients. We identified 674 probe sets that were associated with MRD on day 19 (P < .006); 40 of the identified genes predicted relapse (P < .03). Among these, 14 showed independent prognostic significance after adjustment for age, leukocyte count at diagnosis, and genetic subtype. More than half of the 40 genes and nearly all of the 14 genes were functionally related, as indicated by their roles in the regulation of cell proliferation. Underexpression of genes promoting cell proliferation was associated with resistance to chemotherapy. The biologic processes regulated by the genes we identified appear to be key determinants of the early cytoreductive response to remission induction therapy and subsequent clinical outcome in childhood ALL. Incorporation of the expression levels of these genes into existing strategies of risk classification could improve clinical management.
Developmental- and differentiation-specific patterns of human γ- and β-globin promoter DNA methylation
Authors: Mabaera Rodwell , Richardson Christine A. , Johnson Kristin , Hsu Mei , Fiering Steven , Lowrey Christopher H.
Published: April 2007

The mechanisms underlying the human fetal-to-adult β-globin gene switch remain to be determined. While there is substantial experimental evidence to suggest that promoter DNA methylation is involved in this process, most data come from studies in nonhuman systems. We have evaluated human γ- and β-globin promoter methylation in primary human fetal liver (FL) and adult bone marrow (ABM) erythroid cells. Our results show that, in general, promoter methylation and gene expression are inversely related. However, CpGs at −162 of the γ promoter and −126 of the β promoter are hypomethylated in ABM and FL, respectively. We also studied γ-globin promoter methylation during in vitro differentiation of erythroid cells. The γ promoters are initially hypermethylated in CD34+ cells. The upstream γ promoter CpGs become hypomethylated during the preerythroid phase of differentiation and are then remethylated later, during erythropoiesis. The period of promoter hypomethylation correlates with transient γ-globin gene expression and may explain the previously observed fetal hemoglobin production that occurs during early adult erythropoiesis. These results provide the first comprehensive survey of developmental changes in human γ- and β-globin promoter methylation and support the hypothesis that promoter methylation plays a role in human β-globin locus gene switching.
Epitope specificity and isotype of monoclonal anti-D antibodies dictate their ability to inhibit phagocytosis of opsonized platelets
Authors: Kjaersgaard Mimi , Aslam Rukhsana , Kim Michael , Speck Edwin R. , Freedman John , Stewart Donald I. H. , Wiersma Erik J. , Semple John W.
Published: April 2007

Rh immune globulin (WinRho SDF; Cangene, Mississauga, ON, Canada) is an effective treatment for autoimmune thrombocytopenic purpura; however, maintaining a sustained supply for its use in autoimmune thrombocytopenic purpura and its primary indication, hemolytic disease of the newborn, makes the development of alternative reagents desirable. We compared Rh immune globulin and 6 human monoclonal anti-D antibodies (MoAnti-D) with differing isotypes and specificities for their ability to opsonize erythrocytes and inhibit platelet phagocytosis in an in vitro assay. Results demonstrated that opsonization of erythrocytes with Rh immune globulin significantly (P < .001) reduced phagocytosis of fluorescently labeled opsonized platelets in an Fc-dependent manner. Of the MoAnti-D that shared specificity but differed in isotype, only IgG3 antibodies could significantly (P < .001) inhibit platelet phagocytosis. In contrast, 2 MoAnti-D shared isotypes and differed in specificity; however, only one could significantly (P < .001) inhibit platelet phagocytosis. The results suggest that MoAnti-D epitope specificity and isotypes are critical requirements for optimal inhibition of opsonized platelet phagocytosis.
G-protein-coupled receptor expression, function, and signaling in macrophages
Authors: Lattin Jane , Zidar David A , Schroder Kate , Kellie Stuart , Hume David A , Sweet Matthew J
Published: April 2007

G-protein-coupled receptors (GPCRs) are widely targeted in drug discovery. As macrophages are key cellular mediators of acute and chronic inflammation, we review here the role of GPCRs in regulating macrophage function, with a focus on contribution to disease pathology and potential therapeutic applications. Within this analysis, we highlight novel GPCRs with a macrophage-restricted expression profile, which provide avenues for further exploration. We also review an emerging literature, which documents novel roles for GPCR signaling components in GPCR-independent signaling in macrophages. In particular, we examine the crosstalk between GPCR and TLR signaling pathways and highlight GPCR signaling molecules which are likely to have uncharacterized functions in this cell lineage.
Large defects of type I allergic response in telomerase reverse transcriptase knockout mice
Authors: Ujike-Asai Azusa , Okada Aki , Du Yuchen , Maruyama Mitsuo , Yuan Xunmei , Ishikawa Fuyuki , Motoo Yoshiharu , Isobe Kenichi , Nakajima Hideo
Published: April 2007

Telomerase is critically important for the maintenance of a constant telomere length, which in turn, is related to the concepts of longevity and oncogenesis. In addition, it has been well documented that telomerase activity is expressed in immune cells in a highly regulated manner. We have studied systemic anaphylaxis in mouse telomerase reverse transcriptase knockout (mTERT−/−) mice to understand the significance of telomerase activity and telomere stability in mast cells, which induce a type I allergic response. Compared with wild-type mice, mTERT−/− mice displayed largely attenuated, IgE-mediated, passive anaphylactic responses, which were observed even in the early generations of mTERT−/− mice, and had decreased numbers of mast cells in vivo and impaired development of bone marrow-derived mast cells (BMMCs) induced by IL-3 or stem cell factor in vitro. Moreover, in mTERT−/− mice, BMMCs exhibited a large morphology and low proliferation rate, while they possessed a comparable degranulation capacity and cell surface expression level of c-kit and FcεRI. These findings imply that telomerase activity has a definitive impact on the type I allergic response by altering the character of effecter mast cells.
Genetics of Healthy Aging in Europe
Authors: FRANCESCHI CLAUDIO , BEZRUKOV VLADYSLAV , BLANCHÉ HÉLÈNE , BOLUND LARS , CHRISTENSEN KAARE , BENEDICTIS GIOVANNA DE , DEIANA LUCA , GONOS EFSTHATIOS , HERVONEN ANTTI , YANG HUANNING , JEUNE BERNARD , KIRKWOOD TOM B. L. , KRISTENSEN PETER , LEON ALBERTA , PELICCI PIER GIUSEPPE , PELTONEN LEENA , POULAIN MICHEL , REA IRENE MAEVE , REMACLE JOSÉ , ROBINE JEAN MARIE , SCHREIBER STEFAN , SIKORA EWA , SLAGBOOM PIETERNELLA ELINE , SPAZZAFUMO LIANA , STAZI MARIA ANTONIETTA , TOUSSAINT OLIVIER , VAUPEL JAMES W.
Published: April 2007

Abstract:  The aim of the 5‐year European Union (EU)‐Integrated Project GEnetics of Healthy Aging (GEHA), constituted by 25 partners (24 from Europe plus the Beijing Genomics Institute from China), is to identify genes involved in healthy aging and longevity, which allow individuals to survive to advanced old age in good cognitive and physical function and in the absence of major age‐related diseases. To achieve this aim a coherent, tightly integrated program of research that unites demographers, geriatricians, geneticists, genetic epidemiologists, molecular biologists, bioinfomaticians, and statisticians has been set up. The working plan is to: (a) collect DNA and information on the health status from an unprecedented number of long‐lived 90+ sibpairs (n= 2650) and of younger ethnically matched controls (n= 2650) from 11 European countries; (b) perform a genome‐wide linkage scannning in all the sibpairs (a total of 5300 individuals); this investigation will be followed by linkage disequilibrium mapping (LD mapping) of the candidate chromosomal regions; (c) study in cases (i.e., the 2650 probands of the sibpairs) and controls (2650 younger people), genomic regions (chromosome 4, D4S1564, chromosome 11, 11.p15.5) which were identified in previous studies as possible candidates to harbor longevity genes; (d) genotype all recruited subjects for apoE polymorphisms; and (e) genotype all recruited subjects for inherited as well as epigenetic variability of the mitochondrial DNA (mtDNA). The genetic analysis will be performed by 9 high‐throughput platforms, within the framework of centralized databases for phenotypic, genetic, and mtDNA data. Additional advanced approaches (bioinformatics, advanced statistics, mathematical modeling, functional genomics and proteomics, molecular biology, molecular genetics) are envisaged to identify the gene variant(s) of interest. The experimental design will also allow (a) to identify gender‐specific genes involved in healthy aging and longevity in women and men stratified for ethnic and geographic origin and apoE genotype; (b) to perform a longitudinal survival study to assess the impact of the identified genetic loci on 90+ people mortality; and (c) to develop mathematical and statistical models capable of combining genetic data with demographic characteristics, health status, socioeconomic factors, lifestyle habits.
Cross‐Talk between Aging and Cancer
Authors: FRAGA MARIO F. , AGRELO RUBEN , ESTELLER MANEL
Published: April 2007

Abstract:  The risk of having cancer increases with age probably because progenitor cells from mature organisms accumulate enough molecular lesions to evade the homeostatic control of their tissular contexts. Molecular lesions can be genetic (mutations, deletions, or translocations) and/or epigenetic. Epigenetic signaling, including DNA methylation and histone modification, is essential for normal development and becomes altered during Aging and by cancer. Several epigenetic alterations, such as global hypomethylation and CpG island hypermethylation, are progressively accumulated during Aging and directly contribute to cell transformation. Intriguingly, others, such as those involved in the control of telomere length and several epigenetic enzymes belonging to the family of nicotinamide adenine dinucleotide (NAD)(+) dependent deacetylases known as sirtuins, exhibit a well‐defined progression during Aging that is dramatically reverted in transformed cells. We discuss the biological significance of both groups of epigenetic modifications in terms of their relative contribution to ontogenic development, senescence, and cell proliferation.
Genetics of Inflammation in Age‐Related Atherosclerosis
Authors: GRIMALDI MARIA PAOLA , VASTO SONYA , BALISTRERI CARMELA RITA , DI CARLO DANIELE , CARUSO MARCO , INCALCATERRA EGLE , LIO DOMENICO , CARUSO CALOGERO , CANDORE GIUSEPPINA
Published: April 2007

Abstract:  In response to tissue injury elicited by trauma or infection, the inflammatory response, as a complex network of molecular and cellular interactions, sets an answer directed to facilitate a return to physiological homeostasis and tissue repair. The role of the genetic background and the subsequent predisposition toward the extent of the inflammatory response is determined by gene variability encoding endogenous mediators involved in the inflammatory pathway. Due to its clinical relevance, the genetics of inflammation in aging will be studied using an inflammatory disease like atherosclerosis as an example. Several studies have reported a significant difference in distribution, between patients and controls, of genes involved in inflammation. So, the proinflammatory alleles are underrepresented in control subjects and overrepresented in patients affected by atherosclerosis. These studies will allow building a risk profile that potentially enables the early identification of individuals susceptible to disease and the possible design or use of drug at the right dose for a desired effect, that is, a pharmacogenomic approach for this disease.
Lumbar Spinal Stenosis in Elderly Patients
Authors: KAPTAN HULAGU , KASIMCAN OMUR , CAKIROGLU KUTAY , ILHAN MUSTAFA NECMI , KILIC CELAL
Published: April 2007

Abstract:  Over a 3‐year period in our clinic, surgeons operated on 32 persons over 65 years old with lumbar spinal stenosis. This article presents the retrospective analysis of the clinical, radiological, and short‐term surgical outcomes. The stenosis seen most commonly among the elderly develops focally at the intervertebral junctions as a result of a complex process of disc degeneration, facet arthropathy, ligamentum flavum hypertrophy, spondylosis, and sometimes spondylolisthesis. All patients underwent a midline decompressive laminectomy with foraminotomies at the affected levels, and discectomy was performed in persons with lumbar disc hernia. Average age was 71.15 ± 5.09 (65–80); 50% (16) were women, and 50% (16) were men. The most frequent symptoms were pain (96.9%) and neurological claudication (90.6%). The average preoperative duration of the symptoms was 139.87 ± 115.03 weeks. The most frequent neurological symptoms were reflex disturbances (62.5%), Lasèques's sign (SLR) (+)(53%), and motor deficit (50%). The anteroposterior diameter of the spinal canal was less than 11.5 mm in 71.9% of the cases. In 62.5% of the patients, partial recovery was observed in the short term; 68.8% of the patients underwent laminectomy. Of those, 87.5% had total and 12.5% had partial laminectomies. In addition to laminectomy, discectomy was performed in 31.3% of the patients. Total laminectomy was more likely to be performed on patients older than 65 years, because the anteroposterior diameter was more likely to be below 11.5 mm in this cohort of patients. In lumbar stenosis, surgical treatment—decompression—is an effective method. Surgery has been demonstrated to be effective even in patients over the age of 75 years.
PGC‐1α‐Induced Mitochondrial Alterations in 3T3 Fibroblast Cells
Authors: LIANG HUIYUN , BAI YIDONG , LI YOUFEN , RICHARDSON ARLAN , WARD WALTER F.
Published: April 2007

Abstract:  Peroxisome proliferation activator receptor (PPAR) γ‐coactivator 1α (PGC‐1α), a transcription coactivator, functions as a master regulator of a wide array of metabolic and physiological processes and is an essential factor in the process of mitochondrial biogenesis. Transfection of NIH 3T3 fibroblasts with a mouse cDNA for PGC‐1α led to the induction of markers of mitochondrial biogenesis, that is, mitochondrial transcription factor A (mtTFA), cytochrome c, and mitochondrial DNA (mtDNA). Mitochondrial biogenesis‐associated net protein synthesis appears to be accomplished by a reduction in the rate of mitochondrial protein degradation with little or no change in the rate of protein synthesis. Overexpression of PGC‐1α did not adversely affect cellular proliferation. Cellular ATP levels were increased in the transfected cells and they were more resistant to oxidative stress than the control nontransfected 3T3 cells. This resistance to oxidative stress was manifested by both an improved viability and the maintenance of mitochondrial membrane potential in the transfected cells when exposed to t‐butyl hydroperoxide (t‐BOOH). It therefore appears that PGC‐1α overexpression stimulates mitochondrial biogenesis in 3T3 cells making them more resistant to oxidative stressors.
Proteome Alterations in Rat Mitochondria Caused by Aging
Authors: DENCHER NORBERT A. , FRENZEL MONIKA , REIFSCHNEIDER NICOLE H. , SUGAWA MICHIRU , KRAUSE FRANK
Published: April 2007

Abstract:  Analysis of the protein profile of mitochondria and its age‐dependent variation is a promising approach to unravel mechanisms involved in aging and age‐related diseases. Our studies focus on the mammalian mitochondrial membrane proteome, especially of the inner mitochondrial membrane with the respiratory chain complexes and other proteins possibly involved in life‐span control and aging. Variations of the mitochondrial proteome during aging, with the emphasis on the abundance, composition, structure, and activity of membrane proteins, are examined in various rat tissues by native polyacrylamide gel electrophoresis techniques in combination with MALDI‐TOF mass spectrometry. In rat brain, age‐modulated differences in the abundance of various mitochondrial and nonmitochondrial proteins, such as Na,K‐ATPase, HSP60, mitochondrial aconitase‐2, V‐type ATPase, MFoF1 ATP synthase, and the OXPHOS complexes I–IV are detected. During aging, a decrease in the amount of intact MFoF1 ATP synthase occurs in the cortex. As analytical technique, native PAGE separates not only individual proteins but also multi‐subunit (membrane) proteins, (membrane) protein supercomplexes as well as interacting proteins in their native state. It reveals the occurrence and architecture of supramolecular assemblies of proteins. The age‐related alterations in the oligomerization of the MFoF1 ATP synthase observed by us in rat cortex might be one clue for understanding the link between respiration and longevity. Also, the abundance of OXPHOS supercomplexes, that is, the natural assemblies of the respiratory complexes I, III, and IV into supramolecular stoichiometric entities, such as I1III2IV0‐4, can differ between young and aged cortex tissue. Age‐related changes in the supramolecular architecture of OXPHOS complexes might explain alterations in ROS production during aging.
The Role of the MORF/MRG Family of Genes in Cell Growth, Differentiation, DNA Repair, and Thereby Aging
Authors: PENA ANDREANA N. , PEREIRA‐SMITH OLIVIA M.
Published: April 2007

Abstract:  The discovery that replicative cellular senescence is a dominant phenotype over immortality led to the discovery that there are at least four unique genetic subgroups of immortal cell lines that use distinct mechanistic pathways to evade cell cycle exit. Study of one of these genetic complementation groups demonstrated that one gene, MORF4, possessed the ability to induce senescence in group B cell lines. The MRG family of genes, of which MORF4 is a member, has since proven important for cellular aging, proliferation, positive and negative transcriptional regulation, and DNA damage repair. MRG15, the evolutionary ancestor of the family, is highly conserved in yeast, C. elegans, drosophila, plants, and mammals and has been implicated in chromatin remodeling in these species. Our proteomics studies have found that MRG15 is unique among mammalian genes in that it associates with both histone deacetylases and histone acetyl transferase complexes, and thus potentially plays a role in both transcriptional silencing and activation. Its knockout in mice is embryonic lethal, resulting in improper organogenesis, as well as cell proliferation and DNA damage repair defects. Future study of these genes will help clarify the role of chromatin remodeling in aging, cellular proliferation, and DNA damage repair.
CARF Binds to Three Members (ARF, p53, and HDM2) of the p53 Tumor‐Suppressor Pathway
Authors: KAMRUL HASAN M. , WADHWA RENU , KAUL SUNIL C.
Published: April 2007

Abstract:  The INK4a locus (chromosome 9p21) encodes two structurally distinct tumor‐suppressor proteins, p16INK4a and the alternative reading frame protein, ARF (p19ARF in mouse and p14ARF in human). Each of these proteins has a major role in cell cycle control and senescence pathways. We originally identified a novel collaborator of ARF, CARF, from a two‐hybrid interactive screen using p19ARF as bait and found that CARF interacts with ARF in the perinucleolar region and activates p53 function. In the absence of ARF, it interacts with p53 directly leading to ARF‐independent enhancement of p53 function and in turn undergoes a negative feedback regulation. Very recently, we found that CARF interacts with HDM2 and undergoes degradation by an HDM2‐dependent proteasome pathway. CARF may exert a vital control on p53‐HDM2‐p21WAF1 pathway that is central to the cell cycle control, senescence, and DNA damage response of human cells.
β‐Galactosidase Activity as a Biomarker of Replicative Senescence during the Course of Human Fibroblast Cultures
Authors: MAIER ANDREA B. , WESTENDORP RUDI G. J. , VAN HEEMST DIANA
Published: April 2007

Abstract:  It has been called into question whether the commonly used β‐galactosidase staining is a reliable biomarker of cellular senescence because induction of β‐galactosidase activity also occurs independently of senescence. Here, we tested whether cytochemically detectable β‐galactosidase activity is reproducible and reflects the rate of cellular aging in vitro. Therefore, we serially cultured fibroblasts from 12 different donors and stained the cells for β‐galactosidase at pH 6 until the onset of the permanent growth arrest of the individual cultures. All fibroblast strains displayed a high replicative capacity with a similar growth pattern during the exponential growth phase and a very high interbiopsy variability in the onset of decreased mitotic activity and in the onset of growth arrest. Correspondingly, β‐galactosidase activity was low during the exponential growth phase, with an individually defined significant increase in activity when the growth speed of the culture decreased. The increase in β‐galactosidase activity was a better predictor for the onset of the decreased growth speed than the chronological life span of the culture expressed in population doublings. Within the phase of decreased mitotic activity, we observed a high fluctuation in the percentage of positively stained fibroblasts. Thus, our results support β‐galactosidase activity as a reliable biomarker for the course of replicative senescence, if used under defined standardized conditions.
A Dual Role of p21 in Stem Cell Aging
Authors: JU ZHENYU , CHOUDHURY AAHELI ROY , RUDOLPH K. LENHARD
Published: April 2007

Abstract: A decline in adult stem cell function occurs during aging, likely contributing to the decline in organ homeostasis and regeneration with age. An emerging field in aging research is to analyze molecular pathways limiting adult stem cell function in response to macromolecular damage accumulation during aging. Current data suggest that the p21 cell cycle inhibitor has a dual role in stem cell aging: On one hand, p21 protects adult stem cells from acute genotoxic stress by preventing inappropriate cycling of acutely damaged stem cells. On the other hand, p21 activation impairs stem cell function and survival of aging telomere dysfunctional mice indicating that p21 checkpoint function is disadvantageous in the context of chronic and persistent damage, which accumulates during aging. This article focuses on these dual roles of p21 in aging stem cells.
Vascular Smooth Muscle and Endothelial Functions in Aging
Authors: YILDIZ OGUZHAN
Published: April 2007

Abstract:  Aging is one of the main risk factors for the development of atherosclerosis and, therefore, for coronary artery disease. Age‐associated remodeling of the vascular wall includes luminal enlargement, intimal and medial thickening, and increased vascular stiffness. As aging occurs, smooth muscle cells (SMCs) progressively migrate from the tunica media and accumulate into the tunica intima. Aging also associates with changes of SMC proliferative and apoptotic behavior and response to growth factors, such as transforming growth factor‐β1. Aging induces a reduction in the density of the α‐subunit of Ca2+‐activated K+ channels in coronary smooth muscle and increases the response to endothelial constrictor factors and K+. Accordingly, we have recently shown that the vasodilatory effect of male sex hormone testosterone, which is mediated through large conductance Ca2+‐activated K+ channel opening action, decreases with age. Apart from age‐associated remodeling of the vascular wall, endothelial function declines with age. This is most obvious from the attenuation of endothelium‐dependent dilator responses, which is a consequence of the alteration in the expression and/or activity of the endothelial nitric oxide (NO) synthase, upregulation of the inducible NO synthase, and increased formation of reactive oxygen species. In fact, in the course of aging, there is an alteration in the equilibrium between relaxing and contracting factors released by the endothelium. Hence, there is a progressive reduction in the participation of NO and endothelium‐derived hyperpolarizing factor (EDHF) associated with increased participation of oxygen‐derived free radicals and cyclooxygenase‐derived prostanoids. Also, the endothelin‐1 and angiotensin II pathways may play a role in age‐related endothelial dysfunction. Aging is also associated with a reduction in the regenerative capacity of the endothelium and endothelial senescence, which is characterized by an increased rate of endothelial cell apoptosis. Thus, aging elicits several changes in the vascular endothelium gradually altering its phenotype from an anti‐ to a proatherosclerotic one. In conclusion, it becomes increasingly evident that the blood vessel structural and functional disturbances, which characterize vascular aging, make a major contribution to aging‐related target organ damage. The use of drugs, including antioxidant therapy, lipid‐lowering drugs, and estrogens, seems to be promising.
The Differentiation‐Associated Linker Histone, H1.0, during the in Vitro Aging and Senescence of Human Diploid Fibroblasts
Authors: SEKERI‐PATARYAS KALLIOPE E. , SOURLINGAS THOMAE G.
Published: April 2007

Abstract:  There are numerous similarities between aging/senescence and differentiation. One key similarity is that in both biological processes chromatin remodeling events occur. It is now known that during both processes there is a reorganization of eu‐ and heterochromatic domains and an increase in heterochromatin, known as heterochromatinization. Previous work of more than two decades has shown that the replacement H1 linker histone subtype, H1.0, accumulates during terminal differentiation in numerous cell/tissue systems. However, work with this differentiation‐associated H1 subtype in aging cell systems has only recently been accomplished. In this article, we outline the cumulative results from our investigations of H1.0 protein and mRNA levels in the in vitro aging cell system of human diploid fibroblasts (HDFs) and discuss the potential rationale of why this particular subtype was found to accumulate during both these processes.
Quantum Dot‐Based Mortalin Staining as a Visual Assay for Detection of Induced Senescence in Cancer Cells
Authors: KAUL ZEENIA , YAGUCHI TOMOKO , CHIURA HIROSHI X. , KAUL SUNIL C. , WADHWA RENU
Published: April 2007

Abstract:  Quantum dots (QDs) are fluorescent nanocrystals that are emerging as fine alternatives to the conventional organic dyes. They have several advantages including greater photostability and a wider range of excitation–emission wavelengths. By using mortalin staining as a model, we initially demonstrated that the QDs are more stable and provide better resolution in protein imaging in fixed cells. With the help of an internalizing antibody, we generated internalizing QD (i‐QD) and demonstrated its inertness to cell replication, structure, and viability. Based on the superior resolution, stability and inertness, we propose the use of QD staining of mortalin as a cell‐based visual assay to screen for senescence‐inducing drugs, proteins, and siRNAs.
Adult‐Limited Dietary Restriction Slows Gompertzian Aging in Caenorhabditis elegans
Authors: LENAERTS ISABELLE , EYGEN SYLVIE VAN , FLETEREN JACQUES VAN
Published: April 2007

Abstract:  Dietary restriction (DR) delays the onset of age‐related deterioration and extends the life span in a variety of model organisms. In many species, age changes in mortality obey the Gompertz equation, which describes an exponential increase with age in age‐specific mortality rate. Recently, this model has been used in fruitflies and rodents to investigate the mechanism by which DR reduces adult mortality. We report that food restriction imposed by axenic culture reduces the exponential increase of age‐specific mortality of Caenorhabditis elegans. Furthermore, the life span appears largely independent of nutritional status during development, as shown by shifting worms to different food concentrations shortly before adulthood. When DR was exerted after reproduction, a smaller reduction in Gompertzian aging was seen. Thus, the demographic changes exerted by DR in C. elegans resemble those seen in rats, yet are different to those seen in Drosophila and mice.
Fruit Polyphenols and Their Effects on Neuronal Signaling and Behavior in Senescence
Authors: JOSEPH JAMES A. , SHUKITT‐HALE BARBARA , LAU FRANCIS C.
Published: April 2007

Abstract:  The onset of age‐related neurodegenerative diseases superimposed on a declining nervous system could exacerbate the motor and cognitive behavioral deficits that normally occur in senescence. It is likely that, in cases of severe deficits in memory or motor function, hospitalization and/or custodial care would be a likely outcome. This means that unless some way is found to reduce these age‐related decrements in neuronal function, healthcare costs will continue to rise exponentially. Thus, it is extremely important to explore methods to retard or reverse the age‐related neuronal deficits as well as their subsequent, behavioral manifestations. Applying molecular biological approaches to slow aging in the human condition may be years away. So it is important to determine what methods can be used today to increase healthy aging, forestall the onset of these diseases, and create conditions favorable to obtaining a “longevity dividend” in both financial and human terms. In this regard, epidemiological studies indicate that consumption of diets rich in antioxidants and anti‐inflammatory compounds, such as those found in fruits and vegetables, may lower the risk of developing age‐related neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases (AD and PD). Research suggests that the polyphenolic compounds found in fruits, such as blueberries, may exert their beneficial effects by altering stress signaling and neuronal communication, suggesting that interventions may exert protection against age‐related deficits in cognitive and motor function. The purpose of this article is to discuss the benefits of these interventions in rodent models and to describe the putative molecular mechanisms involved in their benefits.
Psoralea corylifolia L. Inhibits Mitochondrial Complex I and Proteasome Activities in SH‐SY5Y Cells
Authors: TANG SOON YEW , GRUBER JAN , WONG KIM PING , HALLIWELL BARRY
Published: April 2007

Abstract:  The growing interest in alternative medicines, including traditional medicinal plants, has caused some health concerns due to poor awareness in the general population of the possible side effects from inappropriate practices. Psoralea corylifolia L. has been used in Chinese and Indian traditional medicine for the treatment of various inflammatory diseases of the skin and to improve vitality. Our data show that the extract obtained from the seeds of Psoralea corylifolia L. decreased mitochondrial complex I and proteasome activities; and oxidative stress might be an early event.
Effects of Deleting Mitochondrial Antioxidant Genes on Life Span
Authors: UNLU ERCAN SELCUK , KOC AHMET
Published: April 2007

Abstract:  Reactive oxygen species (ROS) damage biomolecules, accelerate aging, and shorten life span, whereas antioxidant enzymes mitigate these effects. Because mitochondria are a primary site of ROS generation and also a primary target of ROS attack, they have become a major focus area of aging studies. Here, we employed yeast genetics to identify mitochondrial antioxidant genes that are important for replicative life span. In our studies, it was found that among the known mitochondrial antioxidant genes (TTR1, CCD1, SOD1, GLO4, TRR2, TRX3, CCS1, SOD2, GRX5, PRX1), deletion of only three genes, SOD1 (Cu, Zn superoxide dismutase), SOD2 (Manganese‐containing superoxide dismutase), and CCS1 (Copper chaperone), shortened the life span enormously. The life span decreased 40% for Δsod1 mutant, 72% for Δsod2 mutant, and 50% for Δccs1 mutant. Deletion of the other genes had little or no effect on life span.
Influence of Aging and Enriched Environment on Motor Activity and Emotional Responses in Mice
Authors: ZAMBRANA CLAUSTRO , MARCO EVA M. , ARRANZ LORENA , De CASTRO NURIA M. , VIVEROS MARIA PAZ , FUENTE MÓNICA DE LA
Published: April 2007

Abstract:  We have evaluated different behavioral parameters in ICR (CD1) female mice of three different ages (38–39 weeks: mature; 62 weeks: late mature; 90 weeks: old), and addressed the effects of an enriched housing condition. We employed the following battery of tests: Holeboard, open field, elevated plus‐maze (EPM), and forced swimming test (FST). The results suggest that aging process differentially affects diverse aspects of behavior. With respect to motor activity, late mature animals were more affected by enrichment, whereas old animals appeared to be more affected when emotional responses were considered. We propose that the diminished percentage of time in the open arms of the EPM showed by enriched mice may be indicative of decreased novelty seeking, whereas their decreased climbing behavior may indicate a reduced escape‐related behavior in an inescapable situation.
Increased Acute Myocardial Infarction Rates and Cardiovascular Risk Factors among Patients with Human Immunodeficiency Virus Disease
Authors: Triant Virginia A. , Lee Hang , Hadigan Colleen , Grinspoon Steven K.
Published: April 2007

Context: Metabolic changes and smoking are common among HIV patients and may confer increased cardiovascular risk.

Objective: The aim of the study was to determine acute myocardial infarction (AMI) rates and cardiovascular risk factors in HIV compared with non-HIV patients in two tertiary care hospitals.

Design, Setting, and Participants: We conducted a health care system-based cohort study using a large data registry with 3,851 HIV and 1,044,589 non-HIV patients. AMI rates were determined among patients receiving longitudinal care between October 1, 1996, and June 30, 2004.

Main Outcome Measures: The primary outcome was myocardial infarction, identified by International Classification of Diseases coding criteria.

Results: AMI was identified in 189 HIV and 26,142 non-HIV patients. AMI rates per 1000 person-years were increased in HIV vs. non-HIV patients [11.13 (95% confidence interval [CI] 9.58–12.68) vs. 6.98 (95% CI 6.89–7.06)]. The HIV cohort had significantly higher proportions of hypertension (21.2 vs. 15.9%), diabetes (11.5 vs. 6.6%), and dyslipidemia (23.3 vs. 17.6%) than the non-HIV cohort (P < 0.0001 for each comparison). The difference in AMI rates between HIV and non-HIV patients was significant, with a relative risk (RR) of 1.75 (95% CI 1.51–2.02; P < 0.0001), adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. In gender-stratified models, the unadjusted AMI rates per 1000 person-years were higher for HIV patients among women (12.71 vs. 4.88 for HIV compared with non-HIV women), but not among men (10.48 vs. 11.44 for HIV compared with non-HIV men). The RRs (for HIV vs. non-HIV) were 2.98 (95% CI 2.33–3.75; P < 0.0001) for women and 1.40 (95% CI 1.16–1.67; P = 0.0003) for men, adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. A limitation of this database is that it contains incomplete data on smoking. Smoking could not be included in the overall regression model, and some of the increased risk may be accounted for by differences in smoking rates.

Conclusions: AMI rates and cardiovascular risk factors were increased in HIV compared with non-HIV patients, particularly among women. Cardiac risk modification strategies are important for the long-term care of HIV patients.