bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of Scavenger Receptor for Phosphatidylserine and Oxidized Lipoprotein (SR‐PSOX) in Human Atheroma
Authors: MINAMI MANABU , KUME NORIAKI , SHIMAOKA TAKESHI , KATAOKA HIROHARU , HAYASHIDA KAZUTAKA , YONEHARA SHIN , KITA TORU
Published: July 2010

Abstract: Recently, we identified a novel macrophage cell‐surface receptor for oxidized low‐density lipoprotein (Ox‐LDL), designated SR‐PSOX (scavenger receptor for phosphatidylserine and oxidized lipoprotein). Here we examine SR‐PSOX expression in human atherosclerotic lesions using carotid endarterectomy specimens from 21 patients, directional coronary atherectomy specimens from 11 patients, and normal aortas from 2 patients. RT‐PCR analysis demonstrated that SR‐PSOX expression was upregulated in atherosclerotic lesions, but undetectable in normal aortas. Immunohistochemistry showed that SR‐PSOX was abundantly expressed by macrophages in the intima of atherosclerotic lesions. Taken together, SR‐PSOX may be involved in Ox‐LDL uptake and subsequent foam cell transformation in macrophages in vivo and therefore may play important roles in human atherosclerotic lesion formation.
Roles of p63 in Differentiation of Müllerian Duct Epithelial Cells
Authors: KURITA TAKESHI , CUNHA GERALD R.
Published: July 2010

Abstract: In the mouse female reproductive tract, p63, a homologue of the p53 tumor suppressor gene, is highly expressed in basal cells of the vaginal and cervical epithelium, but not in the uterine epithelium. P63 is undetectable in the undifferentiated epithelium of the embryonic Müllerian duct. The Müllerian vaginal epithelium becomes p63 positive and stratified during the first week of postnatal development. P63 expression in the Müllerian vaginal epithelium is induced by vaginal mesenchyme. When vaginal mesenchyme was combined with uterine epithelium from newborn mouse, the uterine epithelium was induced to undergo vaginal differentiation and to express p63. Conversely, when the vaginal epithelium from the newborn mouse was recombined with uterine mesenchyme, it underwent uterine differentiation and failed to express p63. After the uterine epithelium or vaginal epithelium differentiates, the expression status of p63 in uterine (negative) and vaginal (positive) epithelia is not altered by heterotypic mesenchyme. Studies with p63‐null mice demonstrate that p63 is essential for vaginal epithelial differentiation, because p63‐null Müllerian vaginal epithelium developed as uterine epithelium. Thus, p63 determines whether Müllerian duct epithelial cells become uterine or vaginal. Misexpression of p63 in uterine and vaginal epithelial lesions induced by neonatal diethylstilbestrol (DES) exposure induces pathological changes. Irregularities in p63 expression (and thus epithelial differentiation) are observed in the uterine and vaginal epithelia of neonatally DES‐exposed mice during the first week of postnatal development. Thus, neonatal DES exposure abnormally transforms uterine and vaginal epithelial differentiation by perturbing epithelial expression of p63 during development.
Caenorhabditis elegans as an Environmental Monitor Using DNA Microarray Analysis
Authors: CUSTODIA N. , WON S. J. , NOVILLO A. , WIELAND M. , LI C. , CALLARD I. P.
Published: July 2010

Abstract: In order to assist in the identification of possible endocrine disrupting chemicals (EDC) in groundwater, we are developing Caenorhabolitis elegans as a high throughput bioassay system in which responses to EDC may be detected by gene expression using DNA microarray analysis. As a first step we examined gene expression patterns and vitellogenin responses of this organism to vertebrate steroids, in liquid culture. Western blotting showed the expected number and size of vitellogenin translation products after estrogen exposure. At 10−9 M, vitellogenin decreased, but at 10−7 and 10−5, vitellogenin was increased. Testosterone (10−5 M) increased the synthesis of vitellogenin, but progesterone‐treated cultures (10−5 M) had less vitellogenin. Using DNA microarray analysis, we examined the pattern of gene expression after progesterone (10−5, 10−7, and 10−9 M), estrogen (10−5 M), and testosterone (10−9 M) exposure, with special attention to the traditional biomarker genes used in environmental studies [vitellogenin, cytochrome P450 (CYP), glutathione s‐transferase (GST), metallothionein (MT), and heat shock proteins (HSP)]. GST and P450 genes were affected by estrogen (10−5 M) and progesterone (10−5 and 10−7 M) treatments. For vitellogenin genes, estrogen treatment (10−5 M) caused overexpression of the vit‐2 and vit‐6 genes (2.68 and 3.25 times, respectively). After progesterone treatment (10−7 M), the vit‐5 and vit‐6 were down‐regulated and vit‐1 up‐regulated (3.59‐fold). Concentrations of testosterone and progesterone at 10−9 M did not influence the expression of the vit, CYP, or GST genes. Although the analysis is incomplete, and low doses and combinations of EDC need to be tested, these preliminary results indicate C. elegans may be a useful laboratory and field model for screening EDC.
Are Male Reproductive Disorders a Common Entity?
Authors: BOISEN K. A. , MAIN K. M. , RAJPERT‐DE MEYTS E. , SKAKKEBAEK N. E.
Published: July 2010

Abstract:Growing evidence from clinical and epidemiological studies points to a synchronized increase in the incidence of male reproductive problems, such as genital abnormalities, testicular cancer, reduced semen quality, and subfertility. Together these male reproductive problems may reflect the existence of one common entity, atesticular dysgenesis syndrome(TDS). Experimental and epidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadal development during fetal life. The recent rise in the prevalence of TDS may be causally linked to endocrine disrupters affecting genetically susceptible individuals. We recommend that future epidemiological studies on trends in male reproduction do not focus on one symptom only, but take all aspects of TDS into account. The potential impact of adverse environmental factors and the role of genetic polymorphisms involved in gonadal development requires further research.
Estrogen‐Associated Genes in Uterine Leiomyoma
Authors: LI SHUANFANG , McLACHLAN JOHN A.
Published: July 2010

Abstract: Uterine leiomyomas or fibroids are classified as a benign uterine disease in that the polyps display no malignant growth. However, uterine leiomyomas are a leading cause of morbidity, infertility, and hysterectomy in women. Since leiomyomas are known to be sensitive to estrogen for their growth, we have examined uterine genes known to be estrogen responsive in affected and unaffected uterine tissue. This information will be useful in determining the contribution, if any, of hormonally active environmental chemicals to this highly prevalent reproductive disorder.
Structure‐Function Relationships in Estrogen Receptors and the Characterization of Novel Selective Estrogen Receptor Modulators with Unique Pharmacological Profiles
Authors: KATZENELLENBOGEN BENITA S. , SUN JUN , HARRINGTON WILLIAM R. , KRAICHELY DENNIS M. , GANESSUNKER DESHANIE , KATZENELLENBOGEN JOHN A.
Published: July 2010

Abstract: This article summarizes recent research on the development of estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) subtype‐selective ligands based on our understanding of structure‐activity relationships in these two estrogen receptors and differences in their ligand binding domains and activation function domains. The use of these ligands should enable greater understanding of the unique biologies mediated by ERα versus ERβ and may, as well, provide selective estrogen receptor modulators having unique biological and pharmacological profiles optimal for prevention and treatment of breast cancer, for menopausal hormone replacement, for prevention of osteoporosis, and for potential cardiovascular benefit.
Quality of Life and Tamoxifen in a Breast Cancer Prevention Trial
Authors: DAY RICHARD
Published: July 2010

Abstract: This report contains a brief summary of the health‐related quality of life findings for 11,064 women taking part in the National Surgical Adjuvant Breast and Bowel Project's P‐1 trial. Women taking part in this trial of tamoxifen versus placebo for breast cancer prevention were ≥35 years old and predominantly white, well educated, and middle class, with a strong professional and technical orientation. Key findings included a lack of difference between the tamoxifen and placebo arms with regard to depression, overall physical or mental quality of life, and weight gain. The tamoxifen arm did show consistent increases in vasomotor (hot flashes) and gynecological (vaginal discharge) symptoms, as well as difficulties in certain domains of sexual functioning. It is concluded that an informed discussion with a woman considering tamoxifen therapy should include these points in the risk‐benefit discussion.
Rationale and Overview of the Raloxifene Use for the Heart (RUTH) Trial
Authors: MOSCA LORI
Published: July 2010

Abstract: Raloxifene is a selective estrogen receptor modulator (SERM) that has beneficial effects on several cardiovascular risk factors and has also been associated with a reduced risk of breast cancer in osteoporosis prevention trials. The Raloxifene Use for the Heart (RUTH) study was designed to test the hypothesis that, compared to placebo, raloxifene at 60 mg/day (1) lowers the risk of the combined end point of coronary death, nonfatal myocardial infarction (MI), and hospitalized acute coronary syndromes other than MI and (2) reduces the risk of invasive breast cancer (coprimary end point) in women at high risk for major coronary events based on established cardiovascular disease (CVD) or multiple risk factors. RUTH is a double‐blind, placebo‐controlled, randomized, clinical trial of 10,101 women aged 55 years or older from 26 countries and is expected to be completed in approximately 5 years.
Raloxifene: Risks and Benefits
Authors: BARRETT‐CONNOR ELIZABETH
Published: July 2010

Abstract: Raloxifene, a selective estrogen receptor modulator (SERM), was designed to have the expected benefits of long‐term estrogen replacement therapy without the risks. This paper reviews the clinical trial evidence for raloxifene benefits and risks, and how they compare with those of hormone replacement therapy (HRT) and relate to the choices of postmenopausal women.
Non‐gaussianity Versus Nonlinearity of Cosmological Perturbations
Authors: Verde Licia
Published: July 2010

Abstract: Following the discovery of the cosmic microwave background, the hot big‐bang model has become the standard cosmological model. In this theory, small primordial fluctuations are subsequently amplified by gravity to form the large‐scale structure seen today. Different theories for unified models of particle physics, lead to different predictions for the statistical properties of the primordial fluctuations, that can be divided in two classes: gaussian and non‐gaussian. Convincing evidence against or for gaussian initial conditions would rule out many scenarios and point us toward a physical theory for the origin of structures.

The statistical distribution of cosmological perturbations, as we observe them, can deviate from the gaussian distribution in several different ways. Even if perturbations start off gaussian, nonlinear gravitational evolution can introduce non‐gaussian features. Additionally, our knowledge of the Universe comes principally from the study of luminous material such as galaxies, but galaxies might not be faithful tracers of the underlying mass distribution. The relationship between fluctuations in the mass and in the galaxies distribution (bias), is often assumed to be local, but could well be nonlinear. Moreover, galaxy catalogues use the redshift as third spatial coordinate: the resulting redshift‐space map of the galaxy distribution is nonlinearly distorted by peculiar velocities. Nonlinear gravitational evolution, biasing, and redshift‐space distortion introduce non‐gaussianity, even in an initially gaussian fluctuation field.

I investigate the statistical tools that allow us, in principle, to disentangle the above different effects, and the observational datasets we require to do so in practice.
An Attempt to Do Without Dark Matter
Authors: Kinney William H. , Brisudova Martina
Published: July 2010

Abstract: The discrepancy between dynamical mass measures of objects such as galaxies and the observed distribution of luminous matter in the universe is typically explained by invoking an unseen “dark matter” component. Dark matter must necessarily be nonbaryonic. We introduce a simple hypothesis to do away with the necessity for dark matter by introducing an additional nongravitational force coupled to baryon number as a charge. We compare this hypothesis to Milgrom's modified Newtonian dynamics. The model ultimately fails when confronted with observation, but it fails in an interesting way.
Aging: Overview
Authors: Harman Denham
Published: July 2010

Abstract: Aging is a universal process that began with the origination of life about 3.5 billion years ago. Accumulation of the diverse deleterious changes produced by aging throughout the cells and tissues progressively impairs function and can eventually cause death. Aging changes can be attributed to development, genetic defects, the environment, disease, and an inborn process—the aging process. The chance of death at a given age serves as a measure of the average number of aging changes accumulated by persons of that age, that is, of physiologic age, and the rate of change of this measure as the rate of aging. Chances for death are decreased by improvements in general living conditions. As a result, during the past two millennia average life expectancy at birth (ALE‐B), determined by the chances for death, of humans has risen from 30 years, in ancient Rome, to almost 80 years today in the developed countries. Chances for death in the developed countries are now near limiting values and ALE‐Bs are approaching plateau values that are 6‐9 years less than the potential maximum of about 85 years. Chances for death are now largely determined by the inherent aging process after age 28. Only 1.1% of female cohorts in Sweden die before this age; the remainder die off at an exponentially increasing rate with advancing age. The inherent aging process limits ALE‐B to around 85 years, and the maximum life span (MLS) to about 122 years. Past efforts to increase ALE‐B did not require an understanding of aging. Such knowledge will be necessary in the future to significantly increase ALE‐B and MLS, and to satisfactorily ameliorate the medical, economic, and social problems associated with advancing age. The many theories advanced to account for aging should be used, to the extent it is feasible, to help with these important practical problems, including applications of the free radical theory of aging. Past measures evolved by societies to ensure adequate care for older individuals are rapidly becoming inadequate because of changes in life style, the growing percentage of older people, declining fertility rates, and the diminishing size of the work forces to provide for the elderly. Measures are being advanced to help with this problem. Prospects are bright for further increases in the span of functional life and improvements in the lives of the elderly.
Implications of Protein Degradation in Aging
Authors: Goto Sataro , Takahashi Ryoya , Kumiyama Atsushi , Radák Zsolt , Hayashi Toshiaki , Takenouchi Masaki , Abe Ryoichi
Published: July 2010

Abstract: Aging is characterized by accumulation of potentially harmful altered proteins that could lead to gradual deterioration of cellular functions and eventually result in increased probability of death. Metabolic turnover of proteins thus plays an essential role in maintaining the life of an organism. In this article we summarize our current knowledge on age‐related changes in protein turnover with special reference to degradation. Increase in half‐life of proteins with advancing age is well documented. Qualitative rather than quantitative changes of proteasomes appear to be responsible for this change. Dietary restriction and moderate long‐term exercise seem to restore higher proteasome activity and turnover rate of proteins in aged animals.
Calorie Restriction Enhances the Expression of Key Metabolic Enzymes Associated with Protein Renewal during Aging
Authors: Spindler Stephen R.
Published: July 2010

Abstract: Our studies show that dietary caloric restriction (CR) alters the expression of key metabolic enzymes in a manner consistent with an increased rate of extrahepatic protein turnover and renewal during aging. Of the key hepatic gluconeogenic enzyme genes affected by CR, glucose 6‐phosphatase mRNA increased 1.7‐ and 2.3‐fold in young and old CR mice. Phosphoenolpyruvate carboxykinase mRNA increased 2‐fold in young mice, and its mRNA and activity increased 2.5‐ and 1.7‐fold in old mice. These changes indicate that CR enhances the enzymatic capacity for gluconeogenesis. The carbon required for gluconeogenesis appears to be generated from peripheral protein turnover. Muscle glutamine synthetase mRNA increased 1.3‐ and 2.1‐fold in young and old CR mice, suggesting increased disposal of nitrogen and carbon derived from protein catabolism for energy. mRNA for the key liver nitrogen disposal enzymes glutaminase, carbamyl phosphate synthase I, and tyrosine aminotransferase were increased by 2.4‐, 1.8‐, and 1.8‐fold in CR mice. Consistent with increased hepatic nitrogen disposal, hepatic glutamine synthetase mRNA and activity were each decreased about 40% in CR mice. Together, these and our other published data suggest that CR enhances and maintains protein turnover, and thus protein renewal, into old age. These effects are likely to resist the well‐documented decline in whole body protein renewal with age. Enhanced renewal may reduce the level of damaged and toxic proteins that accumulate during aging, contributing to the extension of life span by CR.
Cajal and Consciousness
Authors: MARIJUÁN PEDRO C.
Published: July 2010

Abstract:One hundred years after Santiago Ramón Cajal established the bases of modern neuroscience in his masterpieceTextura del sistema nervioso del hombre y de los vertebrados, the question is stated again: What is the status of consciousness today? The responses in this book, by contemporary leading figures of neuroscience, evolution, molecular biology, computer science, and quantum physics, collectively compose a fascinating conceptual landscape. Both the evolutionary emergence of consciousness and its development towards the highest level may be analyzed by a wealth of new theories and hypotheses, including Cajal's prescient ones. Some noticeable gaps remain, however. Celebrating the centennial ofTexturais a timely occasion to reassess how close—and how far—our system of the sciences is to explaining consciousness.
Similarity, Invariance, and Musical Variation
Authors: MCADAMS STEPHEN , MATZKIN DANIEL
Published: July 2010

Abstract: Perceptual similarity underlies a number of important psychological properties of musical materials, including perceptual invariance under transformation, categorization, recognition, and the sense of familiarity. Mental processes involved in the perception of musical similarity may be an integral part of the functional logic of music composition and thus underly important aspects of musical experience. How much and in what ways can musical materials be varied and still be considered as perceptually related or as belonging to the same category? The notions of musical material, musical variation, perceptual similarity and invariance, and form‐bearing dimensions are considered in this light. Recent work on similarity perception has demonstrated that the transformation space for a given musical material is limited by several factors ranging from degree of match of the values of auditory attributes of the events composing the sequences to their relations of various levels of abstraction and to the degree that the transformation respects the grammar of the musical system within which the material was composed. These notions and results are considered in the light of future directions of research, particularly concerning the role of similarity and invariance in the understanding of musical form during listening.
Brain Specialization for Music
Authors: PERETZ ISABELLE
Published: July 2010

Abstract:Brain specialization for music refers to the possibility that the human brain is equipped with neural networks that are dedicated to the processing of music. Finding support for the existence of such music‐specific networks suggests that music may have biological roots. Conversely, the discovery that music may have systematic associations with other cognitive domains or variable brain organization across individuals supports the view that music is a cultural artifact. Currently, the evidence favors the biological perspective. There are numerous behavioral indications that music‐specific networks are isolable in the brain. These neuropsychological observations are briefly reviewed here with special emphasis on a new condition, that of congenital amusia (also commonly referred to as tone deafness).
A Nosology of Disorders of Attention
Authors: MIRSKY ALLAN F. , DUNCAN CONNIE C.
Published: July 2010

Abstract: The trailblazing research on sleep mechanisms and petit mal epilepsy, conducted during the period from 1940 through 1970, illuminated the brain substrate for normal consciousness and attention, as well as their disorders. This research helped inform and structure our neuropsychologically based model of the “elements” of attention. The model has been used to assess attention in the research laboratory and clinic, and has led to a “nosology of disorders of attention,” which is presented here in preliminary form. The nosology reviews the possible causes of the symptom(s) of impaired attention, as well as suggesting a blueprint for future research in this area.
Adult ADHD
Authors: KINSBOURNE MARCEL , De QUIROS GUILLERMO B. , RUFO DOLORES TOCCI
Published: July 2010

Abstract: Many adults with ADHD respond to stimulant therapy, but controlled medication assessments have not been reported. We administered an effortful working memory task in four half‐day sessions, double blind, at methylphenidate levels of 0, 5, 10 and 20 mg. Dose‐response curves were established individually. Fifteen of 17 patients displayed a favorable response to one or more levels of medication; that is, they achieved more correct responses and less variability than on placebo. Each dose level elicited optimal performance from some of the patients. Unlike monitoring by self‐report, the objective medication assessment offers an expeditious approximation to the ultimate optimal dose, potentially saving the patient weeks on an ineffective and/or excessive dosage regime.
Adults ADHD
Authors: WOLF LORRAINE E. , WASSERSTEIN JEANETTE
Published: July 2010

Abstract: This concluding paper raises some final questions and issues that the authors feel should receive more emphasis in future research on ADHD in adults. One significant problem for our field is the upward extension of child‐based models and approaches without proper adaptation to adults. With adults differing patterns of comorbidity and symptom heterogeneity pose new conceptual, diagnostic, and treatment challenges. As an illustration, we review ten common presenting complaints in adults and their link to the underlying core ADHD deficits of hyperkinesis, inattention, and impulsivity. While these core symptoms are often overt problems in children, in adults subtler executive dysfunction appears. Even though the growing consensus is that ADHD is a disorder of executive functions (EF), the details of the EF/ADHD connection remain unclear and may be far more complex in adults. That complexity is mirrored in the widening anatomic representation of EF, extending beyond the frontal lobes into the subcortex and other nonfrontal regions. More research will be needed to follow the developmental trajectory of executive dysfunction in ADHD over the life cycle and tie this to the developmental neuropsychology of EF. Psychosocial context and nongenetic familial influence are also critical variables that need greater consideration when characterizing and measuring ADHD symptoms in adults. Finally, until we have reached consensus on adult subject selection, we may not be able to enhance diagnostic rigor or expand our conceptual framework for understanding the underlying pathophysiology of ADHD in adults.
The Depressed Suicidal Patient
Authors: Nemeroff Charles B. , Compton Michael T. , Berger Joseph
Published: July 2010

Abstract: Depressive disorders are associated with significant psychosocial impairment and disability. Depression should be thoroughly evaluated, as should current and past suicidality and potential risk factors for suicide. Mortality by suicide characterizes the course of major affective disorders in approximately 15% of those suffering from these illnesses. Several neurobiological correlates of suicidality have been discovered. Treatment of depression with suicidality may involve hospitalization, pharmacotherapy, electroconvulsive therapy, and psychotherapy. Special populations include children and adolescents, the elderly, medically ill patients, patients with comorbid personality disorders, and patients with comorbid substance abuse disorders. Clinicians encountering patients with depressive disorders should be proficient in the assessment and treatment of depression with suicidality.
Suicide: What is in the Clinician's Mind?
Authors: Roose Steven P.
Published: July 2010

Abstract: The assessment and treatment of the suicidal patient challenge all clinicians, regardless of training or theoretical orientation, to draw upon their knowledge and judgment to formulate the best treatment plan possible. As great as the influence of demographics, genetics, and psychobiology are, what is in the mind of the clinician, whether it is anxiety, confidence, knowledge, or uncertainty, will determine the fate of the suicidal patient.
Sensitization, Subjective Health Complaints, and Sustained Arousal
Authors: Ursin Holger , Eriksen Hege R.
Published: July 2010

Abstract:The purpose of this presentation is to discuss the possibility that sensitization is a psychobiological mechanism underlying not only multiple chemical sensitivity (MCS), but a much more general cluster of illness, referred to as “subjective health complaint. Sustained arousal, or sustained “stress” responses, may be an important factor for the development of these conditions. Patients with subjective complaints without objective changes are sometimes referred to as having “fashionable diagnoses” or “unexplained symptoms”. They may be given diagnoses like MCS, epidemic fatigue, chronic fatigue syndrome, burnout, stress, a variety of intoxications, environmental illness, radiation, multiple chemical hypersensitivity, food intolerance, functional dyspepsia, irritable bowel, myalgic encephalitis, postviral syndrome, yuppie flu, fibromyalgia, or vital exhaustion. One issue is whether this is one general condition or separate entities. Another issue is whether sensitization may be the psychobiological mechanism for most or all of these conditions. Finally, is it likely that sustained arousal may facilitate the development of sensitization in some or many neural circuits? In this review, the main emphasis will be on musculoskeletal pain. This is the most frequent and most expensive condition for sickness compensation and disability. The comorbidity of other complaints, however, will also be taken into account.
Cytokine‐Induced Sickness Behavior: Mechanisms and Implications
Authors: Dantzer Robert
Published: July 2010

Abstract: Sickness behavior refers to a coordinated set of behavioral changes that develop in sick individuals during the course of an infection. At the molecular level, these changes are due to the brain effects of proinflammatory cytokines such as interleukin‐1 (IL‐1) and tumor necrosis factor alpha (TNFα). Peripherally released cytokines act on the brain via a fast transmission pathway involving primary afferent nerves innervating the bodily site of inflammation and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission. At the behavioral level, sickness behavior appears to be the expression of a central motivational state that reorganizes the organism priorities to cope with infectious pathogens. There is evidence that the sickness motivational state can interact with other motivational states and respond to nonimmune stimuli probably by way of sensitization and/or classical conditioning. However, the mechanisms that are involved in plasticity of the sickness motivational state are not yet understood.
Acquiring Symptoms in Response to Odors: A Learning Perspective on Multiple Chemical Sensitivity
Authors: Van den Bergh Omer , Devriese Stephan , Winters Winnie , Veulemans Hendrik , Nemery Benoit , Eelen Paul , van de Woestijne Karel P.
Published: July 2010

Abstract: In this chapter, a learning account is discussed as a potential explanation for the symptoms in multiple chemical sensitivity. Clinical evidence is scarce and anecdotal. A laboratory model provides more convincing results. After a few breathing trials containing CO2‐enriched air as an unconditioned stimulus in a compound with harmless odor substances as conditioned stimuli, subjective symptoms are elicited and respiratory behavior is altered by the odors only. Also, mental images can become conditioned stimuli to trigger subjective symptoms. The learning effects cannot be explained by a response bias or by conditioned arousal, and they appear to involve basic associative processes that do not overlap with aware cognition of the relationship between the odors and the CO2 inhalation. Learned symptoms generalize to new odors and they can be eliminated in a Pavlovian extinction procedure. In accordance with clinical findings, neurotic subjects and psychiatric cases are more vulnerable to learning subjective symptoms in response to odors. Consistent with a learning account, cognitive‐behavioral treatment techniques appear to produce beneficial results in clinical cases. Several criticisms and unresolved questions regarding the potential role of learning mechanisms are discussed.
Heat Transfer Technology for Internal Passages of Air‐Cooled Blades for Heavy‐Duty Gas Turbines
Authors: WEIGAND BERNHARD , SEMMLER KLAUS , Von WOLFERSDORF JENS
Published: July 2010

Abstract:The present review paper, although far from being complete, aims to give an overview about the present state of the art in the field of heat transfer technology for internal cooling of gas turbine blades. After showing some typical modern cooled blades, the different methods to enhance heat transfer in the internal passages of air‐cooled blades are discussed. The complicated flows occuring in bends are described in detail, because of their increasing importance for modern cooling designs. A short review about testing of cooling design elements is given, showing the interaction of the different cooling features as well. The special focus of the present review has been put on the cooling of blades for heavy‐duty gas turbines, which show several differences compared to aero‐engine blades.
Experimental Investigation of Film Cooling Flow Induced by Shaped Holes on a Turbine Blade
Authors: BARTHET Sylvain , BARIO François
Published: July 2010

Abstract: The present study is the second half of a piece of work carried out in collaboration with SNECMA. It investigates shaped hole film cooling, numerically and experimentally. The aim of this paper is the experimental analysis of shaped hole film cooling on a large scale turbine blade (1.4 m chord).

The test section is a large scale turbine inlet guide vane cascade. The test airfoil is equipped with a row of nine 50° sloped shaped holes. They are located on the suction side at 20% of the curvilinear length of the blade from the stagnation point. The inlet film cooling hole diameter is 12 mm.

The test jet flow is heated to 55°C above the crossflow temperature. Velocity and temperature field measurements have been done to obtain mean and fluctuating values. The results are compared to those obtained by Béral1 on the same experimental apparatus and in the same test conditions, for a row of cylindrical holes.
Aging and the Role of Reactive Nitrogen Species
Authors: DREW BARRY , LEEUWENBURGH CHRISTIAAN
Published: July 2010

The role of reactive oxygen species and its effects on aging has received considerable attention in the past 47 years since Dr. Denham Harman first proposed the “free radical theory of aging.” Though not completely understood due to the incalculable number of pathways involved, the number of manuscripts that facilitate the understanding of the underlying effects of reactive radical species on the oxidative stress on lipids, proteins, and DNA and its contribution to the aging process increases nearly exponentially each year. More recently, the role of reactive nitrogen species, such as nitric oxide and its by‐products—nitrate (NO3−), nitrite (NO2−), peroxynitrite (ONOO−), and 3‐nitrotyrosine—have been shown to have a direct role in cellular signaling, vasodilation, and immune response. Nitric oxide is produced within cells by the actions of a group of enzymes called nitric oxide synthases. Presently, there are three distinct isoforms of nitric oxide synthase: neuronal (nNOS or NOS‐1), inducible (iNOS or NOS‐2), and endothelial (eNOS or NOS‐3), and several subtypes. While nitric oxide (NO•) is a relative unreactive radical, it is able to form other reactive intermediates, which could have an effect on protein function and on the function of the entire organism. These reactive intermediates can trigger nitrosative damage on biomolecules, which in turn may lead to age‐related diseases due to structural alteration of proteins, inhibition of enzymatic activity, and interferences of the regulatory function. This paper will critically review the evidence of nitration and the important role it plays with aging. Furthermore, it will summarize the physiological role of nitration as well as the mechanisms leading to proteolytic degradation of nitrated proteins within biological tissues.
The Role of Apoptosis in the Normal Aging Brain, Skeletal Muscle, and Heart
Authors: POLLACK MICHAEL , PHANEUF SHARON , DIRKS AMIE , LEEUWENBURGH CHRISTIAAN
Published: July 2010

During aging, there is a significant loss of some postmitotic cells, for example, cardiac and skeletal myocytes. Mitochondrial damage and dysfunction with age may trigger increased apoptosis, and this may explain this increase in cell loss. However, it is still unknown if apoptosis plays an important role in normal aging. In vitro it has been shown that several mitochondrial proteins can influence apoptosis, depending on factors such as the mitochondrial membrane potential and cellular redox status. It remains possible that mitochondrial dysfunction due to chronic oxidative stress with age is a cause of apoptosis in vivo. This cell loss may be due to mitochondrial‐triggered apoptosis caused by age‐associated increases in oxidant production or increased activation of mitochondrial permeability transition pores. Results from our laboratory and others are reviewed that relate to apoptosis in the normal aging of the brain cortex, heart, and skeletal muscle. Particular attention is paid to the role of cytochrome c release from mitochondria and alterations in the pro‐ and anti‐apoptotic proteins, Bax and Bcl‐2, respectively. Our results demonstrate that a tissue‐specific adaptation of the Bcl‐2/Bax ratio occurs with age and may directly influence the release of cytochrome c.
Delaying Brain Mitochondrial Decay and Aging with Mitochondrial Antioxidants and Metabolites
Authors: LIU JIANKANG , ATAMNA HANI , KURATSUNE HIROHIKO , AMES BRUCE N.
Published: July 2010

Mitochondria decay with age due to the oxidation of lipids, proteins, RNA, and DNA. Some of this decay can be reversed in aged animals by feeding them the mitochondrial metabolites acetylcarnitine and lipoic acid. In this review, we summarize our recent studies on the effects of these mitochondrial metabolites and mitochondrial antioxidants (α‐phenyl‐N‐t‐butyl nitrone andN‐t‐butyl hydroxylamine) on the age‐associated mitochondrial decay of the brain of old rats, neuronal cells, and human diploid fibroblast cells. In feeding studies in old rats, these mitochondrial metabolites and antioxidants improve the age‐associated decline of ambulatory activity and memory, partially restore mitochondrial structure and function, inhibit the age‐associated increase of oxidative damage to lipids, proteins, and nucleic acids, elevate the levels of antioxidants, and restore the activity and substrate binding affinity of a key mitochondrial enzyme, carnitine acetyltrasferase. These mitochondrial metabolites and antioxidants protect neuronal cells from neurotoxin‐ and oxidant‐induced toxicity and oxidative damage; delay the normal senescence of human diploid fibroblast cells, and inhibit oxidant‐induced acceleration of senescence. These results suggest a plausible mechanism: with age, increased oxidative damage to proteins and lipid membranes, particularly in mitochondria, causes a deformation of structure of enzymes, with a consequent decrease of enzyme activity as well as substrate binding affinity for their substrates; an increased level of substrate restores the velocity of the reaction and restores mitochondrial function, thus delaying mitochondrial decay and aging. This loss of activity due to coenzyme or substrate binding appears to be true for a number of other enzymes as well, including mitochondrial complex III and IV.
Melatonin Reduces Oxidant Damage and Promotes Mitochondrial Respiration
Authors: REITER RUSSEL J. , TAN DUN XIAN , MANCHESTER LUCIEN C. , EL‐SAWI MAMDOUH R.
Published: July 2010

Melatonin has a number of properties as a consequence of which it could be beneficial to animals as they age. Of particular interest are its ubiquitous actions as a direct and indirect antioxidant and free radical scavenger. Besides directly detoxifying a variety of reactive oxygen and reactive nitrogen species, at least one product that is formed as a result of these interactions is also a potent free radical scavenger. Thus, the product that is formed when melatonin detoxifies hydrogen peroxide, that is, N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine is an efficient scavenger, at least equivalent to melatonin itself. This antioxidant cascade increases the ability of melatonin to resist oxidative damage. Other actions of melatonin, such as stimulation of antioxidative enzymes also improves its status as an antioxidant. Finally, recent observations documenting melatonin's ability to stimulate electron transport and ATP production in the inner‐mitochondrial membrane also has relevance for melatonin as an agent that could alter processes of aging. These findings, coupled with diminished melatonin production in advanced age, has prompted scientists to consider melatonin in the context of aging. As of this writing there is no definitive evidence to prove that melatonin alters the rate of aging, although data relating to melatonin deferring some age‐related degenerative conditions is accumulating rapidly.
Prevention of Mitochondrial Oxidative Damage Using Targeted Antioxidants
Authors: KELSO GEOFFREY F. , PORTEOUS CAROLYN M. , HUGHES GILLIAN , LEDGERWOOD ELIZABETH C. , GANE ALISON M. , SMITH ROBIN A. J. , MURPHY MICHAEL P.
Published: July 2010

Mitochondrial‐targeted antioxidants that selectively block mitochondrial oxidative damage and prevent some types of cell death have been developed. These antioxidants are ubiquinone and tocopherol derivatives and are targeted to mitochondria by covalent attachment to a lipophilic triphenylphosphonium cation. Because of the large mitochondrial membrane potential, these cations accumulated within mitochondria inside cells, where the antioxidant moiety prevents lipid peroxidation and protects mitochondria from oxidative damage. The mitochondrially localized ubiquinone also protected mammalian cells from hydrogen peroxide‐induced apoptosis while an untargeted ubiquinone analogue was ineffective against apoptosis. When fed to mice these compounds accumulated within the brain, heart, and liver; therefore, using these mitochondrial‐targeted antioxidants may help investigations of the role of mitochondrial oxidative damage in animal models of aging.
Reaction of Carnosine with Aged Proteins
Authors: HIPKISS ALAN R. , BROWNSON CAROL , BERTANI MARIANA F. , RUIZ EMILIO , FERRO ALBERT
Published: July 2010

Cellular aging is often associated with an increase in protein carbonyl groups arising from oxidation‐ and glycation‐related phenomena and suppressed proteasome activity. These “aged” polypeptides may either be degraded by 20S proteasomes or cross‐link to form structures intractable to proteolysis and inhibitory to proteasome activity. Carnosine (β‐alanyl‐l‐histidine) is present at surprisingly high levels (up to 20 mM) in muscle and nervous tissues in many animals, especially long‐lived species. Carnosine can delay senescence in cultured human fibroblasts and reverse the senescent phenotype, restoring a more juvenile appearance. As better antioxidants/free‐radical scavengers than carnosine do not demonstrate these antisenescent effects, additional properties of carnosine must contribute to its antisenescent activity. Having shown that carnosine can react with protein carbonyls, thereby generating “carnosinylated” polypeptides using model systems, we propose that similar adducts are generated in senescent cells exposed to carnosine. Polypeptide‐carnosine adducts have been recently detected in beef products that are relatively rich in carnosine, and carnosine's reaction with carbonyl functions generated during amino acid deamidation has also been described. Growth of cultured human fibroblasts with carnosine stimulated proteolysis of long‐labeled proteins as the cells approached their “Hayflick limit,” consistent with the idea that carnosine ameliorates the senescence‐associated proteolytic decline. We also find that carnosine suppresses induction of heme‐oxygenase‐1 activity following exposure of human endothelial cells to a glycated protein. The antisenescent activity of the spin‐trap agent α‐phenyl‐N‐t‐butylnitrone (PBN) towards cultured human fibroblasts resides in N‐t‐butyl‐hydroxylamine, its hydrolysis product. As hydroxylamines are reactive towards aldehydes and ketones, the antisenescent activity of N‐t‐butyl‐hydroxylamine and other hydroxylamines may be mediated, at least in part, by reactivity towards macromolecular carbonyls, analogous to that proposed for carnosine.
Therapeutics against Mitochondrial Oxidative Stress in Animal Models of Aging
Authors: MELOV SIMON
Published: July 2010

During the course of normal metabolism, reactive oxygen species (ROS) are produced from within the respiratory chain of the mitochondria. These ROS have the capacity to oxidize and damage a variety of cellular constituents including lipids, DNA, and proteins. We have taken a genetic and pharmacological approach in delineating the range of molecular targets that can be oxidatively damaged by mitochondrial ROS. Specifically, we use mice that are lacking the mitochondrial form of superoxide dismutase (sod 2−/−mice) to better understand the possible phenotypes that can arise from mitochondrial oxidative stress.sod 2−/−mice can be used to test the efficacy of antioxidants, and more generally the efficacy of antioxidants against mitochondrial oxidative stress. We have evaluated superoxide dismutase/catalase mimetics in this mammalian model of mitochondrial oxidative stress, and have shown a high degree of efficacy in protecting against ROS produced within the mitochondria. Similarly, we have employed the nematodeCaenorhabditis elegansto test the hypothesis that effective antioxidant therapy can prolong the life span of an invertebrate.
Membrane Fatty Acid Unsaturation, Protection against Oxidative Stress, and Maximum Life Span
Authors: PAMPLONA REINALD , BARJA GUSTAVO , PORTERO‐OTÍN MANUEL
Published: July 2010

Aging is a progressive and universal process originating endogenously that manifests during postmaturational life. Available comparative evidence supporting the mitochondrial free radical theory of aging consistently indicates that two basic molecular traits are associated with the rate of aging and thus with the maximum life span: the presence of low rates of mitochondrial oxygen radical production and low degrees of fatty acid unsaturation of cellular membranes in postmitotic tissues of long‐lived homeothermic vertebrates in relation to those of short‐lived ones. Recent research shows that steady‐state levels of free radical‐derived damage to mitochondrial DNA (mtDNA) and, in some cases, to proteins are lower in long‐ than in short‐lived animals. Thus, nonenzymatic oxidative modification of tissue macromolecules is related to the rate of aging. The low degree of fatty acid unsaturation in biomembranes of long‐lived animals may confer advantage by decreasing their sensitivity to lipid peroxidation. Furthermore, this may prevent lipoxidation‐derived damage to other macromolecules. Taking into account the fatty acid distribution pattern, the origin of the low degree of membrane unsaturation in long‐lived species seems to be the presence of species‐specific desaturation pathways that determine membrane composition while an appropriate environment for membrane function is maintained. Mechanisms that prevent or decrease the generation of endogenous damage during the evolution of long‐lived animals seem to be more important than trying to intercept those damaging agents or repairing the damage already inflicted. Here, the physiological meaning of these findings and the effects of experimental manipulations such as dietary stress, caloric restriction, and endocrine control in relation to aging and longevity are discussed.
Antiinfection Immunity and Autoimmunity
Authors: ZINKERNAGEL ROLF M.
Published: July 2010

Abstract: This review summarizes findings that indicate that immune reactions of T and B cells depend on thresholds of the binding avidity of the receptor, on antigen amounts, on the time period during which antigen is available in secondary lymphatic tissues, as well as on the detection methods used. Usually immunologically ignored, strictly extralymphatic host cells or their antigens may be released by infection or immunopathology to reach lymphatic organs and induce autoimmune diseases. If we know the infection, we call the disease immunopathologically mediated; if we do not recognize or know it, we call the disease autoimmune.