bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vivo Measurement of Platinum in the Kidneys Using X‐ray Fluorescence
Authors: KADHIM R. , AL‐HUSSANY A. , ALI P. A. , HANCOCK D. A. , EL‐SHARKAWI A. M.
Published: July 2010

Abstract: A noninvasive in vivo method has been developed and optimized for measuring platinum concentrations in the kidneys of patients receiving chemotherapy. The method is based on polarizing the X‐ray beam from an orthovoltage radiotherapy treatment unit, the Pantak DXT‐300, and using the beam to produce emission of the characteristic platinum X‐rays from the kidney. The platinum is derived from platinum‐based chemotherapy drugs, such as cisplatin and its analogues (carboplatin and iproplatin), used to treat cancer patients. The clinical motivation for measuring the platinum concentration in both the kidneys and the tumor is to optimize the treatment by establishing the relationships between the accumulation of the drug at those sites. Such clinical information could be valuable in maximizing the therapeutic ratio toward the tumor tissue and limiting the hazards to the kidney. The performance of the system was experimentally optimized with respect to the applied X‐ray tube voltage, filter material, and polarizer. Additionally, the MCNP‐4B Monte‐Carlo computer code was used to estimate the optimum shielding materials, the thickness surrounding the X‐ray tube, and the arrangement of collimators, to protect patients from the hazards of the scattering radiation. Clinical measurements can be made with a combination of a bilayer of copper and silicon as polarizer, a 0.25‐mm tin filter introduced in the path between the X‐ray beam and the polarizer, and an operating voltage of 220 kV. The minimum detection limit achieved with this arrangement is 16 ppm, for a kidney depth of 3 × 3 cm, with a skin dose of 1.6 mGy and measurement time of 2,000 seconds.
Total Body Protein in Chronic Diseases and in Aging
Authors: HANSEN ROSS D. , RAJA CHAND , ALLENA BARRY J.
Published: July 2010

Abstract: Substantial losses of total body protein (TBP) can occur in chronic diseases and in aging. Such losses impact negatively on immunity and quality of life, and on growth rates in children. Direct measurements of total body nitrogen (TBN) monitor the integrated changes in TBP over time and allow comparison with normal subjects. TBN assessment via neutron capture analysis is therefore the gold‐standard method of TBP estimation, so that risk factors for protein deficit can be identified and patient management optimized. The nitrogen index (NI) can be used to predict prognostic outcome: an NI <0.9 is associated with substantial wasting in HIV disease, an NI <0.8 predicts significant pathophysiology in chronic renal failure, and a low NI is predictive of neutropenia in breast‐cancer patients. These findings emphasize the central importance of adequate protein stores in recovery from disease or in maintaining quality of life. Aging appears to involve a gradual loss of TBP throughout adulthood. Cross‐sectional data suggest that TBP declines curvilinearly with age, such that there is an accelerated decline after 65 years of age. However, longitudinal data are scarce, and little is known about the relative loss of visceral protein, as opposed to skeletal muscle protein. More clearly‐defined data are essential if the effects of aging per se are to be separated from the effects of chronic disease. A further complication is the knowledge that physical activity also declines with age. Thus sarcopenia, the loss of skeletal muscle mass, could primarily result from disuse rather than aging. The economic impact of unsuccessful aging places a pressing need for multicompartment data in longitudinal study designs.
The Reference Child and Adolescent Models of Body Composition: A Contemporary Comparisona
Authors: ELLIS KENNETH J. , SHYPAILO ROMAN J. , ABRAMS STEVEN A. , WONG WILLIAM W.
Published: July 2010

Abstract: Changes in the relative proportions of bone, muscle, water, visceral tissues, and body fat occur during growth. In the 1980s, reference models of body composition for children and adolescents were constructed by adjusting data on total body water (TBW), total body potassium (TBK), and regional bone mineral (BMC) data from several different Caucasian populations. In our study, we measured TBW, TBK, and total body BMC in 856 healthy European‐American, African‐American, and Mexican‐American children. When we reconstructed the reference models using our contemporary data, we found that the body's bone, protein, and fat compartments are slightly but significantly different from the earlier models. Our study provides the range of normal body composition of healthy children, aged 5–18 years, and accounts for differences related to gender and ethnicity.
Body Composition Measurements during Infancy
Authors: KOO WINSTON W. K.
Published: July 2010

Abstract: Infancy is the period of most rapid postnatal growth and is accompanied by major changes in body composition (BC). There are many challenges to successfully measuring BC of infants in vivo, which include the inherent limitations in the underlying assumptions for each technique. The small body mass and rapid nonuniform changes in body parts, that is, the components of BC during infancy, can strain the technical limits of all methods. Many techniques for in vivo BC measurement used in older people have been applied to infants. However, the vast majority of them either are difficult to adapt for widespread use in infants, or the roles and limitations for using them during infancy are ill‐defined because of limited or no critical validation and cross‐calibration studies. Based on validation data from animals, well‐defined methodological issues in data acquisition and analyses, availability of normative data, and pertinent accuracy and precision of the technique to allow us to determinate clinically relevant changes in BC within a reasonable time interval, three techniques appear to be most suitable for in vivo BC measurement in infants. Anthropometric measurements can be used in field studies or for group comparisons, and total body electrical conductivity (TOBEC) and selected dual‐energy X‐ray absorptiometry (DXA) measurements can be used to compare BC in individual infants. DXA has the advantages of being able to measure bone mass and the potential to be adaptable to the widely available existing instruments. However, regardless of the techniques used in measuring BC in infants, meticulous attention to details in data acquisition and data analysis, and a knowledge of the limitations of the particular technique are the prerequisites for generating valid data.
Body Composition Changes during Tanner Stage 5
Authors: HORLICK MARY , THORNTON JOHN , WANG JACK , LEVINE LENORE S. , FEDUN BARBARA , PIERSON RICHARD N.
Published: July 2010

Abstract: Clinicians use the combination of Tanner stage 5 (T5) of puberty, final height, and epiphyseal fusion to define maturity. We tested the hypothesis that changes in body composition related to age are identifiable during T5. Asian, Black, Hispanic, and White T5 adolescents (n= 148, 72 females) had measurements taken of their height, weight, total body potassium by 40K counting, total body water by D2O dilution; and total body bone mineral, fat‐ free mass, and fat mass by dual‐energy X‐ray absorptiometry. The relative increases with age in lean body components were greater than those in height and weight, and were greater in males. Age was a significant determinant of all body components in males, but of only bone mineral in females. The effect of age was independent of ethnicity. These findings suggest an independent effect of age on body composition during T5, especially in males. We propose that peak levels of lean body components should be included in the definition of maturity in certain clinical and metabolic situations.
Body Composition Studies in HIV‐Infected Individuals
Authors: KOTLER DONALD P.
Published: July 2010

Abstract: Malnutrition is common in HIV infection. Early studies demonstrated a disproportionate depletion of body cell mass compared to body weight, plus relative expansion of extracellular water volume. Neutron activation studies showed that both potassium and nitrogen were depleted in the HIV+ subjects, whereas cross‐sectional imaging documented depletion of skeletal muscle mass. The etiology of malnutrition affects the composition of lost weight. Malnutrition is associated with adverse outcomes, whereas clinical stability is associated with nutritional stability. Increasingly, body composition studies are being incorporated into clinical trials. Hypercaloric feeding promotes gains in weight and body fat, but not in lean mass. Adjunctive therapies include anabolic agents, both steroids and recombinant human growth hormone (rhGH), cytokine inhibitors, and resistance training exercise. In addition to increasing fat‐free mass, these therapies also have benefits in quality of life, notably functional performance, as well as physical function. Current research on alterations in body composition in HIV have noted a redistribution of fat, with visceral obesity in patients receiving highly active antiretroviral therapies.
Early Diagnosis of Lymphedema in Postsurgery Breast Cancer Patients
Authors: CORNISH B. H. , CHAPMAN M. , THOMAS B. J. , WARD L. C. , BUNCE I. H. , HIRST C.
Published: July 2010

Abstract: Lymphedema is an accumulation of lymph fluid in the limb resulting from an insufficiency of the lymphatic system. It is commonly associated with surgical or radiotherapy treatment for breast cancer. As with many progressively debilitating disorders, the effectiveness of treatment is significantly improved by earlier intervention. Multiple frequency bioelectrical impedance analysis (MFBIA) previously was shown to provide accurate relative measures of lymphedema in the upper limb in patients after treatment for breast cancer. This presentation reports progress to date on a three‐year prospective study to evaluate the efficacy of MFBIA to predict the early onset of lymphedema in breast cancer patients following treatment. Bioelectrical impedance measurements of each upper limb were recorded in a group of healthy control subjects (n= 50) to determine the ratio of extracellular limb‐fluid volumes. From this population, the expected normal range of asymmetry (99.7% confidence) between the limbs was determined. Patients undergoing surgery to treat breast cancer were recruited into the study, and MFBIA measurements were recorded presurgery, at one month and three months after surgery, and then at two‐month intervals for up to 24 months postsurgery. When patients had an MFBIA measure outside the 99.7% range of the control group, they were referred to their physician for clinical assessment. Results to date: Over 100 patients were recruited into the study over the past two years; at present, 19 have developed lymphedema and, of these, 12 are receiving treatment. In each of these 19 cases, MFBIA predicted the onset of the condition up to four months before it could be clinically diagnosed. The false‐negative rate currently is zero. The study will continue to monitor patients over the remaining year to accurately ascertain estimates of specificity and sensitivity of the procedure.
Similarity of Changes in Body Composition in Intensive Care Patients following Severe Sepsis or Major Blunt Injury
Authors: PLANK L. D. , HILL G. L.
Published: July 2010

Abstract: Critically ill patients admitted to the intensive care unit with severe sepsis or major blunt injury undergo massive changes in body composition. We compared these changes in 12 patients with generalized peritonitis, and in 18 patients with major blunt injury over a 21‐day period soon after their admission. Body composition was measured as soon as the patients were hemodynamically stable, and again 5, 10, and 21 days later. In both groups, losses in total body protein (TBP) were greatest over the first 10 days. TBP lost over the study period averaged 13.1 ± 1.3 (SEM)% for the sepsis group, and 14.6 ± 1.3% for the trauma group. Total body water (TBW) lost postresuscitation averaged 11.1 ± 1.3 L and 6.7 ± 1.1 L for the two groups, respectively, these changes largely being accounted for by changes in extracellular water (ECW). Our results demonstrate a striking similarity in the changes in total body protein for these two groups of critically ill patients. The sepsis patients retained approximately twice the volume of fluid of those with major trauma.
Development of Our Current Understanding of Bioactive Lysophospholipids
Authors: MOOLENAAR WOUTER H.
Published: July 2010

Abstract: Lysophosphatidic acid (LPA) serves as the prototypic lysophospholipid mediator that acts through G‐protein‐coupled receptors to evoke a host of responses in numerous target cells. The hormone‐and growth‐factor‐like activities of LPA, mediated by distinct G proteins, were discovered about 10 years ago. Since then, considerable progress has been made in our understanding of LPA receptor signaling, culminating in the recent identification of a growing family of heptahelical receptors specific for LPA and the structurally related lysolipid, sphingosine‐1‐phosphate (S1P). In addition to stimulating Gi‐Ras‐mediated cell proliferation, LPA and S1P induce rapid Gα12/13‐RhoA‐mediated cytoskeletal changes underlying such diverse responses as neurite retraction, cell rounding, and enhanced tumor cell invasiveness. LPA also triggers inhibition of gap‐junctional communication. This overview focuses on how our understanding of LPA as an intercellular lipid mediator has developed during the last decade.
Lipid Phosphate Phosphatase‐1 in the Regulation of Lysophosphatidate Signaling
Authors: XU JAMES , ZHANG QIU‐XIA , PILQUIL CARLOS , BERTHIAUME LUC G. , WAGGONER DAVID W. , BRINDLEY DAVID N.
Published: July 2010

Abstract:Mammalian lipid phosphate phosphatases (LPPs, or Type 2 phosphatidate phosphohydrolases) constitute a family of enzymes that belongs to a phosphatase superfamily. The LPPs dephosphorylate a variety of bioactive lipid phosphates including phosphatidate, lysophosphatidate, sphingosine 1‐phosphate, and ceramide 1‐phosphate. Mouse LPP‐1 was stably expressed in rat2 fibroblasts to determine its structural and functional properties. Transduced cells showed increased dephosphorylation of exogenous lysophosphatidate. This result is compatible with mutational studies that show the active site of LPP‐1 to be located on the external surface of the plasma membrane. Elevated LPP‐1 activity attenuated the ability of lysophosphatidate to stimulate mitogen‐activated protein kinase (ERK1 and 2) activities and DNA synthesis. It is concluded that one function of LPP‐1 is to dephosphorylate exogenous lysophosphatidate, thereby attenuating cell signaling through endothelial cell differentiation gene (EDG) receptors.
PPAR‐γ‐Mediated Regulation of Normal and Malignant B Lineage Cells
Authors: PADILLA JOSUÉ , KAUR KULJEET , HARRIS SARAH G. , PHIPPS RICHARD P.
Published: July 2010

Abstract: Prostaglandins of the E‐series stimulate B lymphocytes by enhancing immunoglobulin‐class switching and antibody production. Little is known about whether or not other prostaglandins affect B lineage cells and perhaps counterbalance the stimulatory effects of PGE2. PGD2 is a major product of cyclooxygenase in bone marrow and in macrophages, suggesting a role for this lipid product in immunological responses. PGD2 undergoes dehydration to the biologically active prostaglandin 15‐deoxy‐Δ12,14‐PGJ2 (15d‐PGJ2) that binds to the nuclear receptor known as peroxisome proliferator‐activated receptor gamma (PPAR‐γ). We found that normal mouse B cells and a Wvariety of B lymphoma cells (e.g., 70Z/3, WEHI‐231, CH12, and J558) express PPAR‐γmRNA and the 67‐kDa PPAR‐γ protein. 15d‐PGJ2 had a dose‐dependent antiproliferative/cytotoxic effect on normal and malignant B cells, as shown by 3H‐thymidine and MTT assays. Only PPAR‐γ agonists (i.e., thiazolidinediones) mimicked the effect of 15d‐PGJ2 on B lineage cells, indicating that the mechanism by which 15d‐PGJ2 negatively affects B lineage cells involves PPAR‐γ. The mechanism whereby PPAR‐γ agonists induced cytotoxicity is via apoptosis, as shown by Annexin V assays. PPAR‐γ agonists may serve as a counterbalance to the stimulating effects of PGE2, which promotes B‐cell differentiation. The use of prostaglandins, such as 15d‐PGJ2, and synthetic PPAR‐γ agonists to induce apoptosis in B lineage cells may lead to the development of therapies for fatal PGE2‐resistant B lymphomas.
Neurobiology of Receptor‐Mediated Lysophospholipid Signaling: From the First Lysophospholipid Receptor to Roles in Nervous System Function and Development
Authors: CHUN JEROLD , WEINER JOSHUA A. , FUKUSHIMA NOBUYUKI , CONTOS JAMES J. A. , ZHANG GUANGFA , KIMURA YUKA , DUBIN ADRIENNE , ISHII ISAO , HECHT JONATHAN H. , AKITA CAROL , KAUSHAL DHRUV
Published: July 2010

Abstract: Identification of the first lysophospholipid receptor, LPA1/Vzg‐1, cloned by way of neurobiological analyses on the embryonic cerebral cortex, has led to the realization and demonstration that there exist multiple, homologous LP receptors, including those encoded by a number of orphan receptor genes known as “Edg,” all of which are members of the G‐protein‐coupled receptor (GPCR) superfamily. These receptors interact with apparent high affinity for lysophosphatidic acid (LPA) or sphingosine‐1‐phosphate (S1P or SPP), and are referred to based upon their functional identity as lysophospholipid receptors: LPA and LPB receptors, respectively, with the expectation that additional subgroups will be identified (i.e., LPC, etc.). Here an update is provided on insights gained from analyses of these receptor genes as they relate to the nervous system, particularly the cerebral cortex, and myelinating cells (oligodendrocytes and Schwann cells).
EDG Receptors as a Therapeutic Target in the Nervous System
Authors: BEER MARGARET S. , STANTON JOSEPHINE A. , SALIM KAMRAN , RIGBY MICHAEL , HEAVENS ROBERT P. , SMITH DAVID , MCALLISTER GEORGE
Published: July 2010

Abstract:EDG receptors are a family of closely related G‐protein‐coupled receptors, so‐called since the first family member to be cloned is encoded by anendothelialdifferentiationgene. Of the six family members identified, five use lysophospholipids as their endogenous ligands. The sixth receptor, EDG‐6, remains an orphan. These receptors activate multiple secondary‐messenger pathways involving coupling to Gi, Gq/11, and G12/13 trimeric guanine nucleotide‐binding proteins and are thought to play an important role in cell growth, development and maintenance, and cytoskeletal‐dependent changes.

EDG receptors are expressed in most mammalian cells and tissues, each subtype having a distinct distrubution pattern, raising the possibility of tissue‐specific biological roles that could be explored in drug‐discovery programs. In this study the distribution of EDG‐receptor mRNA within the nervous system has been investigated. As seen in peripheral tissues, these receptors appear to be discretely localized within specific brain regions and cell types. For example, EDG‐1, ‐3, ‐4 receptors are confined to neuronal cells, EDG‐2 receptors to white matter tracts, while EDG‐5 receptors appear to be expressed in various cell types, including neuronal cells, white matter tracts, and ependymal cells. EDG‐6‐receptor mRNA was not detected in the nervous system.

Speculation as to the role of these receptors in physiological/pathophysiological processes, particularly those involving cell development, proliferation, maintenance, migration, differentiation, plasticity, and apoptosis can be made from such distribution studies. EDG receptors located in brain neuronal cells might, for example, influence apoptosis and be involved in cell rescue following ischemic damage or during the early stages of progressive neurodegenerative diseases. Those restricted to oligodendrocytes might play a crucial role in myelination and offer a potential target in the treatment of demyelinating diseases, such as multiple sclerosis. In order to explore the role of these receptors, it is necessary to identify selective compounds. To this end we have developed an agonist‐induced [35S]GTPγS binding assay using an HEK cell line expressing a pertussis‐toxin‐insensitive human‐EDG‐2‐receptor‐rat‐Giα1‐fusion protein. Such as assay system ovecomes the problems associated with the almost ubiquitous responsiveness of mammalian cells to lysophospholipid. This assay lends itself to high throughput application, opening up the possibility of identifying compounds to further probe the therapeutic potential of EDG receptor manipulation
Lysophospholipid Growth Factors in the Initiation, Progression, Metastases, and Management of Ovarian Cancer
Authors: FANG XIANJUN , GAUDETTE DOUGLAS , FURUI TATSURO , MAO MULING , ESTRELLA VERONICA , EDER ASTRID , PUSTILNIK TERRI , SASAGAWA TAKAYO , LAPUSHIN RUTHIE , YU SHIANGXING , JAFFE ROBERT B. , WIENER JON R. , ERICKSON JAMES R. , MILLS GORDON B.
Published: July 2010

Abstract:Levels of lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC) are elevated in the plasma and ascites of ovarian cancer patients, but not in most other tumor types. LPA increases cell proliferation, cell survival, resistance to cisplatin, cell shrinkage, and production of vascular endothelial growth factor, urokinase plasminogen activator, and LPA itself in ovarian cancer cells, but not in normal ovarian surface epithelial cells. PSP24 and members of the endothelial differentiation gene (EDG) family (EDG1, EDG2, EDG4, and EDG7) of G protein‐coupled receptors mediate LPA signaling. Ovarian cancer cell lines do not express EDG1 mRNA, have variable EDG2 mRNA and protein levels, and frequently exhibit elevated levels of EDG4 mRNA and protein, suggesting that EDG4 may contribute to the deleterious effects of LPA in ovarian cancer. In contrast, activation of the EDG2 LPA receptor on ovarian cancer cells may lead to apoptosis and counter the effects of other LPA receptors. Thus, the development of agonists and antagonists for the appropriate spectrum of LPA receptors may alter proliferation, apoptosis, or response to therapy of ovarian cancer cells. Indeed, over 60% of all current drugs target the G protein‐coupled family of receptors, making the LPA receptor family a “drugable” target. LPC, although not as thoroughly studied, increases cellular proliferation and mediates multiple other functions through unique signaling pathways.
Detection of Microsatellite Alterations in the DNA Isolated from Tumor Cells and from Plasma DNA of Patients with Lung Cancer
Authors: BRUHN N. , BEINERT T. , OEHM C. , JANDRIG B. , PETERSEN I. , CHEN X. Q. , POSSINGER K. , FLEISCHHACKER M.
Published: July 2010

Abstract: In this paper, we show that the same panel of three microsatellite markers is useful for the detection of alterations in the DNA of tumor cells and plasma from patients diagnosed with SCLC and NSCLC. In 31% of the SCLC patients, we detected a microsatellite alteration(s) or LOH in at least one locus. In the group of patients diagnosed with NSCLC, a microsatellite alteration or LOH was detected in at least one locus in 33% of the patients. In all but 2 patients, the identical alteration observed in the DNA from tumor cells was also detected in the DNA isolated from blood plasma. This work confirms the results described by other groups and it extends the diagnostic possibilities of finding tumor cell‐specific DNA alterations also in the DNA freely circulating in plasma and serum of patients with cancer.
DNA Release by Line‐1 (L1) Retrotransposon Could It Be Possible?
Authors: ALVES GILDA , KAWAMURA MÁRCIA T. , NASCIMENTO PATRÍCIA , MACIEL CARLA , OLIVEIRA JOSÉ ANTÔNIO , TEIXEIRA ANSELMO , CARVALHO MARIA DA GLÓRIA C.
Published: July 2010

Abstract: We have verified the presence of line‐1 retrotransposon (L1) in plasma DNA in 15/17 brain tumor (glioma) patients and in 6/6 healthy people by applying PCR amplification of part of the L1 5′ end. The same samples were separately amplified for K‐ras. Results suggested that L1 sequences are circulating throughout the body. We hypothesized the participation of transposable elements such as L1 in a putative DNA release mechanism.
Fetal DNA in Maternal Plasma
Authors: LO Y. M. DENNIS
Published: July 2010

Abstract: Recently, cell‐free fetal DNA has been found in maternal plasma and serum. This discovery opens up a new field of investigation and provides an easily accessible source of fetal genetic material for prenatal diagnosis. Prenatal diagnostic applications of fetal DNA in maternal plasma include the investigation of sex‐linked disorders and fetal rhesus D status determination. Cell‐free fetal DNA has been found to be present in much higher fractional concentrations than fetal nucleated cells in maternal blood. The concentration of fetal DNA increases throughout pregnancy, with a sharp rise towards the end of gestation. Abnormally high levels of cell‐free DNA have been found in pregnancies complicated by preeclampsia and preterm labor, an observation that has potential diagnostic and pathophysiologic implications. Much remains to be learned regarding the mechanisms of production and clearance of maternal plasma fetal DNA. It is hoped that the eagerly awaited answers to these and other questions may ultimately enhance our understanding of the fetomaternal relationship.
Desires in Human Mating
Authors: BUSS DAVID M.
Published: July 2010

Abstract:This chapter traces theoretical and empirical progress in the study of human mating over the past few decades. Early pre‐evolutionary formulations proposed that men and women were identical in their mating motivations. Most were simplistic, typically postulating a single motive for mating: the search for similarity, equity, or complementarity. Given the large sex differences in human reproductive biology, notably women bearing the burdens of internal fertilization and a greater obligatory parental investment, it would be extraordinarily unlikely that evolution by selection would fail to forge sex‐differentiated mating strategies. Empirical research over the past 15 years has robustly confirmed evolutionary predictions in the domains of desire for sexual variety, the importance of fertility cues, and the importance of resource‐provisioning. Recent work has revealed a hidden side of women's sexuality‐a desire for extra‐pair partners and the conditions under which this desire is expressed. We now have the theoretical and empirical outlines of an evolutionary formulation of human mating strategies.
Human Sexual Selection, Good Genes, and Special Design
Authors: GANGESTAD STEVEN W.
Published: July 2010

Abstract:Evolutionary psychology seeks to understand the functional design underlying psychological processes and behavior. Theories of selection pressures developed within evolutionary biology are key components of this understanding. Because past selection pressures responsible for current design cannot be directly observed, theoretical understandings of the psychological processes and behavior must be inferred. The most important epistemological concept within evolutionary psychology is that of special design‐evidence that a feature exhibits specificity, efficiency, and economy for producing a particular beneficial effect. A variety of sexual‐selection processes have been proposed to account for aspects of human mating. These processes are not mutually exclusive. More than one may account for aspects of human mating. A core task of evolutionary psychology within this domain is to identify which processes account for which phenomena. I have attempted to illustrate how the search for special design is central to this endeavor.
The Optimal Number of Fathers: Evolution, Demography, and History in the Shaping of Female Mate Preferences
Authors: HRDY SARAH BLAFFER
Published: July 2010

Abstract:Around the world polygynous marriage (one man, several women) is vastly more common than polyandrous marriage (one woman, several men), and women tend to be more cautious about entering into sexual relationships than men are. Such patterns are often assumed to reflect essential differences between the sexes. However, the same dichotomy between “ardent” males and “coy” females is not found in other primates. Furthermore, under a range of circumstances females enhance their reproductive success by mating with multiple partners and usepolyandrous mating(soliciting copulations from several or more males) to circumvent male‐imposed costs on their free choice of mates. The existence of one‐male mating systems does not prove that females “naturally” gravitate to them. Typically monandrous (copulating with just one partner) mating systems are maintained by one male excluding rivals or by other circumstances that distort female options. As with many other animals, primate females (including women) can benefit reproductively from polyandrous matings. Understanding this takes us beyond narrow research programs intent on demonstrating “universal” differences between the sexes, and allows us to study females as flexible and opportunistic individuals who confront recurring reproductive dilemmas and tradeoffs within a world of shifting options.
The Other “Closest Living Relative”: How Bonobos (Pan paniscus) Challenge Traditional Assumptions about Females, Dominance, Intra‐ and Intersexual Interactions, and Hominid Evolution
Authors: PARISH AMY R. , DE WAAL FRANS B. M. , HAIG DAVID
Published: July 2010

Abstract: Chimpanzee (Pan troglodytes) societies are typically characterized as physically aggressive, male‐bonded and male‐dominated. Their close relatives, the bonobos (Pan paniscus), differ in startling and significant ways. For instance, female bonobos bond with one another, form coalitions, and dominate males. A pattern of reluctance to consider, let alone acknowledge, female dominance in bonobos exists, however. Because both species are equally “man's” closest relative, the bonobo social system complicates models of human evolution that have historically been based upon referents that are male and chimpanzee‐like. The bonobo evidence suggests that models of human evolution must be reformulated such that they also accommodate: real and meaningful female bonds; the possibility of systematic female dominance over males; female mating strategies which encompass extra‐group paternities; hunting and meat distribution by females; the importance of the sharing of plant foods; affinitive inter‐community interactions; males that do not stalk and attack and are not territorial; and flexible social relationships in which philopatry does not necessarily predict bonding pattern.
Melanin Accumulation Accelerates Melanocyte Senescence by a Mechanism Involving p16INK4a/CDK4/pRB and E2F1
Authors: BANDYOPADHYAY DEBDUTTA , MEDRANO ESTELA E.
Published: July 2010

Abstract: Cellular and molecular evidence suggests that senescence is a powerful tumor‐suppressor mechanism that prevents most higher eukaryotic cells from dividing indefinitely in vivo. Recent work has demonstrated that α‐mel‐anocyte stimulating hormone (α‐MSH) or cholera toxin (CT) can activate a cAMP pathway that elicits proliferative arrest and senescence in normal human pigmented melanocytes. In these cells, senescence is associated with increased binding of p16INK4a to CDK4 and loss of E2F‐binding activity. Because senescence may provide defense against malignant transformation of melanocytes, and because pigmentation is a strong defense against melanoma, we examined the ability of melanocytes derived from light and dark skin to respond to CT. Here we demonstrate that in melanocytes derived from dark‐skinned individuals, CT‐induced melanogenesis is associated with accumulation of the tumor suppressor p16INK4a, underphosphorylated retinoblastoma protein (pRb), downregulation of cyclin E, decreased expression of E2F1, and loss of E2F‐regulated S‐phase gene expression. In contrast to other senescent cell types, melanocytes have reduced or absent levels of the cyclin‐dependent kinase inhibitors p27Kip1 and p21Waf‐1. Importantly, melanocytes derived from light‐skinned individuals accumulated smaller amounts of melanin than did those from dark‐skinned individuals under the same conditions, and they continued to proliferate for several more division cycles. This delayed senescence may result from reduced association of p16 with CDK4, reduced levels of underphos‐phorylated pRb, and steady levels of cyclin E and E2F1. Because cyclin E‐CDK2 inhibition is required for p16‐mediated growth suppression, 1 upregulation of p16 and downregulation of cyclin E appear essential for maintenance of terminal growth and senescence. Given the rising incidence of melanoma, identification of major growth regulatory proteins involved in senescence should shed light on the biology of this genetically mysterious tumor.
Role of Oxidative Stress in Telomere Length Regulation and Replicative Senescence
Authors: VON ZGLINICKI THOMAS
Published: July 2010

Abstract: Replicative senescence is tied into organismal aging processes in more than one respect, and telomeres appear to be the major trigger of replicative senescence under many conditions in vitro and in vivo. However, the structure‐function relationships in telomeres, the mechanisms of telomere shortening with advancing replicative age, and the regulation of senescence by telomeres are far from understood. Combining recent data on telomere structure, function of telomere‐binding proteins, and sensitivity of telomeres to oxidative damage, an integrative model of telomere shortening and signaling is developed. The model suggests that t‐loop formation hinders access of repair proteins to telomeres, leading to accumulation of abasic sites and single‐strand breaks. These might contribute to accelerated telomere shortening by transient stalling of replication as well as, if present in high concentrations, to a relief of torsional tension which might destabilize the telomeric loop structure. As a result, the single‐stranded G‐rich overhang, which is present at the very ends of telomeres but is normally protected at the base of the telomeric loop, will be exposed to the nucleoplasm. Free G‐rich telomeric single strands are a strong inductor of the p53 pathway, and exposure of the overhangs seems to be the first step in the signal transduction cascade to replicative senescence.
Aging and Longevity: A Paradigm of Complementation between Homeostatic Mechanisms and Genetic Control?
Authors: PETROPOULOU CHARIKLIA , CHONDROGIANNI NIKI , SIMÕES DAVINA , AGIOSTRATIDOU GEORGIA , DROSOPOULOS NATALIA , KOTSOTA VIOLETTA , GONOS EFSTATHIOS S.
Published: July 2010

Abstract: Aging is a universal and inevitable phenomenon that affects nearly all animal species. It can be considered the product of an interaction between genetic, environmental, and lifestyle factors, which in turn influence longevity that varies between and within species. It has been proposed not only that the aging process is under genetic control, but that it can also be considered a result of the failure of homeostasis due to the accumulation of damage. This review article discusses these issues, focusing on the function of genes that associate with aging and longevity, as well as on the molecular mechanisms that control cell survival and maintenance during aging.
Inflamm‐aging: An Evolutionary Perspective on Immunosenescence
Authors: FRANCESCHI CLAUDIO , BONAFÈ MASSIMILIANO , VALENSIN SILVANA , OLIVIERI FABIOLA , DE LUCA MARIA , OTTAVIANI ENZO , DE BENEDICTIS GIOVANNA
Published: July 2010

Abstract: In this paper we extend the “network theory of aging,” and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as “inflamm‐aging,” is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age‐related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ‐specific age‐related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
Transgenic Mouse Models of Alzheimer's Disease
Authors: BORNEMANN KLAUS D. , STAUFENBIEL MATTHIAS
Published: July 2010

Abstract: Alzheimer's disease (AD) pathology is characterized by Aβ peptide‐containing plaques, neurofibrillary tangles consisting of hyperphosphorylated tau, extensive neuritic degeneration, and distinct neuron loss. We generated several transgenic mouse lines expressing the human amyloid precursor protein (APP751) containing the AD‐linked KM670/671NL double mutation (Swedish mutation) under the control of a neuron‐specific Thy‐1 promoter fragment. In the best APP‐expressing line (APP23), compact Aβ deposits can be detected at 6 months of age. These plaques dramatically increase with age, are mostly Congo Red positive, and accumulate typical plaque‐associated proteins such as heparansulfate proteoglycan and apolipoprotein E. Activated astrocytes and microglia indicative of inflammatory processes reminiscent of AD accumulate around the deposits. Furthermore, plaques are surrounded by enlarged dystrophic neurites as visualized by neurofilament or Holmes‐Luxol staining. Strong staining for acetylcholinesterase activity is found throughout the plaques and is accompanied by local distortion of the cholinergic fiber network. All congophilic plaques contain hyperphosphorylated tau reminiscent of early tau pathology. Modern stereologic methods demonstrate a significant loss of neurons in the hippocampal CA1 region, correlating with an increasing Aβ plaque load. Interestingly, APP23 mice develop cerebral amyloid angiopathy in addition to amyloid plaques even though the APP transgene is only expressed in neurons. Crossbreeding of APP23 mice with transgenic mice carrying AD‐linked presenilin mutations but not wild‐type presenilin resulted in enhanced formation of pathology. In conclusion, our APP transgenic mice present many pathologic features, similar to those observed in AD and therefore offer excellent tools for studying the contribution of Aβ to AD pathogenesis.
Biogerontology: The Next Step
Authors: RATTAN SURESH I.S.
Published: July 2010

Abstract: After a long period of collecting empirical data describing the changes in organisms, organs, tissues, cells, and macromolecules, biogerontological research is now able to develop various possibilities for intervention. Because aging is a stochastic and nondeterministic process characterized by a progressive failure of maintenance and repair, it is reasoned that genes involved in homeodynamic repair pathways are the most likely candidate gerontogenes. A promising approach for the identification of critical gerontogenic processes is through the hormesis‐like positive effects of mild stress. Stimulation of various repair pathways by mild stress has significant effects on delaying the onset of various age‐associated alterations in cells, tissues, and organisms.
Peripheral Opioid Modulation of Visceral Paina
Authors: GEBHART G. F. , SU XIN , JOSHI SHAILEN , OZAKI N. , SENGUPTA J. N.
Published: July 2010

Abstract:Opioids are widely and successfully used for control of pain, including pain arising from the viscera. Constipating, sedating, respiratory depressant and other effects of opioids, however, often limit their long‐term use in the treatment of a variety of visceral pain states. Accordingly, understanding visceral pain mechanisms and its modulation is important to developing improved strategies for pain control.
Tobacco Dependence: Global Public Health Potential for New Medications Development and Indications
Authors: HENNINGFIELD JACK E. , FANT REGINALD V. , GITCHELL JOSEPH , SHIFFMAN SAUL
Published: July 2010

Abstract: Current trends indicate that approximately 500 million of the world's existing cigarette smokers will prematurely die of causes that could be prevented by treatment of their addiction to tobacco delivered nicotine. Initial pharmacologically based treatment offerings and approaches have proven the concept that increasing the accessibility and diversity of treatment modalities helps more people quit smoking. These treatments have also shown, however, that the vast majority of smokers continues to find treatment less attractive and less accessible than cigarettes whose appeal is constantly stimulated by new formulations, marketing strategies, and implied claims of reduced risk. There appears to be considerable untapped potential public health benefit, as well as commercial opportunity, for medication developers to reach an increasing fraction of smokers who find current treatments unacceptable, inaccessible, or ineffective. The global opportunities to serve public health via medication development are growing even more rapidly as country after country recognizes the impending economic and health care problems posed by tobacco dependence and are opening their doors to treatment. Three areas of medications development offer particular promise: new forms of nicotine delivery, non‐nicotine based medications, and new indications to reach those who are unable or unwilling to completely quit. This article discusses the biobehavioral rationale for medication development, the opportunities, and some of the prominent technical and regulatory challenges.
Pathology of Hereditary Nonpolyposis Colorectal Cancer
Authors: JASS JEREMY R.
Published: July 2010

Abstract: The magnitude of the pathologist's role in the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) is underestimated. The diagnostic features are not specific to HNPCC cancers, but relate to all cancers showing high levels of DNA microsatellite instability (MSI‐H). Three major groups of MSI‐H cancers can be recognized by histopathological criteria: (1) right‐sided poorly differentiated cancers, (2) right‐sided mucinous cancers, and (3) adenocarcinomas in any location showing tumor‐infiltrating (intraepithelial) lymphocytes (TIL). The poorly differentiated cancers are relatively well circumscribed and the cells are arranged in sheets or trabeculae. TIL may be very numerous in poorly differentiated cancers. The presence of TIL as estimated in H&E sections equates with a percentage of intraepithelial T cells (CD3+) in the range of 4 to 30%. Most of the T cells are CD8+ (cytotoxic T cells). Peritumoral lymphocytes and the so‐called Crohn's‐like reaction are associated with TIL, but are harder to quantify. Of the 15% of colorectal cancers that are MSI‐H, 13% will be sporadic and 2% will occur in the context of HNPCC. HNPCC should be suspected if the patient is young (less than 55 years) because sporadic MSI‐H cancers (associated with hypermethylation of the promoter region of hMLH1) occur almost exclusively in elderly subjects. Workup of a suspected case should include DNA microsatellite testing with a panel of mononucleotide (e.g., BAT26, BAT25) and dinucleotide (e.g., D5S346, D2S123, and D177S250) markers before referral to a cancer family or clinical genetics clinic. Immunohistochemical staining for hMLH1 and hMSH2 identifies the underlying mutation in a proportion of cases. The colorectal adenoma is the usual precursor lesion in HNPCC, though serrated polyps are implicated in a small subset.
Altered Mechanisms of Apoptosis in Colon Cancer: Fas Resistance and Counterattack in the Tumor‐Immune Conflict
Authors: O'CONNELL JOE , BENNETT MICHAEL W. , NALLY KENNETH , HOUSTON AILEEN , O'SULLIVAN GERALD C. , SHANAHAN FERGUS
Published: July 2010

Abstract: Fas (CD95/APO‐1) is a cell surface “death receptor” that mediates apoptosis upon engagement by its ligand, FasL. Fas‐mediated apoptosis of lymphocytes normally serves immunoregulatory roles, including tolerance acquisition, immune response termination, and maintenance of immune privilege in certain organs. Colon tumors can exploit this lymphocyte death program by expressing FasL. This may enable colon tumors to mount a “Fas counterattack” against antitumor lymphocytes, impairing antitumor immune responses. FasL‐expressing colon tumor‐derived cell lines can trigger Fas‐mediated apoptosis of cocultured T cells in vitro. FasL expressed in esophageal cancer has been significantly associated with apoptosis and depletion of tumor‐infiltrating lymphocytes (TIL) in vivo. FasL may also facilitate metastatic colonization of Fas‐sensitive organs such as the liver, by inducing apoptosis of target organ cells. Normal colonic epithelial cells express Fas and are relatively sensitive to Fas‐mediated apoptosis. By contrast, colon tumor‐derived cell lines are usually resistant to induction of Fas‐mediated apoptosis, and colon cancer cells frequently coexpress Fas and FasL. The mechanisms allowing resistance to Fasmediated apoptosis are complex, and defects have been identified at several levels of Fas signal transduction. The “Bcl‐2 rheostat” may be pitched against apoptosis in colon cancer, inasmuch as overexpression of Bcl‐2, downregulation of Bak, and mutation of Bax are common defects in colon tumors. Caspase‐1 is also downregulated in colon cancer. The high frequency of p53 mutations in late‐stage cancers may also inhibit Fas signaling. Fundamental defects in apoptosis signaling may contribute to both immuno‐ and chemoresistance in colon cancer and allow expression of FasL to counterattack antitumor lymphocytes.
Oscillatory Activity in Entorhinal Neurons and Circuits: Mechanisms and Function
Authors: DICKSON CLAYTON T. , MAGISTRETTI JACOPO , SHALINSKY MARK , HAMAM BASSAM , ALONSO ANGEL
Published: July 2010

Abstract: Layers II and V of the entorhinal cortex (EC) occupy a privileged anatomical position in the temporal lobe memory system that allows them to gate the main flow of information in and out of the hippocampus, respectively. In vivo studies have shown that layer II of the EC is a robust generator of theta as well as gamma activity. Theta may also be present in layer V, but the layer V network is particularly prone to genesis of short‐lasting high‐frequency oscillations (“ripples”). Interestingly, in vitro studies have shown that EC layers II and V, but not layer III, have the potential to act as independent pacemakers of population oscillatory activity. Moreover, it has also been shown that sub‐groups of principal neurons both within layers II and V, but not layer III, are endowed with autorhythmic properties. These are characterized by subthreshold oscillations where the depolarizing phase is driven by the activation of “persistent” Na+ channels. We propose that the oscillatory properties of layer II and V neurons and local circuits are responsible for setting up the proper temporal dynamics for the coordination of the multiple sensory inputs that converge onto EC and thus help to generate sensory representations and memory encoding.