bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiomyopathy and Encephalopathy in AIDS
Authors: ANTINORI ANDREA , GIANCOLA MARIA LETIZIA , ALBA LUCIA , SOLDANI FABIO , GRISETTI SUSANNA
Published: July 2010

Abstract: HIV encephalopathy has been in the past years the most typical CNS disorder in patients with AIDS. Histologic abnormalities consist in astrocytosis, myelin pallor, infiltration by infected macrophages, resident microglia and multinucleated giant cells, generally in absence of direct infection of neurons. Mononuclear phagocytes in the brain are the main target of HIV‐1 infection and the site of productive viral replication, and viral stimulation leads to the release of neurotoxic products causing neurologic damage. Subclinical cardiac abnormalities are common in HIV+ patients and several studies suggested a role for cytokines and other inflammatory products as mediators of cardiac abnormalities. The common pathway for neurologic and cardiac manifestations supports the relationship between neurologic disease and cardiac dysfunction in HIV infection. Clinical observations suggest that cardiomyopathy could be associated with encephalopathy in HIV+ patients and that it may affect survival. Antiretroviral therapy may reduce impact of neurologic and cardiac abnormalities by suppressing plasma HIV‐1 viral load.
Apoptosis and the Heart
Authors: TOMEI L. DAVID , UMANSKY SAMUIL R.
Published: July 2010

Abstract: Cardiomyopathies are observed with increasing frequency in association with AIDS and HIV infection. Although indirect evidence exists suggesting an association between apoptosis regulation and HIV infection, there is yet no direct evidence that HIV‐associated cardiomyopathies involve increased level of apoptosis in the heart. However, since it is now known that apoptosis plays a significant role in heart injury associated with other conditions such as ischemia/reperfusion and heart failure, there is a possibility that dysregulation of apoptosis plays a similarly important role in HIV‐associate cardiomyopathies. Here we will briefly review the evidence that apoptotic death of cardiomyocytes occurs and what novel therapeutic strategies may be suggested.
Cardiac Manifestations of HIV Infection in Infants and Children
Authors: KEESLER MARCIE J. , FISHER STACY D. , LIPSHULTZ STEVEN E.
Published: July 2010

Abstract: Cardiac manifestations of HIV infection in children are common, but etiologies, contributing factors, and the natural history are largely unexplored. The Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted Human Immunodeficiency Virus Infection Study (P2C2 HIV Study) was initiated in 1989 by the National Heart, Lung and Blood Institute, USA. A primary objective of this study is to examine the epidemiology of cardiovascular problems associated with HIV infection in a cohort of children vertically infected. Findings of the study thus far show that cardiovascular problems associated with HIV infection including left ventricular dysfunction and increased left ventricular mass are common and clinically important indicators of survival for children infected with HIV.
Clinical Manifestation of HIV‐Related Pulmonary Hypertension
Authors: PETROSILLO NICOLA , PELLICELLI ADRIANO M. , BOUMIS EVANGELO , IPPOLITO GIUSEPPE
Published: July 2010

Abstract: In recent years, much more thought has been given to the pathogenic role of HIV and to the clinical manifestations of HIV‐related pulmonary hypertension (HRPH), which currently represents one of the most severe events during HIV disease. HRPH occurs in early and late stages of HIV infection and does not seem to be related to the degree of immune deficiency. Many of the symptoms in HRPH result from right ventricular dysfunction: the first clinical manifestation is effort intolerance and exertional dyspnea that will progress to the point of breathlessness at rest. The diagnosis of HRPH can be made only after all etiologies for pulmonary hypertension have been excluded. Echocardiography has been proven to be an extremely useful tool for diagnosing HRPH, and Doppler echocardiography can be used to estimate systolic pulmonary artery pressure and to monitor the effects of therapy. Assessment of hemodynamic measures by catheterization remains, however, the best test for evaluating response to therapy. Cardiac catheterization is mandatory to characterize the disease and exclude an underlying cardiac shunt as etiology. Vasodilators have been extensively used in the treatment of pulmonary hypertension, since vasoconstriction is a determinant characteristic of this disease. However, HRPH remains a progressive disease for which treatment is often unsatisfactory and there is no cure. As new, more efficient antiretroviral treatment are introduced, clinicians should expect to encounter an increasing number of cases of pulmonary hypertension in HIV+ patients in the future.
Cardiovascular Monitoring and Therapy for HIV‐Infected Patients
Authors: LIPSHULTZ STEVEN E. , FISHER STACY D. , LAI WYMAN W. , MILLER TRACIE L.
Published: July 2010

Abstract: Cardiovascular complications are important contributors to morbidity and mortality in HIV‐infected patients. These complications can usually be detected at subclinical levels with monitoring, which can help guide targeted interventions. This article reviews available data on types and frequency of cardiovascular manifestations in HIV+ patients and proposes monitoring strategies aimed at early subclinical detection. In particular, we recommend routine echocardiography for HIV+ patients, even those with no evidence of cardiovascular disease. We also review preventive and therapeutic cardiovascular interventions. For procedures that have not been studied in HIV+ patients, we extrapolate from evidence‐based guidelines for the general population.
Hemodynamics and the Focal Origin of Atherosclerosis
Authors: DAVIES PETER F. , SHI CONGZHU , DePAOLA NATACHA , HELMKE BRIAN P. , POLACEK DENISE C.
Published: July 2010

Abstract: Atherosclerosis originates at predictable focal and regional sites that are associated with complex flow disturbances and flow separations in large arteries. The spatial relationships associated with hemodynamic shear stress forces acting on the endothelial monolayer are considered in experiments that model regions susceptible to atherosclerosis (flow disturbance) and resistant to atherosclerosis (undisturbed flow). Flow disturbance in vitro induced differential expression at the single gene level as illustrated for the intercellular communication gene and protein, connexin 43. Transcription profiles of individual endothelial cells isolated from both disturbed and undisturbed flow regions exhibited more expression heterogeneity in disturbed than in undisturbed flow. We propose that within highly heterogeneous populations of endothelial cells located in disturbed flow regions, proatherosclerotic gene expression may occur within the range of expression profiles induced by the local hemodynamics. These may be sites of initiation of focal atherosclerosis. Mechanisms are proposed to account for heterogeneous endothelial responses to shear stress by reference to the decentralized model of endothelial mechano‐transduction. Length scales ranging from centimeters to nanometers are useful in describing regional, single cell, and intracellular mechanotransduction mechanisms.
Perivascular Responses after Angioplasty Which May Contribute to Postangioplasty Restenosis
Authors: WILCOX JOSIAH N. , OKAMOTO EI‐ICHI , NAKAHARA KEN‐ICHI , VINTEN‐JOHANSEN JAKOB
Published: July 2010

Abstract: These studies suggest that the adventitia may play a role in vascular lesion formation after balloon overstretch injury of pig coronary arteries by contributing to the cellular mass of the neointima and the synthesis of growth factors. In addition, the adventitia may contribute to vascular remodeling and constriction of the external elastic lamina through accumulation of myofibroblasts containing alpha smooth muscle actin in the adventitia surrounding the injury site. Inhibition of myofibroblast proliferation and/or recruitment by intravascular brachytherapy positively affects vascular remodeling through its action on adventitial cells. Inflammation is a major event associated with balloon angioplasty, resulting in the sequential recruitment of neutrophils (2‐24 hours) and monocyte/macrophages (24‐72 hours) predominantly into the adventitia surrounding the injury site. It is hypothesized that inflammatory cells release cytokines and/or increase the production of superoxides which stimulate the proliferation and recruitment of adventitial myofibroblasts. Inflammatory and proliferative responses were not confined to the local adventitia but were found extending as far as 1‐3 mm away from the injured vessel in the distal perivascular tissues. Studies were performed to examine the expression of genes associated with cell migration at early times after injury in an attempt to determine the source of the adventitial myofibroblasts. Expression of genes involved in cell migration including MMP‐2, MMP‐9, and tenascin was found as early as 2 hours following angioplasty in the intramyocardial, pericardial, and adipose tissue fibroblasts. While these studies suggest that local tissue was the source of the myofibroblasts recruited to the injury site, we have been unable to confirm this finding by direct fluorescent labeling of adventitial cells. Recent work from our laboratory suggests that myofibroblast precursors may be isolated from buffy coat preparations from peripheral blood. These results lead us to hypothesize that stem cells that differentiate into myofibroblasts may be recruited in early inflammatory infiltrates in the adventitia. Clearly, additional work will have to be directed at a more detailed examination of the response of adventitial and other perivascular cells and tissues to balloon injury to determine their sources and their role in regulating vascular lesion development.
Endothelial Atheroprotective and Anti‐inflammatory Mechanisms
Authors: BERK BRADFORD C. , ABE JUN‐ICHI , MIN WANG , SURAPISITCHAT JAMES , YAN CHEN
Published: July 2010

Abstract: Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, whereas laminar flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor‐α (TNF), have been shown to stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent data suggest that steady laminar flow decreases EC apoptosis and blocks TNF‐mediated EC activation. EC apoptosis is likely important in the process termed “plaque erosion” that leads to platelet aggregation. Steady laminar flow inhibits EC apoptosis by preventing cell cycle entry, by increasing antioxidant mechanisms (e.g., superoxide dismutase), and by stimulating nitric oxide‐dependent protective pathways that involve enzymes PI3‐kinase and Akt. Conversely, our laboratory has identified nitric oxide‐independent mechanisms that limit TNF signal transduction. TNF regulates gene expression in EC, in part, by stimulating mitogen‐activated protein kinases (MAPK) which phosphorylate transcription factors. We hypothesized that fluid shear stress modulates TNF effects on EC by inhibiting TNF‐mediated activation of MAP kinases. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm2) on TNF‐stimulated activity of two MAP kinases: extracellular signal regulated kinase (ERK1/2) and c‐Jun N‐terminal kinase (JNK). Flow alone stimulated ERK1/2 activity, but decreased JNK activity compared to static controls. TNF (10 ng/ml) alone activated both ERK1/2 and JNK maximally at 15 minutes in human umbilical vein EC (HUVEC). Pre‐exposing HUVEC for 10 minutes to flow inhibited TNF activation of JNK by 46%, but it had no significant effect on ERK1/2 activation. Incubation of EC with PD98059, a specific mitogen‐activated protein kinase kinase inhibitor, blocked the flow‐mediated inhibition of TNF activation of JNK. Flow‐mediated inhibition of JNK was unaffected by 0.1 mM L‐nitroarginine, 100 μM 8‐bromo‐cyclic GMP, or 100 μM 8‐bromo‐cyclic AMP. Transfection studies with dominant negative constructs of the protein kinase MEK1 and MEK5 suggested an important role for BMK1 in flow‐mediated regulation of TNF signals. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms.
Metabolism of Triglyceride‐Rich Lipoproteins and Their Role in Atherosclerosis
Authors: TANAKA AKIRA , AI MASUMI , KOBAYASHI YASUSHI , TAMURA MICHIRO , SHIMOKADO KENTARO , NUMANO FUJIO
Published: July 2010

Abstract: Recent large‐scale clinical trials indicate that hypertriglyceridemia is a risk factor in coronary artery disease; however, the mechanism has not yet been completely clarified. We are currently studying the metabolism of triglyceride‐rich lipoproteins and their role in atherosclerosis. Remnants, one of atherogenic lipoproteins, showed a marked increase and remained high even 8 hours after fat loading, especially in patients with coronary artery disease or diabetes mellitus. This shows that the postprandial state persists almost the whole day in these patients. Accordingly, it may be important to assess postprandial remnant concentrations when evaluating risk factors for atherosclerosis. We identified apo B100 expression in the epithelial cells of the small intestine by immunoblotting with anti‐apo B100 monoclonal antibody and dot‐blotting of PCR‐amplified cDNA. This indicates that not only apo B48, but also apo B100 is expressed in human small intestinal epithelium. The expression of apo B100 suggests that dietary VLDL may be synthesized in human small intestinal epithelium and converted into LDL, which may play an important role in atherosclerosis. A new receptor, apo B48, which binds and internalizes triglyceride‐rich lipoproteins via a domain in apo B48, was identified in human monocyte‐macrophages. The receptor differs from the scavenger receptor family and LDL receptor family because it does not bind acetyl LDL and it does bind VLDL devoid of apo E. Immunohistochemical studies indicate colocalization of anti‐apo B48 receptor antibody in human atherosclerotic lesion foam cells, suggesting that apo B48 receptor may contribute to foam cell formation and atherosclerosis.
Decoy Oligodeoxynucleotides As Novel Cardiovascular Drugs for Cardiovascular Disease
Authors: MORISHITA RYUICHI , AOKI MOTOKUNI , KANEDA YASUFUMI
Published: July 2010

Abstract: Gene therapy is emerging as a potential strategy in the treatment of cardiovascular disease such as restenosis after angioplasty, vascular bypass graft occlusion, and transplant coronary vasculopathy, for which no known effective therapy exists. One strategy for combatting disease processes is to target the transcriptional process. Application of DNA technology such as antisense strategy to regulate the transcription of disease‐related genes in vivo has important therapeutic potential. Recently, transfection of cis‐element double‐stranded oligodeoxynucleotides (= decoy) as a powerful tool in a new class of antigene strategies for gene therapy was reported. Transfection of double‐stranded oligodeoxynucleotides corresponding to cis sequence will result in the attenuation of authentic cis‐trans interaction, leading to the removal of trans‐factors from the endogenous cis‐elements with subsequent modulation of gene expression. This “decoy” strategy is not only a novel strategy for gene therapy as an antigene strategy, but also a powerful tool for the study of endogenous gene regulation in vivo as well as in vitro. In this review, we focus on the future potential of decoy oligodeoxynucleotide‐based gene therapy in the treatment of cardiovascular disease.
Regulation of LIF Receptor Expression in Vascular Smooth Muscle
Authors: WORLD CAMERON J. , ROLFE BARBARA E. , CAMPBELL JULIE H.
Published: July 2010

Abstract: Previous studies in our laboratory have shown that the pleiotropic cytokine leukemia inhibitory factor (LIF) inhibits neointimal formation and the development and progression of atherosclerotic and restenotic lesions in a rabbit model of disease. The present study demonstrates an upregulation of both the LIF receptor (LIFR)‐α subunit and the signal transducing subunit gp130 following endothelial denudation of the carotid artery by balloon catheter. Continuous infusion of LIF (30 μg/kg/day) resulted in the downregulation of LIFR‐a in injured arteries in vivo. Similarly, smooth muscle cells in vitro treated with LIF exhibited a time‐dependent reduction in LIFR‐a protein expression and the subsequent reduction in transcription of the TIMP‐1 gene. However, in the presence of an intact endothelium, LIFR‐a was upregulated in response to LIF, and accordingly the downstream induction of iNOS expression was also increased. Thus, LIF exerts more potent antiatherogenic effects in the vasculature when the endothelium is intact.
Control of Smooth Muscle Cell Function by Membrane‐Type Matrix Metalloproteinases
Authors: SHOFUDA KEN‐ICHI , HASENSTAB DAVID , SHOFUDA TOMOKO , KENAGY RICHARD D. , CLOWES ALEXANDER W.
Published: July 2010

Abstract: Vascular smooth muscle cells (SMCs) express membrane‐type matrix metalloproteinases‐1 and ‐3 (MT1‐ and MT3‐MMPs). Expression is induced by PDGF in culture or by balloon injury in rat carotid arteries. In this study, we tried to define their functions in SMCs by transducing MT1‐ and MT3‐MMP cDNAs into baboon‐cultured SMCs, using adenoviral vectors. Overexpression of MT1‐MMP increased the conversion of proMMP‐2 to the activated form. In contrast, in MT3‐MMP overexpressing cells, MMP‐2 activation was partial. However, both MT1‐ and MT3‐MMP overexpression elicited morphological alterations (cell rounding), which was prevented by BB94 addition. The cells, which unverwent this change, showed reduced adhesion to matrices and increased migration in a Boyden chamber.
Increased Cholesteryl Ester Transfer Protein and Changes in Lipid Metabolism from Initiating Insulin Therapy
Authors: AI MASUMI , TANAKA AKIRA , BABA TOSHIYA , YUI KATSUMASA , NUMANO FUJIO
Published: July 2010

Abstract: Insulin therapy is often necessary for glycemic control, and its effect on plasma lipids is an important issue with respect to arteriosclerosis. Previous reports suggested that increased cholesteryl ester transfer protein (CETP) appeared in diabetic patients with hyperinsulinemia or given a lot of insulin is atherogenic. We investigated whether insulin always increases CETP and whether increased CETP by insulin is always atherogenic. In 40 patients the amount and activity of CETP were assessed before and 2 weeks after initiation of insulin therapy. After starting insulin, plasma concentrations of total cholesterol, triglycerides, LDL‐cholesterol, and remnant lipoprotein cholesterol decreased. No change occurred in HDL‐cholesterol. Starting insulin therapy increased the amount and activity of CETP. No significant correlation was observed between changes in CETP and in lipids including HDL‐cholesterol or apolipoprotein concentrations. This is the first prospective study to show increased CETP activity after initiation of insulin therapy. After initiating insulin, CETP increases without accompanying atherogenic changes in lipid metabolism. Based on the changes observed, CETP in itself does not have atherogenicity and the increase, but no excess, of CETP by appropriate insulin therapy cannot be atherogenic.
Angioscopic Evaluation of the Effect of Estrogen on Ovariectomized Japanese Monkeys
Authors: IKEDA N. , TORII R.
Published: July 2010

Abstract: Using angioscopy to study the atheroprotective effect of estrogen, atherosclerotic changes in surgically postmenopausal Japanese monkeys were observed for a long period. Changes in serum lipids and estradiol were also followed. About 3‐6 months after the 2% cholesterol diet, serum cholesterol increased up to three times normal value, and atheroma was first found at the orifice of major branches of the abdominal aorta. However, in the other group of 2% cholesterol including an oral estrogen diet, the appearance of atheroma was inhibited until 12 months, although serum cholesterol increased gradually. The chronologic investigation was continued over 3 years. From these results we concluded that the most important atheroprotective effect of estrogen is the direct inhibition of atherosclerosis in the arterial wall, and improvement in lipid metabolism is of secondary importance.
Expression of Peroxisome Proliferator‐Activated Receptor Subtypes in Human Atherosclerosis
Authors: SUEYOSHI SUMIHISA , YAMADA TSUTOMU , NIIHASI MARI , KUSUMI YOSHIAKI , OINUMA TOSHINORI , ESUMI MARIKO , TSURU KIYOYUKI , IMAI SHIGERU , NEMOTO NORIMICHI , SAKURA ISAMU , MITSUMATA MASAKO
Published: July 2010

Abstract: To clarify the involvement of peroxisome proliferator‐activated receptors (PPARs) in atherosclerotic plaque formation, we investigated the expression patterns of mRNA and protein of PPARα and PPARγ in human aorta. Atheromatous plaque, fatty streak, and diffuse intimal thickening (DIT) were separated macroscopically, and each sample was divided into halves. Half of them were used for analysis of mRNA expression with reverse transcription‐polymerase chain reaction and the others were used for histologic analysis. Both PPARα and PPARγ mRNA were detected in all atheromatous plaques, all fatty streaks, and in some DIT. However, expressions of PPARα and PPARγ were obviously less frequently found in DIT than in atheromatous plaques, and the intensity of these expressions was stronger in the atheromatous plaques than in the DIT. Compared with PPARα, PPARγ mRNA was expressed more frequently in atheromatous plaques. In atheromatous plaques, PPARγ mRNA was expressed independently, whereas PPARα mRNA was coexpressed with PPARγ. PPARγ protein was obviously found in the nuclei of endothelial cells, macrophages, mononuclear cells, and smooth muscle cells in the aortic intima. These results suggest that expressions of PPARα and PPARγ in human aortic wall are involved in atherogenesis from the early stages.
Effects of Phytoestrogens and Synthetic Combinatorial Libraries on Aromatase, Estrogen Biosynthesis, and Metabolism
Authors: BRUEGGEMEIER ROBERT W. , GU XINJU , MOBLEY JAMES A. , JOOMPRABUTRA SURACHAI , BHAT ABHIJIT S. , WHETSTONE JENNIFER L.
Published: July 2010

Abstract: Approximately 60% of breast cancer patients have hormone‐dependent breast cancer containing estrogen receptors and requiring estrogen for tumor growth. The extent of estrogen biosynthesis and metabolism in the breast cancer tissue microenvironment influences breast‐tumor development and growth, and endogenous and exogenous agents may alter the levels of hormonally active estrogens and their metabolites. Isoflavonoid phytoestrogens such as genistein exhibit numerous biochemical activities; however, their effects on estrogen biosynthesis and metabolism in breast cancer cells have not been fully examined. MCF‐7 cells (hormone‐dependent) and MBA‐MB‐231 cells (hormone‐independent) were treated with genistein (100 nM) for five days and then incubated with radiolabeled estradiol (100 nM, 2.5 μCi) for 0 to 48 h. Media were extracted with ethyl acetate, and the organic residues analyzed by reverse‐phase HPLC with a radioactivity flow detector. The major metabolite formed in all cases is estrone, although differences were observed between the cell lines and the various drug treatments. The formation of estrone in untreated MCF‐7 cells (approximately 9.3% of radioactivity at 24 h) is relatively limited, in contrast to untreated MDA‐MB‐231 cells (approximately 32.0% of radioactivity at 24 h). Treatment of MCF‐7 cells with 100 nM genistein increased the conversion of estradiol to estrone up to 19.5% in 24 h. The effect of genistein on estrone formation in MDA‐MB‐231 cells resulted in 37.7% of the radioactivity being estrone. Thus, genistein treatment of breast cancer cells resulted in increased 17‐βhydroxysteroid dehydrogenase activity and elevated formation of estrone. Increased levels of oxidative 17‐βhydroxysteroid dehydrogenase activity (Type II) were confirmed by Western blots. Therefore, exposure of breast cancer cells to genistein results in elevated conversion of estradiol to estrogenically weaker or inactive metabolites. The regulation of breast‐tissue aromatase by exogenous agents such as drugs and environmental agents is being investigated. The benzopyranone‐ring system is a molecular scaffold of considerable interest, and this scaffold is found in flavonoid natural products that have weak aromatase inhibitory activity. Medicinal chemistry efforts focus on diversifying the benzopyranone scaffold and utilizing combinatorial chemistry approaches to construct small benzopyranone libraries as potential aromatase inhibitors. Several compounds in the initial libraries have demonstrated moderate aromatase inhibitory activity in screening assays.
Tissue‐Specific Estrogen Biosynthesis and Metabolism
Authors: SIMPSON EVAN R. , CLYNE COLIN , SPEED CAROLINE , RUBIN GARY , BULUN SERDAR
Published: July 2010

Abstract: While the ovaries are the principal source of systemic estrogen in the premenopausal nonpregnant woman, other sites of estrogen biosynthesis are present throughout the body and these become the major sources of estrogen beyond menopause. These extragonadal sources of estrogen are small, but may play an important, though hitherto largely unrecognized, physiological and pathophysiological role. Aromatase activity in extragonadal sites contributes to this source of estrogen and may contribute to breast tumor development and/or growth. Selective aromatase modulators (SAMs) may have a role to play in the treatment of estrogen‐dependent diseases, such as breast cancer.
A Brief Review of the International Breast Cancer Intervention Study (IBIS), the Other Current Breast Cancer Prevention Trials, and Proposals for Future Trialsa
Authors: CUZICK J.
Published: July 2010

Abstract: The available results from breast cancer chemoprevention trials are reviewed. Four trials using tamoxifen have been performed, of which three have reported efficacy results. A fifth trial using raloxifene has also been published. The largest tamoxifen trial shows approximately a 50% reduction in breast cancer incidence in the short term, but the two smaller trials have not found any incidence reduction. Greater agreement exists for side effects: thromboembolic disease and endometrial cancers are raised about 2‐ to 3‐fold when tamoxifen is used for 5 years. The possible reasons for the discrepancy in breast cancer reduction are explored. A review of trial parameters does not clearly explain this difference, and a metanalysis indicates that all results are compatible with a 42% reduction in short‐term incidence. Several important questions remain about the clinical implication of this result, including the effect on mortality, the appropriate risk groups for chemoprevention, and the long‐term effects on incidence. Continued follow‐up of these trials is crucial for resolving these issues.
Cardiovascular Trials of Estrogen Replacement Therapy
Authors: HERRINGTON DAVID M. , KLEIN KAREN POTVIN
Published: July 2010

Abstract: An impressive body of evidence has suggested that estrogen therapy should be helpful to slow the pathogenesis or progression of atherosclerosis. Estrogen's favorable effects on lipids and endothelial function, coupled with extensive observational epidemiology and data from animal models of atherosclerosis, persuaded many that hormone replacement therapy (HRT) would be helpful for both primary and secondary prevention of coronary disease. Recently, several randomized clinical trials of HRT have been completed, and several more are currently under way. These trials include both primary and secondary prevention cohorts and use clinical as well as anatomic manifestations of atherosclerosis as outcomes. These trials are producing surprising and controversial results that will radically alter contemporary understanding of the role of HRT for cardiovascular disease prevention. This review briefly describes the findings of the Heart and Estrogen/Progestin Replacement Study, the Estrogen Replacement and Atherosclerosis Trial, and other recently completed clinical trials. Trials that are under way are also described and discussed.
Preventing and Treating Osteoporosis
Authors: SHERMAN SHERRY
Published: July 2010

Abstract: Osteoporosis has been defined as “a progressive systemic disease characterized by low bone density and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.” Osteoporosis and the consequences of compromised bone strength—particularly vertebral and hip fractures—are a significant cause of frailty, and increased morbidity and even mortality and hence are a serious and costly public health problem in the elderly population However, due to remarkable advances in basic and clinical research and in drug design, development, and testing, a number of efficacious, evidence‐based options are available for the prevention and treatment of osteoporosis. These options extend far beyond estrogen/progestin therapy and include lifestyle and dietary changes such as increasing weight‐bearing activity, enhancing calcium and vitamin D intake, as well as incorporating pharmacologic agents such as the bisphosphonates and selective estrogen receptor modulators (SERMs) such as raloxifene. In addition to its efficacy in increasing bone mineral density and reducing vertebral fractures by almost 40% in women with osteoporosis, the SERM raloxifene appears to promote a cardioprotective profile and to offer some protection against breast cancer. The potential of raloxifene to prevent or delay the development of a number of chronic diseases of aging such as osteoporosis, cardiovascular disease, and perhaps even Alzheimer's disease has stimulated the development and refinement of subsequent generations of SERMs aimed at maximizing beneficial effects in a wide variety of tissues while eliminating deleterious outcomes and side effects.
The Estimation and Use of Absolute Risk for Weighing the Risks and Benefits of Selective Estrogen Receptor Modulators for Preventing Breast Cancer
Authors: GAIL MITCHELL H.
Published: July 2010

Abstract: In order to weigh the risks and benefits of intervention with selective estrogen response modifiers for preventing breast cancer, one needs to consider the effects of intervention on several health outcomes. For example, tamoxifen was shown to reduce the risks of breast cancer and hip fracture while increasing the risks of endometrial cancer and cardiovascular end points, including stroke. One approach to weighing risks and benefits is to estimate the net effect of the intervention on the absolute risk of each of the relevant health outcomes. To estimate this net effect, one needs to know not only the relative risk from the intervention, but also the absolute risk of the health outcome in the absence of intervention. Intervention trials yield unbiased estimates of intervention relative risks, but data are usually too limited to estimate these relative risks precisely for subgroups or for rare health outcomes. Moreover, intervention trials are usually too small to provide data for developing a model for estimating the individualized absolute risk of various health outcomes in the absence of intervention. The model of Gail et al. for projecting the individualized risk of breast cancer, as modified for use in the Breast Cancer Prevention Trial, has been validated. To weigh various risks and benefits of interventions, there is a need for research to develop such models for a range of health outcomes.
The Breast Cancer Continuum
Authors: LEWIS JERRY P.
Published: July 2010

Abstract: The Breast Cancer Continuum includes women at high risk, as in the Breast Cancer Prevention Trial; those with a history of atypical ductal hyperplasia (ADH) or lobular carcinoma in situ (LCIS); women with ductal carcinoma in situ (DCIS); those with <1 cm invasive disease or node‐negative or node‐positive disease; and those at risk of developing contralateral breast cancer. Women in all these categories benefit from therapeutic intervention with tamoxifen because each clinical state is associated with a certain probability of having early undiagnosed invasive breast cancer responsive to tamoxifen. This framework, relating these disorders to each other through their 5‐year incidence of developing invasive breast cancer, leads to important conclusions relative to pharmaceutical drug development strategies, including chemoprevention investigations.
Opportunities for Future Research
Authors: SHERMAN SHERRY , DUNN BARBARA K.
Published: July 2010

Abstract: Remarkable progress has been made in SERM development. Profiles of new SERMs indicate great potential for efficacy in the prevention and treatment settings, in more than one physiological system, and with improved risk/benefit ratios. The concept of what is achievable with respect to broad‐spectrum disease prevention and what constitutes an “ideal” SERM is likely to undergo considerable reevaluation over time. The development of new, more broadly efficacious SERMs will require continued exploration of the effects of estrogen at the cellular and molecular level in tissues and physiologic systems throughout the body. A better understanding is needed of the mechanisms of the biological actions that are mediated through major forms of the estrogen receptor. High priority must be placed on elucidation of the role of the coregulators of estrogen receptor (ER) action. The quest for a SERM(s) with the “optimal clinical profile” also constitutes a major research challenge with respect to designing clinical trials that are simultaneously parsimonious with respect to time, monetary, and human resources and yet capable of delivering unequivocal outcomes with respect to primary end points. A vigorous research effort is needed to identify highly sensitive and specific surrogate measures to facilitate future clinical studies. Research to identify and validate relevant measures of safety is also essential to inform the risk/benefit balance and, thus, the ultimate usefulness of SERMs and their potential for long‐term use. Future advances in the modulation of ER action are likely to have profound effects—not only on diseases and conditions known (or later discovered) to be related to estrogen action, but on the development of paradigms for understanding and modifying the action of other nuclear hormone receptors in the prevention and treatment of additional age‐ and disease‐related pathologies.
Stress Resistance by Caloric Restriction for Longevity
Authors: Yu Byung P. , Chung Hae Young
Published: July 2010

Abstract: Hardly an aspect of aging is more important than an organism's ability to withstand stress or to resist both internally and externally imposed insults. We know that as organisms loose their ability to resist these insults, aged organisms suffer more than the young. Therefore, a prime strategy for an organism's survival has been the evolutionarily adapted defense systems that guard against insult. For better survivability, an organism's defense system must be maximized to its full effect through well‐coordinated networks of diverse biologically responsive elements. Although terms like stress, resistance, and adaptability have long been used in biology, they remain mechanistically and quantitatively poorly defined. In a gerontological context, stress resistance or susceptibility are often discussed in association with an organism's vulnerability to disease and age‐related damage. However, to date, there is no clear molecular delineation of cellular and molecular mechanisms for such complex biological phenomena. The life‐prolonging action of caloric restriction (CR) seems to offer an excellent opportunity for investigating the interrelationship between stress and the aging process. As an omnipotent intervention, CR provides a unique opportunity to probe the organism's ability to withstand age‐related stress as a survival strategy. In this context, the antiaging action of CR can be viewed as “nutritional stress,” because the organism's reduced caloric intake seems to be a stimulatory metabolic response for survivability. Recent gerontologic research has provided sufficient experimental data supporting this antiaging property of CR, of which several pertinent, key examples are discussed below.
DNA Polymerase‐β May Be the Main Player for Defective DNA Repair in Aging Rat Neurons
Authors: Rao Kalluri Subba , Annapurna V. V. , Raji N. S.
Published: July 2010

Abstract: A close relationship between the DNA repair potential of various organisms and their rate of aging has been long suspected. We have been looking into the steps of the DNA repair process in isolated neurons from rats of different ages. Unscheduled DNA synthesis (UDS) was low in aging neurons, and also the response of these cells to raise their DNA repair capacity against a mutagenic challenge was poor. Attempts to identify the possible defective locus in the overall DNA repair pathways indicated that the step involving DNA polymerase may be defective. The activity of DNA polymerase‐β, the most predominant DNA polymerase in neurons that is generally considered to be a short‐patch repair enzyme, shows a significant decrease in aging neurons. Northern and Southern blotting and immunotitration experiments suggest that there may be an accumulation of inactive β polymerase molecules in the aging rat brain. Most recent preliminary studies reveal significant 3′‐5′ exonuclease activity in rat neurons at all ages. However, extension of a primer in a synthetic oligo duplex, either with a mismatch or correct base pair at the 3′ end of the primer, was low in neurons of any age and was very poor (almost undetectable) in older ones. Supplementation of neuronal extracts with pure polymerase enzyme revealed that only polymerase β, but not polymerase α, was able to increase the primer extension activity significantly in old neurons. These findings are taken to indicate an age‐dependent decline in the DNA repair capacity of neurons and that DNA polymerase β is a key player in the DNA repair mechanisms of nerve cells.
Gene Expression and Regulation in the Extended Longevity Phenotypes of Drosophila
Authors: Arking Robert
Published: July 2010

Abstract: We used both selection and single‐gene mutagenesis studies to identify the mechanisms underlying the genetic control of longevity in Drosophila. The expression of the extended longevity phenotype (ELP) in our forwardselected strains depends on an early and specific upregulation of the antioxidant defense system (ADS) genes and enzymes, which results in decreased oxidative damage levels and a delayed onset of senescence. This mechanism does not alter metabolic rate and is itself reversed by a reverse selection regime. Single‐gene mutational analysis of the regulatory genes controlling ADS gene expression show they are under the positive and negative control of several such genes, each of which can bring about the expression/repression of the ELP. Sister strains with identical ELPs have different patterns of ADS gene expression, showing that phenotypic equivalence does not require molecular equivalence. The organism may have multiple genetic strategies to cope with similar levels of oxidative stress.
Translocational Inefficiency of Intracellular Proteins in Senescence of Human Diploid Fibroblasts
Authors: Lim In Kyoung , Hong Kwang Won , Kwak In Hae , Yoon Gyesoon , Park Sang Chul
Published: July 2010

Abstract: In order to investigate signal transduction pathways and related changes of actin cytoskeleton organization in cellular senescence, H‐ras double mutants—V12S35, V12G37, and V12C40—were constitutively expressed in human foreskin fibroblast (HDF). Senescent HDF cells as well as the H‐ras mutant expressers accumulated p‐Erk1/2 in the cytoplasm with increased MEK activity and failed to translocate it to nuclei on EGF stimulation. Senescent HDF cells, V12S35 and V12G37 expressers, revealed a failure to export actin fiber from nucleus to cytoplasm and also to form stress fibers. Perinuclear expression of Rac1 was prominent in the HDF cells and V12C40 expresser; however, in the V12S35 expresser, translocation of Rac1 from perinucleus to nucleus and strong expression of RhoA were obvious. In summary, the H‐ras double mutant expressers induced premature senescence through the MEK pathway, accompanied by nuclear accumulation of actin and Rac1 proteins, cytoplasmic retention of p‐Erk1/2, and marked induction of RhoA expression, suggesting the translocational inefficiency of the intracellular proteins in the senescent HDF cells.
On the True Role of Oxygen Free Radicals in the Living State, Aging, and Degenerative Disorders
Authors: Zs‐Nagy Imre
Published: July 2010

Abstract: Oxyradicals are generally considered harmful byproducts of oxidative metabolism, causing molecular damage in living systems. They are implicated in various processes such as mutagenesis, aging, and series of pathological events. Although all this may be justified, evidence is accumulating that it is an oversimplified view of the real situation. We can assume nowadays that the living state of cells and organisms implicitly requires the production of oxyradicals. This idea is supported by experimental facts and arguments as follows. (1) Complete inhibition of the oxyradical production by KCN (or by any block of respiration) kills the living organisms much before the energy reserves would be exhausted. (2) Construction of the supramolecular organization of the cells (especially of their membranous compounds) requires the cross‐linking effect of oxyradicals, particularly that of OH· radicals. (3) Blast type cells produce much fewer oxyradicals than do differentiated ones, and interventions increasing the production of OH· radicals induce differentiation of various lines of leukemic (HL‐60 and K562) and normal (fibroblasts, chondroblasts, etc.) cells, while SOD expression increases greatly. (4) It is reasonable to assume that the continuous flux of OH· radicals is prerequisite to maintenance of constant electron delocalization on the proteins, which is a semiconductive phenomenon suggested in 1941 by Szent‐Györgyi, but it has never been proven experimentally. It is theoretically possible to describe the function of the synapses as that of a single p‐n‐p transistor, assuming that the free radical flux maintains electron movements on the subsynaptic structures, while the actual membrane potential is governing the electron flux. This theoretical approach may open completely new possibilities for our understanding of the normal functions of living organisms, such as basic memory mechanisms in brain cells, their aging processes, and therapeutic approaches to many degenerative disorders, such as various types of dementia.
The Inflammation Hypothesis of Aging
Authors: Chung Hae Young , Kim Hyon Jeen , Kim Jung Won , Yu Byung Pal
Published: July 2010

Abstract: Current evidence strongly indicates that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are widely implicated in the inflammatory process. However, mechanistic information is not readily available on the extent to which ROS/RNS contributes to the proinflammatory states of the aging process. The involvement of the underlying inflammation during the aging process and the molecular delineation of anti‐inflammatory action of calorie restriction (CR) is described. Age‐related upregulations of NF‐κB, IL‐β, IL‐6, TNFα, cyclooxygenase‐2, and inducible NO synthase are all attenuated by CR. The suppression of the NF‐κB activation was accomplished by blocking the dissociation of inhibitory IκBα and IκBβ by CR. These findings provide underlying molecular insights into the anti‐inflammatory action of CR in relation to the aging process. Based on these and other available data, it is suggested that the “Inflammation Hypothesis of Aging” supports the molecular basis of the inflammatory process as a plausible cause of the aging process.
The Conscious Cell
Authors: MARGULIS LYNN
Published: July 2010

Abstract: The evolutionary antecedent of the nervous system is “microbial consciousness.” In my description of the origin of the eukaryotic cell via bacterial cell merger, the components fused via symbiogenesis are already “conscious” entities. I have reconstructed an aspect of the origin of the neurotubule system by a hypothesis that can be directly tested. The idea is that the system of microtubules that became neurotubules has as its origin once‐independent eubacteria of a very specific kind. Nothing, I claim, has ever been lost without a trace in evolution. The remains of the evolutionary process, the sequence that occurred that produced Cajal's neuron and other cells, live today. By study of obscure protists that we take to be extant decendants of steps in the evolution of cells, we reconstruct the past directly from living organisms. Even remnants of “microbial mind” can be inferred from behaviors of thriving microorganisms. All of the eukaryotes, not just lichens or an animal's neurons, are products of symbiogenesis among formerly free‐living bacteria, some highly motile. Eukaryotes have evolved by the inheritance of acquired genomes; they have gained all their new features by ingesting and not digesting whole bacterial cells with complete genomes.
Consciousness: The Remembered Present
Authors: EDELMAN GERALD
Published: July 2010

Abstract: This chapter summarizes a theory of consciousness based on brain structure and dynamics. The theory centers around the notion of reentry—ongoing recursive signaling across multiple reciprocally connected brain regions present mainly in the thalamocortical system. It recognized the fundamental beginnings provided by the complementary efforts of Ramon y Cajal and William James.
Music, Cognition, Culture, and Evolution
Authors: CROSS IAN
Published: July 2010

Abstract:We seem able to define the biological foundations for our musicality within a clear and unitary framework, yet music itself does not appear so clearly definable. Music is different things and does different things in different cultures; the bundles of elements and functions that are music for any given culture may overlap minimally with those of another culture, even for those cultures where “music” constitutes a discrete and identifiable category of human activity in its own right. The dynamics of culture, of music as cultural praxis, are neither necessarily reducible, nor easily relatable, to the dynamics of our biologies. Yet music appears to be a universal human competence. Recent evolutionary theory, however, affords a means for exploring things biological and cultural within a framework in which they are at least commensurable. The adoption of this perspective shifts the focus of the search for the foundations of music away from the mature and particular expression of music within a specific culture or situation and on to the human capacity for musicality. This paper will survey recent research that examines that capacity and its evolutionary origins in the light of a definition of music that embraces music's multifariousness. It will be suggested that music, like speech, is a product of both our biologies and our social interactions; that music is a necessary and integral dimension of human development; and that music may have played a central role in the evolution of the modern human mind.