bluuebunny/crossref_metadata_2025 huggingface dataset:
From the Simple Detection of Microchimerism in Patients with Autoimmune Diseases to Its Implication in Pathogenesis
Authors: LAMBERT N. C. , STEVENS A. M. , TYLEE T. S. , ERICKSON T. D. , FURST D. E. , NELSON J. L.
Published: July 2010

Abstract:Long‐term persistence of fetal cells in parous women (fetal microchimerism, FM) as well as maternal cells in their offspring (maternal microchimerism, MM) have been reported. Systemic sclerosis (SSc), primary biliary cirrhosis (PBC), and Sjögren's syndrome (SS) share similar epidemiology with a predilection for females following childbearing years, with clinical similarities to chronic graft‐versus‐host disease, a known condition of chimerism. This led to the hypothesis that FM could be involved in the pathogenesis of autoimmune diseases. Initial investigations were conducted in SSc, where the hypothesis was supported by the more frequent occurrence and, quantitatively, a greater degree of FM in women with SSc compared to matched healthy women. Long‐term persistence, however, of fetal cells in healthy women indicates that FM per se is not sufficient for causing SSc, but may be important in the context of other risk factors, such as genetic susceptibility and HLA relationship among host and nonhost cells. Contradictory results have recently been published for both PBC and SS and cause difficulty in drawing any conclusions about the role of FM in their pathogenesis. On the other hand, MM has been investigated as a risk factor in patients with systemic lupus (SLE) and juvenile dermatomyositis (JDM). A potential role of MM has been suggested in the pathogenesis of SLE. Recent publications also support the hypothesis that MM might lead to increased risks for JDM. In conclusion, contradictory results have been observed. This reflects a need for standardization of protocols and the selection of control populations. Detection of microchimerism has to be quantitatively studied in the context of genetic factors in order to study its relationship to the pathogenesis of autoimmune diseases.
Circulating Fetal RNA in Maternal Plasma
Authors: POON LEO L. M. , LEUNG TSE N. , LAU TZE K. , LO Y. M. DENNIS
Published: July 2010

Abstract: The discovery of cell‐free nucleic acids in plasma has opened up new possibilities for noninvasive clinical diagnosis. We demonstrate the presence of cell‐free fetal RNA in maternal plasma, indicating that plasma fetal RNA might be used as a marker for noninvasive prenatal diagnosis.
Detection of Plasmodium falciparum DNA in Plasma
Authors: GAL SHIRA , FIDLER CARRIE , TURNER SUE , LO Y. M. DENNIS , ROBERTS DAVID J. , WAINSCOAT JAMES S.
Published: July 2010

Abstract: We present a new application in the field of circulating nucleic acids in plasma: the detection of parasite DNA in plasma. We have investigated the presence of Plasmodium falciparum (P. falciparum) DNA in the blood cells and plasma of patients with malaria. Ten blood samples from malaria patients and 9 blood samples from healthy volunteers were collected. Plasma was separated and DNA was extracted from both plasma and blood cells. DNA samples were subjected to a nested polymerase chain reaction (PCR) for the small subunit rRNA gene of P. falciparum and a control amplification of the human rRNA gene. All 6 cases positive by microscopy for P. falciparum were positive by PCR on DNA extracted from blood cells and plasma. Two cases negative by microscopy for malaria were positive by PCR—the blood samples were taken from one of the cases at 7 days after successful treatment of malaria and the other case at the onset of the malaria illness. Two other cases were negative by microscopy and by PCR on blood cells and plasma, both after successful treatment of malaria. The quantitation of Plasmodium DNA in plasma may prove to be a useful prognostic measurement in malaria, and the detection of P. falciparum DNA in archival stored plasma samples may allow the reconstruction of the recent historic evolution of the parasite genome.
Alu Repeat Sequences Are Present in Increased Proportions Compared to a Unique Gene in Plasma/Serum DNA
Authors: STROUN MAURICE , LYAUTEY JACQUELINE , LEDERREY CHRISTINE , MULCAHY HUGH E. , ANKER PHILIPPE
Published: July 2010

Abstract: Small amounts of DNA circulate freely in plasma or serum, but the mechanism of release is not known. To determine if DNA is actively excreted from viable cells, we utilized real‐time PCR to measure the proportion of Alu repeat sequences compared to the β‐globin gene in serum and lymphocyte DNA in 27 cancer patients and 22 healthy controls. The proportion of Alu compared to β‐globin was significantly greater in serum DNA than in lymphocyte DNA both in control subjects (p= 0.003) and in cancer patients (p < 0.001). Overall, the proportion was similar in cancer and control patients (p= 0.79). Further experiments showed that the β‐globin gene was not more vulnerable to degradation by nuclease action than Alu sequences. Our results lead us to conclude that active DNA release is likely to play a significant role in the origin of circulating DNA.
Functionality of Circulating DNA
Authors: GARCÍA‐OLMO DAMIÁN , GARCÍA‐OLMO DOLORES C.
Published: July 2010

Abstract: The detection of free, circulating tumor DNA in the plasma of cancer patients opens up new possibilities for the diagnosis and prognostication of cancer. Whatever might be the mechanism for the presence of such DNA, it is now clear that oncogenes can circulate in the plasma fraction of blood and we can now ask whether this phenomenon has potentially important implications in cancer patients. The results of our experiments, together with previous observations of other authors, have led us to propose the “Hypothesis of Genometastasis”, which suggests that metastases might develop as a result of transfection of susceptible cells in distant target organs with dominant oncogenes that circulate in the plasma and are derived from the primary tumor.
Foreign DNA Integration—Perturbations of the Genome—Oncogenesis
Authors: DOERFLER WALTER , HOHLWEG URTE , MÜLLER KNUT , REMUS RALPH , HELLER HILDE , HERTZ JENNIFER
Published: July 2010

Abstract: We have been interested in the consequences of foreign DNA insertion into established mammalian genomes and have initially studied this problem in adenovirus type 12 (Ad12)‐transformed cells or in Ad12‐induced hamster tumors. Since integrates are frequently methylated de novo, it appears that they might be modified by an ancient defense mechanism against foreign DNA. In cells transgenic for the DNA of Ad12 or for the DNA of bacteriophage λ, changes in cellular methylation and transcription patterns have been observed. Thus, the insertion of foreign DNA can have important functional consequences that are not limited to the site of foreign DNA insertion. These findings appear to be relevant also for tumor biology and for the interpretation of data derived from experiments with transgenic organisms. For most animals, the main portal of entry for foreign DNA is the gastrointestinal tract. Large amounts of foreign DNA are regularly ingested with the supply of nutrients. Starting in 1987/1988, we have been investigating the fate of orally administered foreign DNA in mice. Naked DNA of bacteriophage M13 and the cloned gene for the green fluorescent protein (GFP) of Aequorea victoria have been used as test molecules. Moreover, the plant‐specific gene for the ribulose‐1,5‐bisphosphate carboxylase (rubisco) has been followed in mice after feeding soybean leaves. At least transiently, food‐ingested DNA can be traced to different organs and, after transplacental transfer, to fetuses and newborns. There is no evidence for germ line transmission or for the expression of orally administered GFP DNA.
The Changing Picture of the HIV/AIDS Epidemic
Authors: IPPOLITO GIUSEPPE , GALATI VINCENZO , SERRAINO DIEGO , GIRARDI ENRICO
Published: July 2010

Abstract: Twenty years after it was first recognized, the HIV/AIDS epidemic continues to expand, but its impact varies greatly in different parts of the World. The worst of the epidemic is now centered in developing countries, especially sub‐Saharan Africa, and areas such as Eastern Europe, which was only marginally involved a few years ago but has recently experienced the largest growth in the epidemic. In industrialized countries Highly Active Antiretroviral Therapy (HAART) has changed the natural history of HIV/AIDS, causing a reduction in mortality and morbidity due to HIV/AIDS and related diseases. Many interlocking factors determine the impact of HAART at the population level, including reduction of morbidity and mortality, changes in the natural history of HIV/AIDS and associated illnesses, and the effects of HAART on HIV transmission. To fully appreciate the potential benefits of HAART, the epidemic should continue to be monitored in the future, and the effects of HAART on reducing HIV transmission should also be evaluated. Interventions addressed to encourage the adoption of safer sex practices are badly needed, since a “rebound” in risky sexual behaviors was recently reported among high risk groups, which is, at least in part, attributable to the optimism about new treatments.
Pathogenesis of HIV‐Associated Cardiomyopathy
Authors: BARBARO GIUSEPPE , LIPSHULTZ STEVEN E.
Published: July 2010

Abstract:Reviews and studies published before the introduction of highly active antiretroviral therapy (HAART) regimens have tracked the incidence and course of human immunodeficiency virus (HIV) infection in relation to cardiac illness in both children and adults. HAART regimens have significantly modified the course of HIV disease, with longer survival rates and improvement of life quality in HIV+subjects expected. However, early data raised concerns about HAART's being associated with an increase in both peripheral and coronary arterial diseases. A variety of potential etiologies have been postulated in HIV‐related heart disease, including myocardial infection with HIV itself, opportunistic infections, viral infections, autoimmune response to viral infection, drug‐related cardiotoxicity, nutritional deficiencies, and prolonged immunosuppression. In this review article we discuss HIV‐associated cardiovascular complications, focusing on pathogenetic mechanisms that may play a role in diagnosis, management, and therapy of these complications.
Drugs and Cardiotoxicity in HIV and AIDS
Authors: FANTONI M. , AUTORE C. , Del BORGO C.
Published: July 2010

Abstract:The advent of potent antiretroviral drugs in recent years has had an impressive impact on mortality and disease progression in HIV‐infected patients, so that issues related to long‐term effects of drugs are of growing importance. Hyperlipidemia, hyperglycemia, and lipodystrophy are increasingly described adverse effects of highly active antiretroviral therapy (HAART), in particular when protease inhibitors are used. Hyperlipidemia is strikingly associated with the use of most available protease inhibitors, with an estimated prevalence of up to 50%. Because of the short observation period and the small number of cardiovascular events, epidemiological evidence for an increased risk of coronary heart disease in HIV‐infected patients treated with HAART is not adequate at present; however, it is likely that shortly more data will accumulate to quantify this risk. Before starting HAART and during treatment it is reasonable to evaluate all patients for traditional coronary risk factors, including lipid profile. Among the drugs that are currently used in HIV+patients, antibacterials, antifungals, psychotropic drugs and anti‐histamines have been associated with QT prolongation or torsade de pointe, a life‐threatening ventricular arrhythmia. Among the risk factors that may precipitate an asymptomatic electrocardiographic abnormality into a dangerous arrhythmia is the concomitant use of drugs that share the CYP3A metabolic pathway. Since most protease inhibitors are potent inhibitors of CYP3A, clinicians should be aware of this potentially dangerous effect of HAART. Anthracyclines are potent cytotoxic antibiotics that have been widely used for the treatment of HIV‐related neoplasms. Their cardiotoxicity is well known, ranging from benign and reversible arrhythmias to progressive severe cardiomyopathy. The increased survival and quality of life of HIV+patients emphasize the importance of a high awareness of adverse drug‐related cardiac effects.
Cardiovascular Disease Risk Factors in HIV‐Infected Patients in the HAART Era
Authors: GALLI M. , RIDOLFO A. L. , GERVASONI C.
Published: July 2010

Abstract: HIV infection is accompanied by disturbances in lipid and glucose metabolism, which are further compounded by changes induced by antiretroviral drugs. There is increasing concern that these changes will lead to an epidemic of cardiovascular disease. Cardiovascular disease will no doubt increase, but current data indicate that the average absolute levels are likely to remain low, although patients with additional risks (smoking, hypertension, diabetes, age, family history, etc.) are certainly more susceptible. The complications of therapy need to be taken into account when deciding on the time of treatment, and reducing risk factors should become a routine aspect of the care of an HIV population that now lives longer as a result of highly active antiretroviral therapy.
Metabolic and Morphologic Disorders in Patients Treated with Highly Active Antiretroviral Therapy since Primary HIV Infection
Authors: NARCISO PASQUALE , TOZZI VALERIO , D'OFFIZI GIANPIERO , DE CARLI GABRIELLA , ORCHI NICOLETTA , GALATI VINCENZO , VINCENZI LAURA , BELLAGAMBA RITA , CARVELLI CHIARINA , PURO VINCENZO
Published: July 2010

Abstract: Our objective was to describe morphologic and metabolic disorders in patients treated with highly active antiretroviral therapy (HAART) since primary HIV infection (PHI). Our method was prospective evaluation of patients with PHI initiating HAART at the time of diagnosis. Outcome measures were: development of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and of body shape abnormalities indicative of lipodystrophy, assessed through self‐reported questionnaires and physical examination. Results: From May 1997 to April 2001, 41 patients (35 males) with PHI presented at the National Institute for Infectious Diseases “Lazzaro Spallanzani” in Rome, Italy. A protease inhibitor‐including regimen was started in 30 patients, and a nonnucleoside reverse transcriptase‐inhibitor in 11. Median interval between enrollment and treatment initiation was 30 days (mean 39, range 10–150). Median HAART duration was 19 months (mean 21.2, range 3–47). Thirty‐eight patients had undetectable (less than 80 cp/mL) HIV RNA after a median of 3 months (mean 4.1, range 1–15). Mean CD4 cells count increased from 632/mmc at baseline to 936/mmc at the last follow up. No cases of hyperglycemia (glucose level greater than 110 mg/dL) were observed. After a median of 6 months on HAART, 10 patients developed beyond grade 2 (greater than 240 mg/dL) hypercholesterolemia, 5 developed beyond grade 2 (greater than 400 mg/dL) hypertrygliceridemia, and two developed both. Body mass index did not change significantly. Five patients (12.2%) developed lipodystrophy after a median of 14.5 months (mean 15.3, range 2–30), with an incidence of 7.3 per 100 patient‐years. Conclusions: Dyslipidemia and lipodystrophy can occur in patients treated with HAART since PHI. This risk of should be taken into account when considering this early antiretroviral treatment of HIV infection.
Risk of HIV and Other Blood‐Borne Infections in the Cardiac Setting
Authors: PURO VINCENZO , DE CARLI GABRIELLA , SCOGNAMIGLIO PAOLA , PORCASI ROLANDO , IPPOLITO GIUSEPPE ,   Studio Italiano Rischio Occupazionale HIV
Published: July 2010

Abstract: Health care workers (HCWs) face a well‐recognized risk of acquiring blood‐borne pathogens in their workplace, in particular hepatitis B and C viruses (HBV/HBC) and human immunodeficiency virus (HIV). Additionally, infected HCWs performing invasive exposure‐prone procedures, including in the cardiac setting, represent a potential risk for patients. An increasing number of infected persons could need specific cardiac diagnostic procedures and surgical treatment in the future, regardless of their sex or age. The risk of acquiring HIV, HCV, HBV infection after a single at‐risk exposure averages 0.5%, and 1–2%, and 4–30%, respectively. The frequency of percutaneous exposure ranges from 1 to 15 per 100 surgical interventions, with cardiothoracic surgery reporting the highest rates of exposures; mucocutaneous contamination by blood‐splash occurs in 50% of cardiothoracic operations. In the Italian Surveillance (SIROH), a total of 987 percutaneous and 255 mucocutaneous exposures were reported in the cardiac setting; most occurred in cardiology units (46%), and in cardiovascular surgery (44%). Overall, 257 source patients were anti‐HCV+, 54 HBsAg+, and 14 HIV+. No seroconversions were observed. In the literature, 14 outbreaks were reported documenting transmission of HBV from 12 infected HCWs to 107 patients, and 2 cases of HCV to 6 patients, during cardiothoracic surgery, especially related to sternotomy and its suturing. The transmission rate was estimated to be 5% to 13% for HBV, and 0.36% to 2.25% for HCV. Strategies in risk reduction include adequate surveillance, education, effective sharps disposal, personal protective equipment, safety devices, and innovative technology‐based intraoperative procedures.
Mechanosensitive Endothelial Gene Expression Profiles
Authors: GARCÍA‐CARDEÑA GUILLERMO , COMANDER JASON I. , BLACKMAN BRETT R. , ANDERSON KEITH R. , GIMBRONE MICHAEL A.
Published: July 2010

Abstract: The possibility that hemodynamic forces can act as a “local risk factor” for endothelial dysfunction provides a conceptual framework for the long‐standing observation that the earliest lesions of atherosclerosis develop in a nonrandom pattern, the geometries of which correlate with branch points and other regions of altered blood flow. This has led us to hypothesize that hemodynamic forces, in particular wall shear stresses generated by complex patterns of blood flow, can function as both positive and negative stimuli in atherogenesis via effects on endothelial cell gene expression. To understand how endothelial cells in different regions of the arterial tree acquire both functional and dysfunctional phenotypes due to regional hemodynamics, it was important to begin to delineate, in a comprehensive fashion, the mechanoresponsiveness of endothelial cells. To address this fundamental question, we undertook high‐throughput transcriptional profiling to assess the global patterns of gene expression in cultured endothelial cells exposed to two defined biomechanical stimuli. Analyses of the transcriptional activity of thousands of genes have revealed unique patterns of gene expression associated with certain types of stimuli. These unique gene expression programs and their associated functional phenotypes constitute the strongest evidence to date that vascular endothelial cells can discriminate among different types of biomechanical stimuli. The results of these studies and the working hypotheses inspired by detailed molecular analyses of biomechanically activated vascular endothelium promise to provide new insights into the role of hemodynamics in the pathogenesis of atherosclerosis.
Role of Transcription Factors in Angiogenesis
Authors: SATO YASUFUMI , TERUYAMA KAZUHIDE , NAKANO TOHRU , ODA NOBUYUKI , ABE MAYUMI , TANAKA KATSUHIRO , IWASAKA‐YAGI CHIKA
Published: July 2010

Abstract: Angiogenesis is a complex phenomenon that requires at least migration, proliferation, and tubular morphogenesis of endothelial cells (ECs). Some genes are expressed in ECs during these processes, and therefore the regulation of gene expression in ECs is critical. Increasing evidence suggests that the Ets family of transcription factors plays an important role in angiogenesis. We observed that Ets‐1, a prototype of the Ets family of transcription factors, promoted angiogenesis by inducing the expression of matrix metalloproteinases and integrin β3 in ECs, and the elimination of the transactivation activity of Ets‐1 by a dominant negative molecule inhibited angiogenesis. Apoptosis, a term used to describe the terminal morphological and biochemical events seen in programmed cell death, is critical for the development or reconstitution of multicellular organs. Apoptosis of ECs is observed at the initiation of angiogenesis, at the branching or communication with newly formed vessels, and at the regression of neo‐vessels. The Ets family of transcription factors is generally thought to be anti‐apoptotic. However, there are conflicting reports on the role of Ets‐1 in apoptosis. We examined the role of Ets‐1 in apoptosis of ECs and found that Ets‐1 was pro‐apoptotic to ECs by modulating the expression of several apoptosis‐related genes.
The Prothrombotic Effects of Leptin
Authors: KONSTANTINIDES STAVROS , SCHÄFER KATRIN , LOSKUTOFF DAVID J.
Published: July 2010

Abstract: Human obesity is associated with leptin resistance, elevated leptin levels in the circulation, and increased risk of arterial and venous thrombotic disease. Our studies suggest that elevated leptin levels may directly promote arterial thrombosis in vivo. We found that leptin‐deficient ob/ob mice had prolonged times to thrombosis after arterial injury with ferric chloride and that exogenously administered leptin corrected their phenotype in a dose‐dependent manner. These effects appear to result from a direct, receptor‐mediated effect of leptin on platelets, because leptin stimulated the aggregation of murine (wild‐type and ob/ob) and human platelets, but it had no effect on platelets from leptin receptor‐deficient db/db mice. Moreover, db/db mice had an attenuated thrombotic response to ferric chloride injury (indistinguishable from that of the ob/ob mice), which was unaffected by exogenous leptin. Our results raise the possibility that elevated plasma levels of leptin may contribute to the risk of atherothrombotic complications in human obesity.
New Understanding of Atherosclerosis (Clinically and Experimentally) with Evolving MRI Technology in Vivo
Authors: CORTI ROBERTO , FUSTER VALENTIN , BADIMON JUAN J. , HUTTER RANDOLPH , FAYAD ZAHI A.
Published: July 2010

Abstract: Atherosclerosis and its thrombotic complications are the major cause of morbidity and mortality in industrialized countries. Despite advances in our understanding of the pathogenetic mechanisms and new treatment modalities, the absence of an adequate noninvasive method for early detection limits the prevention or treatment of patients with various degrees and localizations of atherothrombotic disease. High‐resolution magnetic resonance (MR) has recently emerged as one of the most promising techniques for the noninvasive study of atherothrombotic disease. Most importantly, MR can be used to characterize plaque composition and monitor progression. Thus, MR opens new strategies, ranging from the screening of high‐risk patients for early detection and treatment as well as the monitoring of target areas for pharmacological intervention.
Role of CD36, the Macrophage Class B Scavenger Receptor, in Atherosclerosis
Authors: NICHOLSON ANDREW C. , HAN JIHONG , FEBBRAIO MARIA , SILVERSTERIN ROY L. , HAJJAR DAVID P.
Published: July 2010

Abstract: Recent work in the field of atherosclerosis has greatly expanded our knowledge of the pathogenesis of this disease. Scavenger receptors, including CD36, are thought to be most important early in the disease progression during macrophage uptake of modified LDL and foam cell formation. Genetically engineered murine models have been used to elucidate the contribution of the different scavenger receptors, to identify specific ligands related to LDL modifications, and to assess the possible therapeutic ramifications of targeting scavenger receptors. We have demonstrated a major role for CD36 in macrophage foam cell development and subsequent lesion development in vivo. Absence of CD36 in an atherogenic Apo E null background resulted in a 70% decrease in total lesion area in Western diet‐fed mice. We have also made significant progress in our understanding of the regulation of expression of CD36 and have demonstrated that OxLDL can stimulate its own uptake by induction of CD36 gene expression. The mechanism by which OxLDL upregulates CD36 involves activation of the transcription factor, PPAR‐γ.
Lysophosphatidylcholine Inhibits T Cell‐Specific CXC Chemokines IP‐10, MIG, and I‐TAC Expression Induced by IFN‐γ in Human Endothelial Cells
Authors: SHEIKH ABDULLAH MD. , OCHI HIROSHI , MASUDA JUNICHI
Published: July 2010

Abstract: Hypercholesterolemia is reported to be associated with a T helper (Th) 1 to Th2 switch in apoE‐deficient mice. To explore the underlying mechanisms of such immune modulation, we investigated if lysophosphatidylcholine (Lyso‐PC), enriched in oxidized LDL, affects cytokine‐induced expression of Th1 cell‐specific CXC chemokines, IFN‐inducible protein of 10 kDa (IP‐10), monokine induced by IFN‐γ (Mig), and IFN‐inducible T cell a chemoattractant (I‐TAC) in cultured endothelial cells. Lyso‐PC inhibited IFN‐γ‐ or IFN‐γ plus TNF‐α‐induced IP‐10, Mig, and I‐TAC mRNA expression but not that of the IRF‐1 or IRF‐1‐dependent molecule, GBP. It also inhibited IP‐10 protein secretion in conditioned media induced by IFN‐γ or IFN‐γ plus TNF‐α. Western analysis demonstrated that Lyso‐PC inhibited IFN‐γ‐induced STAT‐1α protein expression, but not that of IRF‐1. These results suggest that Lyso‐PC selectively inhibits IP‐10, Mig, and I‐TAC expression through IRF‐1‐independent mechanisms. This inhibitory effect of Lyso‐PC may be involved in the immune modulation by hypercholesterolemia.
Antisense Display: A New Method for Functional Gene Screen and Its Application to Angiogenesis‐Related Gene Isolation
Authors: YONEKURA HIDETO , YASUI KIYOSHI , SAKURAI SHIGERU , LI HUI , YAMAMOTO YASUHIKO , YAMAMOTO HIROSHI
Published: July 2010

Abstract: We have developed an antisense‐oriented method for functional gene screening, which we termed “antisense display.” After evaluation in a cell‐free system, we applied this method to a cellular system for isolating angiogenesis‐related genes and came across a gene previously not described in humans. A screen of 10 mer antisense repertoire led to the identification of a unique ‘angiostatic’ antisense, and the gene corresponding to it was found to be preferentially expressed in vascular endothelial cells, coding for a putative type‐2 membrane protein containing Rab‐GAP/TBC and EF‐hand‐like domains. We named it vascular Rab‐GAP/TBC domain‐containing protein (VRP). The results obtained thus indicate that the antisense display method is useful for the isolation of functional genes responsible for phenotypes concerned.
Abdominal Aortic Aneurysm As an Autoimmune Disease
Authors: HIROSE HITOSHI , TILSON M. DAVID
Published: July 2010

Abstract: The pathogenesis of abdominal aortic aneurysms (AAAs) is unknown. We hypothesize that the autoimmune disease process plays a key role in the development of AAAs. Both cellular and humoral immunity is involved in the pathogenesis of AAAs. Triggers of autoimmunity are multifactorial. Certain HLA typing is closely related to AAAs, and a certain viral infection may have a potential role in the etiology of AAA via a molecular mimicry mechanism. The autoantigen is located in the microfibrillar compartment of the aortic wall as a normal structure. Patients with AAA are immunoreactive with this novel structural protein. If in the future the autoantigen is fully elucidated, serum testing to detect antibody against the autoantigen can be performed.
An Epistemological Inquiry into the Endocrine Disruptor Thesis
Authors: KRIMSKY SHELDON
Published: July 2010

Abstract:For about a decade the termendocrine disruptorhas become synonymous with a new research initiative that has been investigating the effects of hormonally active xenobiotics on biological systems. The scientific thesis behind the new research initiative is discussed and it is argued that there is a need for more emphasis on theory development and conceptual clarification that will give coherence to a field experiencing a rapid growth of empirical studies. Reflections on scientific methodology in this field will also help clarify whether endocrine disruptors symbolize a new etiology of chemically induced disease or represent variations of traditional chemical toxicology.
Developing Animal Models for Analyzing SERM Activity
Authors: EMMEN JUDITH M. A. , KORACH KENNETH S.
Published: July 2010

Abstract: Estrogens have effects on many organ systems, beyond the reproductive system, in both females and males. Estrogen effects are exerted through specific receptors, of which there are two types: estrogen receptor (ER) α and estrogen receptor (ER) β. To study the roles of each receptor in vivo, a series of mice were generated lacking either a functional ERα or ERβ or both. These mice, labeled αERKO, βERKO, or αβERKO, respectively, have been useful in defining the tissue specificities, localization, and functions of each of the estrogen receptors. These mouse models also show great promise for use in defining the effectiveness of putative SERMs.
The Past, Present, and Future of Selective Estrogen Receptor Modulation
Authors: JORDAN V. CRAIG
Published: July 2010

Abstract:The recognition of selective estrogen receptor modulation in the mid‐1980s provided a unique opportunity to develop multifunctional drugs. Tamoxifen, the first selective estrogen receptor modulator (SERM), is the first antiestrogen to be tested successfully for the prevention of breast cancer in high‐risk women. However, the recognition that SERMs maintain bone density and lower circulating cholesterol suggested that the prevention of osteoporosis and coronary heart disease would be beneficial side effects of tamoxifen treatment. This hypothesis has not been pursued in clinical trial, but an alternate hypothesis, that SERMs could be developed to prevent osteoporosis and potentially reduce the risk of breast cancer, has been pursued with raloxifene. Current molecule modeling of the SERM‐ER complex has identified the reason for the promiscuous estrogen‐like actions of tamoxifen compared with raloxifene. Future studies of the signal transduction pathways of the ER alpha (α)‐ and beta (β)‐SERM complexes hold the promise of new drug discoveries and a menu of preventive medicine in clinical practice.
Breast Cancer Prevention with Selective Estrogen Receptor Modulators
Authors: PRITCHARD KATHLEEN I.
Published: July 2010

Abstract: Chemoprevention for breast cancer is both old and new. It has long been appreciated that early ovarian ablation dramatically reduces the incidence of breast cancer in premenopausal women. It was subsequently demonstrated, in the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview, that tamoxifen results in a 40% or greater reduction in the incidence of contralateral breast cancer. Now, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has shown a similar reduction in a randomized trial [Breast Cancer Prevention Trial (BCPT)] comparing tamoxifen and placebo in women aged 35 years or over at increased risk of developing breast cancer because of age, family history, or other factors. In this trial, the incidences of both ductal carcinoma in situ (DCIS) and invasive cancer were reduced. Reduction in incidence was similar over all years of the study and in all subgroups of high‐risk women. However, all of the reduction was confined to estrogen receptor (ER)‐positive tumors. Raloxifene, a newer selective estrogen receptor modulator (SERM) originally developed for osteoporosis, also appears to have a major preventive effect on breast cancer incidence. Limitations in the design and patient population of raloxifene trials, however, have made it difficult to as yet recommend raloxifene for risk reduction of breast cancer. The randomized Study of Tamoxifen and Raloxifene (STAR) study, which will compare raloxifene to tamoxifen in over 20,000 postmenopausal women at increased risk of breast cancer, as well as ongoing and proposed placebo‐controlled studies of tamoxifen, the aromatase inhibitor anastrazole, and other antiestrogens in high‐ or average‐risk postmenopausal women, will provide further results on optimal prevention strategies.
The Royal Marsden Hospital (RMH) Trial
Authors: POWLES TREVOR J.
Published: July 2010

Abstract: The reported interim analysis of the Royal Marsden chemoprevention trial, giving tamoxifen (20 mg/day) for up to 8 years to healthy women at increased risk of breast cancer because of a family history, has failed to confirm the 49% reduction in overall early incidence of breast cancer reported from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P‐1 trial. Although statistically compatible, this discrepancy in results raises the possibility that the sensitivity to tamoxifen chemoprevention may depend on the population characteristics of the participants in the two trials. Younger women who do not have lobular carcinoma in situ or atypical ductal hyperplasia, or who may be at high risk of carrying a breast cancer predisposing gene, may be relatively resistant to tamoxifen chemoprevention. Furthermore, the clinical benefit of a reduction in the early incidence of breast cancer by using tamoxifen in healthy women has not been clearly established by the P‐1 trial because of the lack of mortality data. Use of tamoxifen for risk reduction in healthy women needs to take into account these factors, and more information needs to be gained from the continuing placebo‐controlled trials that are under way.
Effect of Selective Estrogen Receptor Modulators on Reproductive Tissues Other Than Endometrium
Authors: HENDRIX SUSAN L. , McNEELEY S. GENE
Published: July 2010

Abstract: The objective of this paper is to review the published and unpublished knowledge of the effect of selective estrogen receptor modulators on reproductive tissues other than endometrium. Pharmaceutical companies developing or marketing selective estrogen receptor modulators (SERMs) were identified. The investigators at each company responsible for the conduct of investigational trials were contacted and queried about reports of adverse events in any ongoing or completed trials involving SERMs produced by their company. Levormeloxifene and idoxifene trials noted a higher proportion of surgery for pelvic organ prolapse in treated versus untreated women. The development of these pharmaceutical agents was discontinued, primarily for endometrial concerns. However, pelvic organ prolapse was reported to the FDA as an adverse event associated with both drugs. Study weaknesses preclude a definitive association between the agents and pelvic organ prolapse. The treated groups were not necessarily similar for confounding factors such as age, parity, obesity, cigarette smoking, and other risk factors for pelvic organ prolapse. Tamoxifen and raloxifene increase hot flash intensity and frequency. Ovarian cyst formation and uterine fibroid growth have also been reported with some SERMs. The identification and assessment of the impact of current and future SERMs on the pelvic floor and other genital tissues will be important to understanding their potential long‐term application in disease treatment and prevention.
Lensing of the CMB: Non‐Gaussian Aspects
Authors: Zaldarriaga Matias
Published: July 2010

Abstract: We compute the small angle limit of the three‐ and four‐point function of the cosmic microwave background (CMB) temperature induced by the gravitational lensing effect by the large‐scale structure of the universe. We relate the non‐Gaussian aspects presented in this paper with those in our previous studies of the lensing effects. We interpret the statistics proposed in previous work in terms of different configurations of the four‐point function and show how they relate to the statistic that maximizes the S/N.
The Onset of Nonlinearity in Cosmological Structure
Authors: Fry J. N. , Ma Chung‐Pei
Published: July 2010

Abstract: We discuss the progression of growth of cosmological structure, from the quasilinear evolution of nearly Gaussian fluctuations on large scales into highly non‐Gaussian, strongly nonlinear structure on small scales. A systematic development in perturbation theory describes the first departures from homogeneity but fails to reproduce the fully nonlinear results. Physical insight, conceptual models, and symmetries are useful in the strong clustering regime. A phenomenological model with input information from the quasilinear regime provides enticing results for the strongly nonlinear regime.
BRCA1 Gene Sequence Variation in Centenarians
Authors: Vijg Jan , Perls Thomas , Franceschi Claudio , Van Orsouw Nathalie J.
Published: July 2010

Abstract: With the ample gene sequence information that has become available with the human genome project virtually completed, it has become possible to identify functional gene variants and their frequencies in elderly populations with different aging‐related characteristics. Such a genetic epidemiological approach could lead to new insights with respect to the basic mechanisms of aging and longevity as well as the identification of new targets to prevent or retard some of the late‐age adverse effects. Using our recently developed two‐dimensional gene scanning (TDGS) technology platform we demonstrate the feasibility of this approach by screening two different populations of centenarians for polymorphic variation in the BRCA1 breast cancer susceptibility gene, one of the many genes involved in genome maintenance. The initial results obtained with this approach suggest differences in BRCA1 genotype frequencies between the centenarian populations and controls.
Capacity for Recovery and Possible Mechanisms in Immobilization Atrophy of Young and Old Animals
Authors: Zarzhevsky N. , Menashe O. , Carmeli E. , Stein H. , Reznick A. Z.
Published: July 2010

Abstract: The effect of limb immobilization on muscle wasting and recovery of young and old rats was studied. Limb immobilization caused rapid and pronounced muscle weight loss, which was overcome efficiently in the muscles of young animals. However, muscles of old animals did not recover as well, indicating that muscle turnover (degradation and synthesis of proteins) is slower in old muscles than in young ones. The mechanisms of muscle wasting due to immobilization may involve two stages, the fast phase employing calcium‐dependent proteolysis and the slower phase recruiting the lysosomal and ubiquitin‐proteosome systems. The slow phase most probably involves the penetration of white cells between the muscle fibers and involves the secretion of cytokines that mediate a cascade of intracellular events, which culminates in muscle protein degradation. Thus, it was shown in our study and in other similar reports that through the influence of TNF‐α and an increase in oxidative stress, there is marked activation of transcription factor NF‐κB, which in turn induces many proteins to carry the signals that eventually result in protein breakdown. Because protein turnover was shown to slow down with age, it will be of great interest to study these events in aging muscles and to try to ascertain the specific events that make protein breakdown in aged muscles different from that in young ones.
Exercise at Old Age: Does It Increase or Alleviate Oxidative Stress?
Authors: Ji Li Li
Published: July 2010

Abstract: Aging is associated with increased free radical generation in the skeletal muscle that can cause oxidative modification of protein, lipid, and DNA. Physical activity has many well‐established health benefits, but strenuous exercise increases muscle oxygen flux and elicits intracellular events that can lead to increased oxidative injury. The paradox arises as to whether exercise would be advisable to aged population. Research evidence indicates that senescent organisms are more susceptible to oxidative stress during exercise because of the age‐related ultrastructural and biochemical changes that facilitate formation of reactive oxygen species (ROS). Aging also increases the incidence of muscle injury, and the inflammatory response can subject senescent muscle to further oxidative stress. Furthermore, muscle repair and regeneration capacity is reduced at old age that could potentially enhance the accrual of cellular oxidative damage. Predeposition of certain age‐related pathologic conditions may exacerbate the risks. In spite of these risks, the elderly who are physically active benefit from exercise‐induced adaptation in cellular antioxidant defense systems. Improved muscle mechanics, strength, and endurance make them less vulnerable to acute injury and chronic inflammation. Many critical questions remain regarding the relationship of aging and exercise as we enter a new millennium. For example, how does aging alter exercise‐induced intracellular and intercellular mechanisms that generate ROS? Can acute and chronic exercise modulate the declined gene expression of metabolic and antioxidant enzymes seen at old age? Does exercise prevent age‐dependent muscle loss (sarcopenia)? What kinds of antioxidant supplementation, if any, do aged people who are physically active need? Answers to these questions require highly specific research in both animals and humans.
Anti‐aging and Health‐promoting Constituents Derived from Traditional Oriental Herbal Remedies
Authors: Chang Il‐Moo
Published: July 2010

Abstract: Asia, Korea, China, and Japan have legally adopted the traditional Oriental (Chinese) medical system along with the Western system. A number of traditional herbal drugs including the polypharmacy type of prescriptions (a combination of multiple herbs) are available and are widely dispensed. Herbal therapy used in traditional Oriental medicine appears to be quite different from its counterpart Western drug therapy. The polypharmacy type of herbal therapy generally exhibits holistic effectiveness by exerting activities to multitarget organs (organ systems) according to the principles of traditional Oriental medicine. The Traditional Oriental Medicine Database (TradiMed 2000 DB) is a unique database of traditional Oriental herbal therapy containing a variety of information such as formulae, chemical information on ingredients, botanical information on herbal materials, and a dictionary of disease classification (TOM and Western classification). A formula, namely, the Sip‐Jeon‐Dae‐Bo‐Tang consisting of 10 different herbs, was selected by retrieving information from the TradiMed 2000 DB. Then its tonic effects for elderly people were shown as an example.
Consciousness, Reduction, and Emergence
Authors: GELL‐MANN MURRAY
Published: July 2010

Abstract: Consciousness is often seen as requiring a special kind of explanation. But the various aspects of self‐awareness can presumably emerge when certain levels of complexity are reached in an organism: it is not necessary to assume additional mechanisms or hidden causes. Looking at the most fundamental level, that of elementary particle physics, three principles appear—the conformability of nature to herself, the applicability of the criterion of simplicity, and the utility of certain parts of mathematics in describing physical reality—which are in themselves emergent properties of the fundamental laws of physics. At successive levels, it is the availability of similar mathematical descriptions from related problems that makes the next step appear with simplicity and elegance. Thus, once the concept of emergence is properly established, a huge burden is lifted from the inquiring mind. The whole explanatory loop may be closed by looking at the ability of the human mind to figure out the laws of nature. All the other sciences emerge in principle from fundamental physics plus historical accidents, even though “reduction” is obviously inadequate as a strategy. While bridges or staircases are under construction connecting the various sciences, each science needs to be studied at its own level as well. Although the idea of “vital forces” in biology alien to physics and chemistry has largely disappeared, consciousness remains the last refuge of obscurantists. Finally, it is argued that appeals to the alleged weirdness of quantum mechanics are based on a misunderstanding and are unlikely to have any place in a discussion of consciousness.
Co‐Evolution of Human Consciousness and Language
Authors: ARBIB MICHAEL A.
Published: July 2010

Abstract:This article recalls Cajal's brief mention of consciousness in the Textura as a function of the human brain quite distinct from reflex action, and discusses the view that human consciousness may share aspects of “animal awareness” with other species, but has its unique form because humans possess language. Three ingredients of a theory of the evolution of human consciousness are offered: the view that a précis of intended activity is necessarily formed in the brain of a human that communicates in a human way; the notion that such a précis constitutes consciousness; and a new theory of the evolution of human language based on the mirror system of monkeys and the role of communication by means of hand gestures as a stepping‐stone to speech.
Musical Predispositions in Infancy
Authors: TREHUB SANDRA E.
Published: July 2010

Abstract:Some scholars consider music to exemplify the classic criteria for a complex human adaptation, including universality, orderly development, and special‐purpose cortical processes. The present account focuses on processing predispositions for music. The early appearance of receptive musical skills, well before they have obvious utility, is consistent with their proposed status as predispositions. Infants' processing of musical or music‐like patterns is much like that of adults. In the early months of life, infants engage in relational processing of pitch and temporal patterns. They recognize a melody when its pitch level is shifted upward or downward, provided the relations between tones are preserved. They also recognize a tone sequence when the tempo is altered so long as the relative durations remain unchanged. Melodic contour seems to be the most salient feature of melodies for infant listeners. However, infants can detect interval changes when the component tones are related by small‐integer frequency ratios. They also show enhanced processing for scales with unequal steps and for metric rhythms. Mothers sing regularly to infants, doing so in a distinctive manner marked by high pitch, slow tempo, and emotional expressiveness. The pitch and tempo of mothers' songs are unusually stable over extended periods. Infant listeners prefer the maternal singing style to the usual style of singing, and they are more attentive to maternal singing than to maternal speech. Maternal singing also has a moderating effect on infant arousal. The implications of these findings for the origins of music are discussed.
Cerebral Substrates of Musical Imagery
Authors: HALPERN ANDREA R.
Published: July 2010

Abstract: Musical imagery refers to the experience of “replaying” music by imagining it inside the head. Whereas visual imagery has been extensively studied, few people have investigated imagery in the auditory domain. This article reviews a program of research that has tried to characterize auditory imagery for music using both behavioral and cognitive neuroscientific tools. I begin by describing some of my behavioral studies of the mental analogues of musical tempo, pitch, and temporal extent. I then describe four studies using three techniques that examine the correspondence of brain involvement in actually perceiving vs. imagining familiar music. These involve one lesion study with epilepsy surgery patients, two positron emission tomography (PET) studies, and one study using transcranial magnetic stimulation (TMS). The studies converge on the importance of the right temporal neocortex and other right‐hemisphere structures in the processing of both perceived and imagined nonverbal music. Perceiving and imagining songs that have words also involve structures in the left hemisphere. The supplementary motor area (SMA) is activated during musical imagery; it may mediate rehearsal that involves motor programs, such as imagined humming. Future studies are suggested that would involve imagery of sounds that cannot be produced by the vocal tract to clarify the role of the SMA in auditory imagery.