bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mechanisms of Placental Viral Infection
Authors: KOI HIDEKI , ZHANG JIAN , PARRY SAMUEL
Published: July 2010

The placenta is a dynamic organ whose structure and function change throughout pregnancy. There is compelling evidence that the placenta plays an integral role in the vertical transmission of viruses, such as cytomegalovirus and human immunodeficiency virus, from the mother to the fetus. Although the sequelae of congenital viral infection (i.e., fetal anomalies, intrauterine fetal death, and persistent postnatal infection) may be devastating, very little is known about the passage of viruses across the placenta and the pathologic consequences of placental viral infection. We postulate that the syncytiotrophoblast, which forms a continuous barrier between the maternal and fetal circulation, is relatively resistant to viral infection. In support of this hypothesis, we observed that the susceptibility of trophoblast cells to infection by adenovirus and herpes simplex virus and the expression of viral receptors were reduced as trophoblast cells terminally differentiated into syncytiotrophoblast. Conversely, we observed that undifferentiated, extravillous trophoblast cells, which are susceptible to adenovirus infection, underwent pathologic changes (i.e., apoptosis) when infected by adenovirus in the presence of decidual lymphocytes (which were used to simulate the maternal immune response to viral infection). Based on these findings, we speculate that viral infection of extravillous trophoblast cells may negatively impact the process of placental invasion and predispose the mother and fetus to adverse reproductive outcomes that result from placental dysfunction.
Uterine Transplantation, Abdominal Trachelectomy, and Other Reproductive Options for Cancer Patients
Authors: Del PRIORE GIUSEPPE , SMITH J. RICHARD , BOYLE DEBORAH C.M. , CORLESS DAVID J. , ZACHARIA FARIS B.P. , NOAKES DAVID A. , DIFLO THOMAS , GRIFO JAMES A. , ZHANG JOHN J.
Published: July 2010

More and more women with cancer issues are now raising fertility concerns as survival improves and childbearing is delayed. Pregnancy is no longer contraindicated in cancer patients including breast and endometrial cancer survivors. In fact, survival in patients treated for breast cancer who subsequently become pregnant is actually higher than that in patients who do not become pregnant. “Therapeutic” abortions are no longer recommended. Assisted reproductive technology (ART) have been associated with ovarian neoplasms, but the association is probably not causal. Neither ART nor hormone replacement is contraindicated in cancer patients. Our institution is very supportive of patients and the difficult decisions cancer survivors face. Using a program of counseling and close collaboration between oncologists, perinatologists, and reproductive endocrinologists, informed patients are offered every possible option, including ART and uterine transplantation, to achieve their family planning objectives.
Role of the Proteasome in the Regulation of Fetal Fibronectin Secretion in Human Placenta
Authors: MA YUEHONG , D'ANTONA DONATO , LaCHAPELLE LINDA , RYU JAE SHIN , GULLER SETH
Published: July 2010

The goal of the current study was to examine the role of the ubiquitin‐proteasome system (UPS), a pathway of intracellular degradation, in the regulation of fetal fibronectin (FFN) expression in human placenta. Primary cultures of cytotrophoblasts (CTs) and placental mesenchymal cells (PMCs) were isolated from human term placentas and were maintained in serum‐free medium (SFM) in the presence of inhibitors of proteasome‐mediated degradation (e.g., MG132) as well as inhibitors of other proteases. Levels of secreted FFN and interleukin (IL)‐8 in culture media were quantitated by enzyme‐linked immunosorbent assay (ELISA), and cell viability was assessed by trypan blue exclusion. Intracellular levels of FFN and ubiquinated proteins were measured by Western blotting, and levels of fibronectin mRNA were determined following Northern blotting. We found that proteasome inhibitors (MG132, MG262, and PSI) potently suppressed levels of secreted FFN in cultures of CTs, but they not did affect levels of IL‐8. Lysosomal, calpain, and serine protease inhibitors as well as the anti‐inflammatory compound sulfasalazine did not markedly affect levels of secreted FFN in CT cultures. Proteasome inhibitors did not compromise cell viability during the initial 16–18 hours of treatment and did not affect intracellular levels of FFN protein or fibronectin mRNA. The efficacy of suppression of FFN in CT culture media by proteasome inhibitors reflected their effects on intracellular accumulation of ubiquinated proteins. By contrast, the presence of proteasome inhibitors did not alter levels of secreted FFN in cultures of PMCs. We conclude that inhibitors of proteasome‐mediated degradation potently and specifically suppressed extracellular expression of FFN in CTs through a cell type‐specific pathway that did not involve alterations in FFN synthesis. This suggests that accumulation of ubiquinated proteins in the presence of proteasome inhibitors blocks FFN secretion or promotes the extracellular degradation of FFN. This experimental paradigm will be useful for dissecting the role of the UPS in regulating CT function.
Hydrogels for Biomedical Applications
Authors: HOFFMAN ALLAN S.
Published: July 2010

Abstract: This paper reviews the composition and synthesis of hydrogels, the character of their absorbed water, and permeation of solutes within their swollen matrices. The most important properties of hydrogels relevant to their biomedical applications are also identified, in particular for use of hydrogels as drug and cell carriers, and as tissue engineering matrices.
A Novel Class of Amitogenic Alginate Microcapsules for Long‐Term Immunoisolated Transplantation
Authors: ZIMMERMANN ULRICH , THÜRMER FRANK , JORK ANETTE , WEBER MEIKE , MIMIETZ SASKIA , HILLGÄRTNER MARKUS , BRUNNENMEIER FRANK , ZIMMERMANN HEIKO , WESTPHAL INES , FUHR GÜNTER , NÖTH ULRIKE , HAASE AXEL , STEINERT ANDRE , HENDRICH CHRISTIAN
Published: July 2010

Abstract: In the light of results of clinical trials with immunoisolated human parathyroid tissue Ba2+‐alginate capsules were developed that meet the requirements for long‐term immunoisolated transplantation of (allogeneic and xenogeneic) cells and tissue fragments. Biocompatibility of the capsules was achieved by subjecting high‐M alginate extracted from freshly collected brown algae to a simple purification protocol that removes quantitatively mitogenic and cytotoxic impurities without degradation of the alginate polymers. The final ultra‐high‐viscosity, clinical‐grade (UHV/CG) product did not evoke any (significant) foreign body reaction in BB rats or in baboons. Similarly, the very sensitive pERK assay did not reveal any mitogenic impurities. Encapsulated cells also exhibited excellent secretory properties under in vitro conditions. Despite biocompatible material, pericapsular fibrosis is also induced by imperfect capsule surfaces that can favor cell attachment and migration under the release of material traces. This material can interact with free end monomers of the alginate polymers under formation of mitogenic advanced glycation products. Smooth surfaces, and thus topographical biocompatibility of the capsules (visualized by atomic force microscopy), can be generated by appropriate crosslinking of the UHV/CG‐alginate with Ba2+ and simultaneous suppression of capsule swelling by incorporation of proteins and/or perfluorocarbons (i.e., medically approved compounds with high oxygen capacity). Perfluorocarbon‐loaded alginate capsules allow long‐term non‐invasive monitoring of the location and the oxygen supply of the transplants by using 19F‐MRI. Transplantation studies in rats demonstrated that these capsules were functional over a period of more than two years.
An Overview of the Immune System with Specific Reference to Membrane Encapsulation and Islet Transplantation
Authors: GRAY DEREK W.R.
Published: July 2010

Abstract: The concept of immunoisolation by use of a bioartificial membrane is discussed, concentrating on the immunological mechanisms that are likely to be operative in the light of recent information on the workings of the immune system. Special attention is given to the use of encapsulation for the purpose of treating autoimmune diabetes by implantation of xenogeneic islet tissue. It is argued that the term immunoisolation is misleading because the immune system is always activated by the indirect pathway of antigen presentation and that the term immunomodulation would be more appropriate.
Newly Developed Aminopropyl‐Silicate Immunoisolation Membrane for a Microcapsule‐Shaped Bioartificial Pancreas
Authors: SAKAI SHINJI , ONO TSUTOMU , IJIMA HIROYUKI , KAWAKAMI KOEI
Published: July 2010

Abstract: An aminopropyl‐silicate membrane, synthesized from tetramethoxysilane (TMOS) and 3‐aminopropyltrimethoxysilane (APTrMOS) by the sol‐gel method, was formed onto Ca‐alginate gel beads via electrostatic interactions. The permeability of the membrane could be controlled easily by changing the molar ratio of both the precursors ([APTrMOS]/[TMOS]). The aminopropyl‐silicate membrane prepared at a molar ratio of 2.40 rejected γ‐globulin and BSA successfully, whereas it permeated ovalbumin. This result indicates that the molecular weight cutoff point of this newly developed aminopropyl‐silicate membrane is approximately 60 kDa.
Evaluating the Performance of a Hybrid Artificial Liver Support System With a Recoverable Hepatic Failure Rat Model
Authors: IJIMA HIROYUKI , NOGUCHI AYAKO , KATSUNO TAKEYUKI , ONO TSUTOMU , NAKAZAWA KOHJI , FUNATSU KAZUMORI , KAWAKAMI KOEI
Published: July 2010

Abstract: To evaluate the performance of an artificial liver, we created a recoverable hepatic failure rat model. This involves a 30–60 minute warm ischemia, via clamping, of one‐third of the liver with a partial (two‐thirds) hepatectomy. Variations on this method provide for the possibility of several modes of hepatic failure. Survival time of the rats was prolonged (35%) by applying our hybrid artificial liver. However, the extracorporeal circulation is a considerable burden to the rat. Therefore, we need to apply the hybrid artificial liver intermittently and repeatedly.
Development of a Coculture Model of Encapsulated Cells
Authors: CANAPLE LAURENCE , NURDIN NATHALIE , ANGELOVA NELA , HUNKELER DAVID , DESVERGNE BÉATRICE
Published: July 2010

Abstract: In the whole animal, metabolic regulations are set by reciprocal interactions between various organs, via the blood circulation. At present, analyses of such interactions require numerous and uneasily controlled in vivo experiments. In a search for an alternative to in vivo experiments, our work aims at developing a coculture system in which different cell types are isolated in polymer capsules and grown in a common environment. The signals exchanged between cells from various origins are, thus, reproducing the in vivo intertissular communications. With this perspective, we evaluated a new encapsulation system as an artificial housing for liver cells on the one hand and adipocytes on the other hand. Murine hepatocytes were encapsulated with specially designed multicomponent capsules formed by polyelectrolyte complexation between sodium alginate, cellulose sulphate and poly(methylene‐co‐guanidine) hydrochloride, of which the permeability has been characterized. We demonstrated the absence of cytotoxicity and the excellent biocompatibility of these capsules towards primary culture of murine hepatocytes. Encapsulated hepatocytes retain their specific functions—transaminase activity, urea synthesis, and protein secretion—during the first four days of culture in minimum medium. Mature adipocytes, isolated from mouse epidydimal fat, were embedded in alginate beads. Measurement of protein secretion shows an identical profile between free and embedded adipocytes. We finally assessed the properties of encapsulated hepatocytes, cryopreserved over a periods of up to four months. The perspective of using encapsulated cells in coculture are discussed, since this system may represent a promising tool for fundamental research, such as analyses of drug metabolism, intercellular regulations, and metabolic pathways, as well as for the establishment of a tissue bank for storage and supply of murine hepatocytes.
Formation of Sertoli Cell‐Enriched Tissue Constructs Utilizing Simulated Microgravity Technology
Authors: CAMERON DON F. , HUSHEN JOELLE J. , NAZIAN STANLEY J. , WILLING ALISON , SAPORTA SAM , SANBERG PAUL R.
Published: July 2010

Abstract: Cell transplantation therapy for diabetes and Parkinson's disease offers hope for long‐term alleviation of symptoms. However, successful protocols remain elusive due to obstacles, including rejection and lack of tropic support for the graft. To enhance engraftment, testis‐derived postmitotic Sertoli cells have been cotransplanted with islets in the diabetic rat (Db) and neurons in the Parkinsonian rat (PD). Sertoli cell tropic, regulatory, and nutritive factors that nourish and stimulate germ cells also support isolated neurons and islets in vitro. Likewise, immunosuppressive properties of Sertoli cells, extant in the testis, are expressed by extratesticular Sertoli cells evidenced by allo‐ and xenograft immunoprotection of grafts in both the CNS (in the PD model) and the periphery (in the Db model). On this basis, we have created Sertoli islet cell aggregates (SICA) and Sertoli neuron aggregated cells (SNAC) using simulated microgravity culture technology developed by NASA. Isolated rat and pig Sertoli cells were cocultured with neonatal pig islets (SICA) and with immortalized N‐Terra‐2 (NT2) neurons (SNAC) in the HARV biochamber. Formed aggregates were assayed for desirable functional and structural characteristics. Cell viability in SICA and SNAC exceeded 90% and FasL immunopositive Sertoli cells were present in both. Sertoli cells did not interfere with insulin secretion by SICA and promoted differentiation of NT2 cells to the dopaminergic hNT cell type in SNAC. Addition of Matrigel resulted in structural reorganization of the aggregates and enhanced insulin secretion. We conclude that SICA, SNAC, and Matrigel‐induced islet‐ and neuron‐filled “Sertoli cell biochambers” are suitable for long‐term transplantation treatment of Db and PD.
An Approach to Constructing Three‐Dimensional Tissue
Authors: KO IN KAP , IWATA HIROO
Published: July 2010

Abstract: The authors propose an approach to constructing three‐dimensional tissue with capillaries using cellulose hollow fibers. Fibronectin (FN) was immobilized on hollow fibers to assure cell attachment. Bovine coronary artery smooth muscle cells (BCASMC) and L cells were seeded on FN‐immobilized fibers and cultured for an extended period of time. The cells proliferated and formed multicellular layers on the fibers. The hollow fibers were removed by enzymatic digestion using cellulase. The cellulase treatment did not damage L cells, although some cells fell off from the fibers. On the other hand, no deterioration was observed in the BCASMC aggregate structure. The BCASMC aggregates maintained several lumens after removal of the hollow fibers by cellulase digestion. The authors believe that their approach offers a useful method to tissue engineering in preparation of three‐dimensional tissue structure.
Both Maternal and Fetal Cell‐Free DNA in Plasma Fluctuate
Authors: HAHN SINUHE , ZHONG XIAO YAN , BÜRK MARTIN R. , TROEGER CAROLYN , KANG ANJEUNG , HOLZGREVE WOLFGANG
Published: July 2010

Abstract: Elevations in the concentration of cell‐free fetal DNA in maternal plasma have recently been determined in various pregnancy‐related disorders, including preeclampsia, preterm labor, and polyhydramnios. In addition, almost 2‐fold increments in cell‐free fetal DNA levels have been recorded in pregnancies with certain aneuploid fetuses, in particular trisomy 21. These findings have led to the speculation that quantitative assessment of circulatory fetal DNA may be useful in the noninvasive prenatal diagnosis of certain fetal genetic constellations or pregnancy‐related disorders. A premise for any quantitative analysis is that the quantity of the analyte being assayed does not vary greatly over time. As this aspect has not been examined for circulatory DNA levels, we examined these in normal healthy individuals as well as in pregnant women. Our data indicate that severalfold alterations in circulatory DNA amounts do occur over short periods of time. Of particular note is that we observed almost 2‐fold variations in free fetal DNA levels over a period of 3 days, which are in a similar range to the elevations noted in aneuploid pregnancies. Our results, therefore, imply that caution should be used when using small increments in circulatory fetal DNA concentrations for potential diagnostic applications.
Use of Annexin V Antibody to Identify Apoptotic Cells during Pregnancy
Authors: KOLIALEXI AGGELIKI , TSANGARIS GEORGE T. H. , MAVROU ARIADNI , ANTSAKLIS ARISTIDES , TZORTZATOU FOTINI , TOULIATOU VASSILIKI , METAXOTOU CATHERINE
Published: July 2010

Abstract: In a previous study, we demonstrated that apoptosis increased according to gestational age, accounting partly for the presence of free fetal DNA in maternal plasma and serum. Using simultaneous TUNEL assay and FISH analysis, we identified the fetal origin of part of the apoptotic cell population, but very few TUNEL‐positive cells showed hybridization signals since they were in a late apoptosis stage and nuclei were destroyed. In the present study, the apoptotic cell population was identified immunocytochemically using Annexin V, a marker of cells in an early stage of apoptosis. The mean apoptosis rate in mononuclear cells isolated from the peripheral blood of 20 pregnant women in the 16th to 19th week of pregnancy with Annexin V was 6.8 ± 0.5% (range: 4.2–8.1%) compared to 6.14 ± 0.5% (range: 3.7–6.9%) obtained with ethidium bromide staining. FISH using X and Y chromosome‐specific probes was applied in 11 cases known to be carrying male fetuses. Eighty percent of Annexin V+ cells showed hybridization signals, while the proportion of apoptotic cells showing X/Y signals was 7.8% (range: 5–12%). Although our results are still preliminary, it seems that use of Annexin V antibody to detect the apoptotic cell population improves FISH analysis and allows a more accurate estimate of the proportion of fetal cells among the apoptotic cell population.
Derivation of a Prediction Rule for Posttraumatic Organ Failure Using Plasma DNA and Other Variables
Authors: RAINER TIMOTHY H. , LO Y. M. DENNIS , CHAN LISA Y. S. , LAM NICOLE Y. L. , LIT LYDIA C. W. , COCKS ROBERT A.
Published: July 2010

Abstract: The early identification of patients at high risk of developing posttraumatic organ failure would allow preventive therapies to be studied. In this study, highly sensitive and specific guidelines for the early prediction of post‐traumatic organ failure (OF) and multiple organ dysfunction syndrome (MODS) using cell‐free (plasma) DNA and other predictors of posttraumatic complications were derived. As plasma DNA increases after injury and may be used to predict acute lung injury (ALI), we hypothesized that in combination with other predictors it would predict the later development of OF and MODS. Eighty‐three patients (69 males; median age, 36 years) were studied as a consequence of major trauma within 3.5 hours of injury (median time to sampling and assessment, 60 min). Plasma DNA was measured using a real‐time, quantitative, polymerase chain reaction assay for the β‐globin gene. OF and MODS occurred in 20/83 (24%) and 9/79 (11%) cases, respectively. At selected cutoff points, the sensitivity of plasma DNA for predicting OF and MODS ranged from 50% to 100%, specificity ranged from 74% to 95%, and the likelihood ratio ranged from 3.89 to 10.50. Other variables studied included serum albumin, creatine kinase, aspartate transaminase, lactate dehydrogenase, leukocyte count, hematocrit, injury severity score, maximal abbreviated injury score, and shock index. Using a classification and regression tree, plasma DNA and aspartate transaminase at optimal cutoffs predicted OF and MODS with an overall correct classification of 93% and 87%, respectively.
Pathological Findings of HIV‐Associated Cardiovascular Disease
Authors: D'AMATI GIULIA , Di GIOIA CIRA R.T. , GALLO PIETRO
Published: July 2010

Abstract: More effective therapies have improved survival times of HIV+ patients, resulting in a higher prevalence of long‐term complications of the disease. This review focuses on HIV‐associated cardiovascular pathology, correlating the morphologic findings to clinical syndromes of HIV disease/AIDS.
AIDS Cardiomyopathy
Authors: LEWIS WILLIAM
Published: July 2010

Abstract: Cardiomyopathy in AIDS (AIDS CM) is an important and prevalent clinical problem. Mechanisms of AIDS CM are not completely understood. Among the potential etiologies of AIDS CM are HIV‐1, various opportunistic infections, inflammatory reactions, cytokine effects, and cardiotoxicity of prescribed or illicit drugs. The transgenic mouse (TG) offers a unique in vivo way to elucidate mechanisms of AIDS CM. Structural and functional effects of HIV‐1 and specific HIV‐1 gene products on heart tissue can be addressed by TGs. Selective effects of HIV‐1 and antiretroviral therapy may be defined in controlled studies. We utilized AIDS TGs with generalized expression of HIV‐1 gene products in CM models. We treated those TGs with individual and combined antiretroviral therapeutics (HAART) to compare cardiovascular effects of AIDS per se and its therapy. We next developed cardiac‐specific TGs in which selected HIV‐1 genes are driven by α‐myosin heavy chain promoter to target the selected HIV‐1 gene to the cardiac myocyte to define effects of specific HIV‐1 gene products on the cardiac myocyte. Each transgenic approach is a model system that affords a distinct opportunity to explore the pathogenesis and pathophysiology of AIDS CM.
Catheter‐Related Bloodstream Infections in HIV‐Infected Patients
Authors: NICASTRI EMANUELE , PETROSILLO NICOLA , VIALE PIERLUIGI , IPPOLITO GIUSEPPE
Published: July 2010

Abstract: Bloodstream infections (BSI) constitute a significant public health problem and represent an important cause of morbidity and mortality in hospitalized patients, with an approximate incidence of one episode per hundred hospital admissions. Studies on BSI in HIV+ patients have identified central venous catheters (CVC) as a risk factor, with an attributable mortality rate of 10–20%. The long‐term CVC‐related infection risk appeared to be 5 to 10‐fold higher with respect to the infection rates among HIV− patients. CVC associated infection rate ranges from 1.3 to 12 infections per 1,000 catheter‐days. Staphylococcus aureus is the most common etiologic agent causative of CVC‐related BSI, likely the result of the high skin and nasal carriage of this organism among HIV+ patients, mostly intravenous drug users. Coagulase‐negative staphylococci are also frequently identified as cause of CVC‐related BSI, likely the result of breaches in infection control measures and in antiseptic technique during CVC management. Treating bacteremia without catheter removal would be optimal, but the reported efficacy of systemic antibiotic therapy alone is only 25–32%. Conversely, recent studies have shown that, using an antibiotic‐lock procedure, up to 90% of HIV‐infected and uninfected patients achieved complete eradication of catheter‐related BSIs without catheter removal. Clinical trials using new materials such as covalently linked heparin on the CVC surface, electrically charged CVC, novel topical agents that interfere with bacterial colonization, antiadhesin molecules and agents that block the gene expression involved in the biofilm formation, are all needed to reduce the high catheter‐related infection risk among HIV+ patients.
Role of Guidelines in Clinical Practice for the Management of HIV‐Related Diseases
Authors: LAURIA FRANCESCO NICOLA , VANACORE PAOLA , CASCIELLO MASSIMO
Published: July 2010

Abstract: Several guidelines have been developed for the diagnosis, treatment and prevention of infectious diseases. Actually, evidence‐based clinical practice guidelines provide physicians and other health care professionals with scientific information about the most appropriate strategy for the management of these patients, in order to avoid unnecessary or inappropriate interventions. As medical technology rapidly increases and becomes more complex, clinical guidelines can help health care providers to assess current practices and integrate new technological advances. Since AIDS was first recognized nearly 20 years ago, remarkable progress has been made in improving the quality and duration of life for HIV+ patients. In this area, clinical guidelines have been developed to manage patient care, focusing on: antiretroviral therapy, prevention of opportunistic infections, and treatment of tuberculosis. The quality of the guideline is notable when appropriate methodologies are applied. Different methods for developing guidelines are evaluated here: Agency for Health Care Policy and Research (AHPCR) methodology is designed to produce evidence‐based guidelines that are valid, clinically applicable, and flexible. Finally, the problems associated with the implementation of guidelines for HIV‐related diseases and other infectious diseases are examined.
Evidence for the Physiological and Pathological Roles of Adrenomedullin from Genetic Engineering in Mice
Authors: IMAI YASUSHI , SHINDO TAKAYUKI , MAEMURA KOJI , KURIHARA YUKIKO , NAGAI RYOZO , KURIHARA HIROKI
Published: July 2010

Abstract: Adrenomedullin (AM) has been implicated as having hypotensive as well as protective effects on organs and vessels against different kinds of injuries. To elucidate the in vivo pathophysiological roles of adrenomedullin, we established transgenic mice (AMTg) overexpressing adrenomedullin driven by preproendothelin‐1 promoter and adrenomedullin knockout mice (AMKO). Blood pressure in AMTg was significantly lower than that in wild‐type mice, and AMTg was significantly resistant to lipopolysaccharide‐induced septic shock and vascular injuries. On the other hand, heterozygotes of AMKO, AM(+/−), were fully viable and hypertensive as compared with wild littermates. Mice homozygous for adrenomedullin null mutation (AM−/−) were embryonic lethal, and no embryos could survive beyond the midterm of gestation. Collectively, our findings indicate the indispensable role of adrenomedullin in circulatory homeostasis and the organ protection as well as the fetal morphogenesis and the maintenance of pregnancy.
Phenotypic Modulation of Vascular Smooth Muscle Cells
Authors: NAGAI RYOZO , SUZUKI TORU , AIZAWA KENICHI , MIYAMOTO SAKU , AMAKI TOSHIHIRO , KAWAI‐KOWASE KEIKO , SEKIGUCHI KEN‐ICHI , KURABAYASHI MASAHIKO
Published: July 2010

Abstract: The smooth muscle myosin heavy chain (MHC) gene and its isoforms are excellent molecular markers that reflect smooth muscle phenotypes. The SMemb/Nonmuscle Myosin Heavy Chain B (NMHC‐B) is a distinct MHC gene expressed predominantly in phenotypically modulated SMCs (synthetic‐type SMC). To dissect the molecular mechanisms governing phenotypic modulation of SMCs, we analyzed the transcriptional regulatory mechanisms underlying expression of the SMemb gene. We previously reported two transcription factors, BTEB2/IKLF and Hex, which transactivate the SMemb gene promoter based on the transient reporter transfection assays. BTEB2/IKLF is a zinc finger transcription factor, whereas Hex is a homeobox protein. BTEB2/IKLF expression in SMCs is downregulated with vascular development in vivo but upregulated in cultured SMCs and in neointima in response to vascular injury after balloon angioplasty. BTEB2/IKLF and Hex activate not only the SMemb gene but also other genes activated in synthetic SMCs including plasminogen activator inhibitor‐1 (PAI‐1), iNOS, PDGF‐A, Egr‐1, and VEGF receptors. Mitogenic stimulation activates BTEB2/IKLF gene expression through MEK1 and Egr‐1. Elevation of intracellular cAMP is also important in phenotypic modulation of SMCs, because the SMemb promoter is activated under cooperatively by cAMP‐response element binding protein (CREB) and Hex.
Regulation of Immune Mechanisms in Atherosclerosis
Authors: HANSSON GÖRAN K.
Published: July 2010

Abstract: Atherosclerosis is accompanied by a local immune response in plaque, but its role in the pathogenesis of the disease is still unclear. Although we might expect that an (auto)immune response would be an aggravating factor, some of its consequences could be protective. Studies of human plaques and of lesion formation in apo E‐0 mice show that CD4+ T cells and macrophages form an inflammatory infiltrate. Both cell types are activated and secrete proinflammatory cytokines. CD4+ cells respond immunospecifically to oxidized LDL, suggesting that oxidation induces antigenic epitopes on LDL and converts it to an autoantigen. The pathophysiological consequences of this response are probably mediated largely via cytokine secretion and cell‐cell contacts. Th1 cytokines dominate and may promote vascular inflammation; this is enhanced by the increased capacity for activation of NF‐κB in intimal smooth muscle cells. The net effect of such activity appears to be proatherogenic, as can be deduced by cell transfer into immunodeficient apoE‐0 × SCID mice. These data emphasize the importance of inflammation and immune responses in the pathogenesis of atherosclerosis.
Genetic Modifiers of Atherosclerosis in Mice
Authors: SMITH JONATHAN D. , DANSKY HAYES M. , BRESLOW JAN L.
Published: July 2010

Abstract: Common atherosclerosis has a genetic component, but it is difficult to determine the specific genes that play a role in atherosclerosis susceptibility in humans. We have used the apoE‐deficient mouse as a model system to examine the effects of candidate genes on atherosclerosis as well as to perform genomic experiments to map and isolate other genes giving rise to atherosclerosis susceptibility. We have tested the effects of mutations in the MCSF and VCAM‐1 genes on atherosclerosis, and in both of these cases mutations led to gene dosage‐dependent decreases in atherosclerosis. By successive back breeding, we have established apoE‐deficiency on the C57BL/6 and FVB/N inbred mouse strains. Lesions in C57BL/6 mice are about eightfold larger than those in FVB/N mice, and lesions in F1 hybrids are intermediate in size. We have performed quantitative trait locus mapping on two F2 cohorts and discovered atherosclerosis susceptibility loci on chromosomes 10, 14, and 19.
Remnant Lipoproteins and Atherogenesis
Authors: KAWAKAMI AKIO , YOSHIDA MASAYUKI , TANAKA AKIRA , NAKAJIMA KATSUYUKI , YASUKOCHI YUKIO , SHIMOKADO KENTARO , NUMANO FUJIO
Published: July 2010

Abstract: Remnant lipoproteins are reported to play a causative role in atherogenesis. They consist of chylomicron remnants and very low‐density lipoprotein remnants. They are heterogeneous in composition and metabolic pathway and are rapidly taken up from the circulation as soon as they are formed in normal lipid metabolism. These characteristics make it difficult to separate and subsequently analyze remnant lipoproteins. Recently, however, we developed a simple and reliable immunoseparation method to separate remnant lipoproteins, and the cellular mechanism(s) by which they contribute to atherogenesis have been elucidated.
Immunohistochemical Studies on Annexin I and II in Takayasu Arteritis
Authors: OHKAWARA MIHO , KUROIWA TOMOE , NUMANO FUJIO
Published: July 2010

Abstract: Annexin I and II were studied immunohistochemically in arteries involved by Takayasu arteritis. Results suggest that they are important in the pathophysiologic function of macrophages and endothelial cells.
In vivo Gene Transfer of Dominant‐Negative Rho‐Kinase Induces Regression of Coronary Arteriosclerosis in Pigs
Authors: MORISHIGE KUNIO , SHIMOKAWA HIROAKI , ETO YASUHIRO , HOSHIJIMA MASAHIKO , KAIBUCHI KOZO , TAKESHITA AKIRA
Published: July 2010

Abstract: Small GTPase Rho and its target Rho‐kinase play an important role in various cellular functions that may be involved in the pathogenesis of arteriosclerosis. Here we show that adenovirus‐mediated transfer of dominant‐negative Rho‐kinase (AdDNRhoK) induces a regression of coronary constrictive remodeling and abolishes coronary vasospastic activity in vivo. Porcine coronary segments were chronically treated with interleukin‐1β, which resulted in the development of constrictive remodeling and vasospastic responses to serotonin in vivo. AdDNRhoK, but not that of β‐galactosidase, into the interleukin‐1β‐treated coronary segment caused regression of constrictive remodeling and abolished vasospastic activity in 3 weeks. The unregulated phosphorylation of the target proteins of Rho‐kinase at the coronary lesion was significantly suppressed by AdDNRhoK. These results indicate that Rho‐kinase is substantially involved in the mechanism of coronary arteriosclerosis, which can be reversed by selective inhibition of the molecule in our porcine model in vivo.
Extrahepatic Synthesis of FVII in Human Atheroma and Smooth Muscle Cells in Vitro
Authors: WILCOX JOSIAH N. , NOGUCHI SUMIKO , CASANOVA JUAN R. , RASMUSSEN MIRELLA E.
Published: July 2010

Abstract: The present series of experiments provide evidence that FVII is synthesized outside of the liver and is found in a variety of cells in normal and atherosclerotic vessels. In normal vessels FVII was localized to the endothelial cell layer and in adventitial fibroblasts at sites where tissue factor (TF) is also found. In early and advanced atherosclerotic lesions, FVII was mostly found in macrophage‐ rich regions colocalized with TF. Foam cells and macrophages in the necrotic core adjacent to the cholesterol clefts and foamy macrophages in early intimal thickenings all showed strong cytoplasmic staining with FVII antibodies. Although it is possible that FVII protein staining found in normal and atherosclerotic vessels originated from the blood, the finding of FVII mRNA by both in situ hybridization and RT‐PCR suggests that these tissues are sites of FVII synthesis. Additional work demonstrated synthesis of FVII in a variety of tissues and smooth muscle cells and fibroblasts in vitro. The distribution of FVII synthesis in extrahepatic tissues and more recent data regarding thrombin‐independent signaling as a consequence of FVII/TF binding may suggest the possibility of other cellular functions for this coagulation factor.
Selective Estrogen Receptor Modulator Effects on Serum Lipoproteins and Vascular Function in Postmenopausal Women and in Hypercholesterolemic Men
Authors: BLUM ARNON , CANNON RICHARD O.
Published: July 2010

Abstract: Epidemiological observations, clinical mechanistic studies, and basic laboratory research suggest that estrogen therapy is associated with beneficial cardiovascular effects in postmenopausal women. Estrogen has a multitude of biological effects that may account for this apparent benefit (which remains to be proved in randomized clinical trials), including favorable effects on the lipid profile, increased endothelial nitric oxide bioactivity, and enhanced fibrinolysis. However, long‐term estrogen therapy increases the risk of breast and endometrial cancers. Raloxifene, a benzothiophene derivative that binds to the estrogen receptor, is a selective estrogen receptor modulator, producing estrogen‐agonist effects in some tissues (liver, bone) and estrogen‐antagonistic effects in others (breast, uterus), and may prove to be an option for women with atherosclerosis or its risk factors. This review updates the current knowledge of the biological effects of selective estrogen receptor modulators of potential cardiovascular importance in postmenopausal women.
Estrogens, Selective Estrogen Receptor Modulators, and Dementia: What Is the Evidence?
Authors: YAFFE KRISTINE
Published: July 2010

Abstract: At least 10% of people aged 65 or older have some form of cognitive impairment, increasing to around 50% by age 85. Several studies have suggested that estrogen may improve cognitive function or prevent the development of dementia, but other studies have not shown a benefit, and results from large randomized trials are lacking. Fortunately, further trials are currently being conducted. With the recognition that selective estrogen receptor modulators (SERMs) have differential tissue‐dependent effects on estrogen receptor function, there is recent interest in the effects of raloxifene, tamoxifen, and other SERMs on cognition. In this paper, the current state of knowledge of the role of estrogen for preventing dementia in postmenopausal women will be reviewed. In addition, the status of ongoing and recently completed trials of estrogen and SERMs on cognitive function or on Alzheimer's disease severity will be summarized.
FDA Review Practices and Priorities for Drugs Used in Cancer Treatmenta
Authors: KOBAYASHI KEN , DELAP ROBERT J.
Published: July 2010

Abstract: The Federal Food, Drug, and Cosmetic Act and related regulations (21 U.S.C. 301 et seq.) give FDA staff the legal authority and responsibility to review the safety and effectiveness of drugs and biological products (including products used in cancer treatment), from preclinical testing through all phases of clinical research and marketing. FDA review activities in the oncology arena can be divided into five major categories: (1) initial review of investigational new drug (IND) applications; (2) ongoing review of premarketing research (including new research protocols submitted to existing INDs and IND safety reports describing adverse events with the new drug); (3) discussions with commercial sponsors regarding their clinical development plans, including the design and conduct of key studies that are intended to support initial marketing approval for a new product or to support the addition of new indications to the prescribing information for currently marketed products; (4) review of submitted new drug applications (NDAs) or biological licensing applications (BLAs); and (5) continuing review of the safety and effectiveness of marketed products. Through these review activities, FDA staff work to ensure that products approved for marketing for cancer treatment are effective and adequately safe for their intended uses and to ensure that the quality, effectiveness, and safety of products on the market are preserved or enhanced, so patients and physicians may use these products with confidence and with adequate safety. Because these review activities generally fall into a chronologic sequence, the following discussion parallels the development course of a typical new drug.
Negotiating Industry‐Sponsored Clinical Trial Agreements
Authors: ZAPOL NIKKI J.
Published: July 2010

Abstract: A number of possible factors, including issues of cost, enrollment, and time, contribute to the decline in the percentage of industry‐sponsored clinical trials conducted in academic institutions as opposed to those conducted at for‐profit entities. This piece focuses on the agreement negotiation process. If negotiators were given easier access to the sponsor's decision makers, it is likely that the negotiations would proceed more efficiently. Also noted are reports by academic investigators of difficulty in getting access to unblinded trial data, which are needed for patient care and publication.
A Random Walk through Models of Nonlinear Clustering
Authors: Sheth Ravi K.
Published: July 2010

Abstract: A few simple models of the mass function of collapsed objects are presented. The emphasis is on apparently unrelated models which end up giving the same answer for the number density and merger histories of virialized clumps. Models of the spatial distribution of the clumps and how they can be used to model the spatial distribution of the mass are briefly discussed.
Dark Matter Caustics
Authors: Sikivie P. , Kinney W.
Published: July 2010

Abstract: The late infall of cold dark matter onto an isolated galaxy such as our own produces flows with definite velocity vectors at any physical point in the galactic halo. It also produces caustics which are places where the dark matter density is very large. The outer caustics are topological spheres whereas the inner caustics are rings. The self‐similar model of galactic halo formation predicts that the caustic ring radii an follow the approximate law an∼ 1/n. In a recent study of 32 extended and well‐measured galactic rotation curves, we found evidence for this law.
Health Span and Life Span in Transgenic Mice with Modulated DNA Repair
Authors: Walter Christi A. , Zhou Zi‐Qiang , Manguino Diwi , Ikeno Yuji , Reddick Robert , Nelson James , Intano Gabriel , Herbert Damon C. , McMahan C. Alex , Hanes Martha
Published: July 2010

Abstract: One way to better understand the contribution of DNA repair, DNA damage, and mutagenesis in aging would be to enhance DNA repair activity, lower DNA damage, and lower mutagenesis. Because the repair protein O6‐methylguanine‐DNA methyltransferase (MGMT) acts alone and stoichiometrically, the human MGMT (hMGMT) cDNA was selected to test the feasibility of enhancing DNA repair activity in transgenic mice. MGMT activity is largely responsible for ameliorating the deleterious effects of O6‐methylguanine (O6mG) lesions in DNA in a direct reversal mechanism. A transgene was constructed consisting of a portion of the human transferrin (TF) promoter and hMGMT cDNA such that hMGMT is expressed in transgenic mouse brain and liver. Expression of hMGMT was associated with a significant reduction in the occurrence of an age‐related hepatocellular carcinoma in male mice at 15 months of age. Longitudinal and cross‐sectional studies were initiated to determine whether the reduced incidence of hepatocellular carcinoma would impact median or maximum life span. The cross‐sectional study performed on 15‐month‐old male animals confirmed the reduced occurrence of spontaneous hepatocellular carcinoma. At 30 months of age, however, the occurrence of hepatocellular carcinoma in at least one transgenic line was similar to that for nontransgenic animals. The longitudinal study is ongoing; however, at present no significant differences in life span have been detected. Tissues expressing the MGMT transgene also displayed greater resistance to alkylation‐induced tumor formation. These results suggest that transgenes can be used to direct enhanced DNA repair gene expression and that enhanced expression can protect animals from certain spontaneous and induced tumors.
Aging and Caloric Restriction in Nonhuman Primates
Authors: Ingram Donald K. , Chefer Svetlana , Matochik John , Moscrip Tammy D. , Weed James , Roth George S. , Londonb Edythe D. , Lane Mark A.
Published: July 2010

Abstract: In a long‐term longitudinal study of aging in rhesus monkeys, a primary objective has been to determine the effects of aging and caloric restriction (CR) on behavioral and neural parameters. Through the use of automated devices, locomotor activity can be monitored in the home cages of the monkeys. Studies completed thus far indicate a clear age‐related decline in activity consistent with such observations in many other species, including humans. However, no consistent effects of CR on activity have been observed. Selected groups of monkeys have also been involved in brain imaging studies, using magnetic resonance imaging (MRI) and positron emission tomography (PET). MRI studies completed thus far reveal a clear age‐related decline in the volumes of the basal ganglia, the putamen, and the caudate nucleus, with no change in total brain volume. PET analysis has revealed an age‐related decline in the binding potential of dopamine D2 receptors in the same brain regions. These results are consistent with findings in humans. Although additional longitudinal analysis is needed to confirm the present results, it would appear that locomotor activity, volume of the basal ganglia, as well as dopamine D2 receptor binding potential provide reliable, noninvasive biomarkers of aging in rhesus monkeys.
Progress in the Neural Sciences in the Century after Cajal (and the Mysteries That Remain)
Authors: ALBRIGHT THOMAS D. , JESSELL THOMAS M. , KANDEL ERIC R. , POSNER MICHAEL I.
Published: July 2010

Abstract:One hundred years after Santiago Ramón y Cajal provided critical evidence for the “neuron doctrine,” his cellular view of the brain remains the basis of modern neural science. This article begins with a review of how the early work of Ramón y Cajal, Charles Sherrington, and John Eccles and their contemporaries laid the groundwork for our current understanding of the information processing of neural systems and for understanding the task faced by studies of how the brain develops. The visual system is examined in some detail as a model for experimental investigation into the structure, operational mechanisms, and functions of large neural systems. Discussion of the phenomena of visual awareness and consciousness, links between the visual system and other brain systems, and disorders that disrupt voluntary control of cognition and emotion lead to a broader consideration of the problem of consciousness.
Cajal on Neurons, Molecules, and Consciousness
Authors: CHANGEUX JEAN‐PIERRE
Published: July 2010

Abstract: The discovery of chemical synaptic transmission together with the asymmetric distribution of neurotransmitter release sites and receptors offer an explanation for Cajal's theory on dynamic polarization.
Who Was Cajal?
Authors: PORTERA‐SÁNCHEZ ALBERTO
Published: July 2010

Abstract: After a brief introduction, a series of Cajal's own thoughts and recollections of his difficult childhood and adolescence are literally transcribed. They clearly represent the astonishing achievements of an equally astonishing child who was born in a tiny village of the Pyrenees mountains. Even today, visitors find it very difficult to understand how it was possible for a child to free himself from a medieval atmosphere and climb to the highest scientific level: to be awarded with the Nobel Prize in Medicine.
The Brain That Plays Music and Is Changed by It
Authors: PASCUAL‐LEONE ALVARO
Published: July 2010

Abstract: Playing a musical instrument demands extensive procedural and motor learning that results in plastic reorganization of the human brain. These plastic changes seem to include the rapid unmasking of existing connections and the establishment of new ones. Therefore, both functional and structural changes take place in the brain of instrumentalists as they learn to cope with the demands of their activity. Neuroimaging techniques allow documentation of these plastic changes in the human brain. These plastic changes are fundamental to the accomplishment of skillful playing, but they pose a risk for the development of motor control dysfunctions that may give rise to overuse syndromes and focal, task‐specific dystonia.
Aspects of Psychotherapy with Adults with Attention Deficit Disorder
Authors: BEMPORAD JULES R.
Published: July 2010

Abstract: The process of psychotherapy with individuals with Attention Deficit Disorder who may require this form of intervention (in addition to medication and psychoeducation) is described. Salient features of therapy specific to these patients, such as the subjective effects of medication, characteristic defensive operations, and reconciliation with the past, are emphasized.