bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Cyclophilins in Somatolactogenic Action
Authors: RYCYZYN MICHAEL A. , CLEVENGER CHARLES V.
Published: July 2010

Abstract: Prolactin (PRL) and growth hormone (GH) are members of the somatolactogenic hormone family, the pleiotropic actions of which are necessary for vertebrate growth and mammary differentiation. The basis for the specific function of these hormones has remained uncertain; however, their action is associated with internalization and translocation into the nucleus. A yeast two‐hybrid screen identified an interaction between PRL and cyclophilin B (CypB), a peptidyl prolyl isomerase (PPI) found in the endoplasmic reticulum (ER), extracellular space, and nucleus. The interaction between CypB and PRL/GH was confirmed in vitro and in vivo through the use of recombinant proteins and coimmunoprecipitation studies. The exogenous addition of CypB potentiated the proliferation of PRL‐ and GH‐dependent cell lines 18‐ and 40‐fold, respectively. The potentiation of PRL action by CypB was accompanied by a dramatic increase in the nuclear retrotranslocation of PRL. Immunogold electron microscopy has revealed this retrotransport to occur via a vesicular pathway. A CypB mutant, termed CypB‐NT, was generated that lacked the putative wild‐type N‐terminal nuclear localization sequence. Although CypB‐NT demonstrated levels of PRL binding and PPI activity equivalent to wild‐type CypB, it was incapable of mediating the nuclear retrotranslocation of PRL or enhancing PRL‐driven proliferation. These studies reveal CypB as an important chaperone facilitating the nuclear retro‐transport and action of the somatolactogenic hormone family.
Prolactin Regulation of Apoptosis‐Associated Gene Expression in T Cells
Authors: BUCKLEY ARTHUR R. , BUCKLEY DONNA J.
Published: July 2010

Abstract: Evidence accumulated over the last two decades indicates important actions for prolactin (PRL) in regulation of several functions of the immune system. That PRL can serve to facilitate immune cell proliferation is well established. In addition, PRL appears to play a salient role in the genesis and/or potentiation of certain autoimmune diseases. Recent evidence from several laboratories has extended the spectrum of PRL actions in immunological systems to include regulation of lymphocyte pool size through the process of apoptosis. Experimental results obtained using lactogen‐dependent rat pre‐T cell lines, the Nb2 lymphoma, have demonstrated that PRL suppresses cell death mechanisms activated by cytokine/hormone deprivation and cytotoxic drugs such as glucocorticoids. In this paper, we review results from studies conducted to investigate the mechanism(s) underlying PRL‐regulated apoptosis suppression. Effects of the hormone on expression of apoptosis‐associated genes of the Bcl‐2 family as well as the protooncogene pim‐1 in proliferating Nb2 sublines and in cells exposed to apoptotic stimuli are presented. It is concluded that PRL‐mediated apoptosis suppression in immune cells reflects a complex interaction among several gene products.
What's in a Name? Neuroimmunomodulation or Psychoneuroimmunology?
Authors: GREER STEVEN
Published: July 2010

Abstract: Compelling evidence is presented to support the hypothesis that psychological processes affect immune function. Consequently, it is argued that psychological processes should be included in human immunological studies and that neuroimmunomodulation could accurately by called psychoneuroimmunology.
Sympathetic Innervation Affects Superantigen‐Induced Decrease in CD4Vβ8 Cells in the Spleen
Authors: REY ADRIANA DEL , KABIERSCH ALEXA , PETZOLDT SIGRID , RANDOLF ANKE , BESEDOVSKY HUGO O.
Published: July 2010

Abstract: The stimulation by superantigens of T cells expressing an appropriate Vβ chain results in a strong proliferative response that is followed by a state of energy specific for the antigen used. This model was used to continue our studies on immunoregulatory host neuroendocrine responses. We have recently found that four days after administration of the superantigen staphylococcal enterotoxin B (SEB) into mice, that is, at an early stage of the anergic phase, the decrease in the percentage of splenic CD4Vβ8 was accompanied by a decrease in the splenic concentration of the sympathetic neurotransmitter noradrenaline (NA) as compared to vehicle‐injected mice. No comparable changes were detected in the kidney. At this point, blood levels of NA, adrenaline, and corticosterone were comparable in SEB‐ and vehicle‐injected mice. We have also found that the decrease in splenic CD4Vβ8 cells was not observed in animals that had been chemically sympathectomized prior to the administration of the superantigen. These results indicate that the sympathetic response induced by SEB may have immunoregulatory implications.
Cytokine Activation of the HPA Axis
Authors: DUNN ADRIAN J.
Published: July 2010

Abstract:The observation that administration of interleukin‐1 (IL‐1) to animals activates the hypothalamo‐pituitary‐adrenocortical (HPA) axis stimulated great interest in the significance and mechanism of this response, and in whether other cytokines have similar activities. Interleukin‐6 (IL‐6) and tumor necrosis factor α (TNFα) share HPA‐activating activity, although they are less potent and effective than IL‐1, whereas IL‐2 and interferon α(IFNα) lack activity. Small increases in body temperature occur in response to IL‐1, IL‐6 and TNFα, but these changes are prevented by inhibitors of cyclooxygenase (COX) and do not appear to be related to the HPA‐activation. The rapid HPA‐activating effects of IL‐1 are impaired by COX inhibitors, but the more prolonged HPA activation associated with intraperitoneal injections is not affected, indicating multiple mechanisms for IL‐1‐induced HPA activation. The HPA response to IL‐6 is not sensitive to COX inhibitors, but that to TNFα appears to be. The HPA‐activating activity of IL‐1 is associated with increases in the apparent release of brain noradrenaline (NA) and serotonin (5‐HT), but not dopamine, as well as with increased brain tryptophan. The NA changes, but not those in serotonin metabolism and tryptophan, are prevented by COX inhibitors. IL‐6 has effects on serotonin and tryptophan like those of IL‐1, but no detected effect on NA. TNFα has some effect on NA and tryptophan, but only at relatively high doses. IFNα lacks activity on these neurochemicals. Manipulation of noradrenergic, but not serotonergic systems alters the IL‐1‐induced HPA activation, suggesting the involvement of NA. However, brain NA does not appear to be essential for HPA activation in mice.
Thymic Neuroendocrine Self‐Antigens: Role in T‐Cell Development and Central T‐Cell Self‐Tolerance
Authors: GEENEN VINCENT , MARTENS HENRI , BRILOT FABIENNE , RENARD CHANTAL , FRANCHIMONT DENIS , KECHA OUAFAE
Published: July 2010

Abstract: The repertoire of thymic neuroendocrine precursors plays a dual role in T‐cell differentiation as the source of either cryptocrine accessory signals in T‐cell development or neuroendocrine self‐antigens presented by the thymic major histocompatibility complex (MHC) Machinery. Thymic neuroendocrine self‐antigens usually correspond to peptide sequences highly conserved during the evolution of one family. The thymic presentation of some neuroendocrine self‐antigens is not restricted by mhc alleles. Oxytocin (OT) is the dominant peptide of the neurohypophysial family. It is expressed by thymic epithelial and nurse cells (TEC/TNCs) of different species. Ontogenetic studies have shown that the thymic expression of the OT gene precedes the hypothalamic one. Both OT and VP stimulate the phosphorylation of p125FAK and other focal adhesion‐related proteins in murine immature T cells. These early cell activation events could play a role in the promotion of close interactions between thymic stromal cells and developing T cells. It is established that such interactions are fundamental for the progression of thymic T‐cell differentiation. Insulin‐like growth factor 2 (IGF‐2) is the dominant thymic polypeptide of the insulin family. Using fetal thymic organ cultures (FTOCs), the inhibition of thymic IGF‐2‐mediated signaling was shown to block the early stages of T‐cell differentiation. The treatment of FTOCs with an mAb anti‐(pro)insulin had no effect on T‐cell development. In an animal model of autoimmune type 1 diabetes (BB rat), thymic levels of (pro)insulin and IGF‐1 mRNAs were normal both in diabetes‐resistant and diabetes‐prone BB rats. IGF‐2 transcripts were clearly identified in all thymuses from diabetes‐resistant adult (5‐week) and young (2‐ and 5‐days) BB rats. In marked contrast, the IGF‐2 transcripts were absent and the IGF‐2 protein was almost undetectable in ±80% of the thymuses from diabetes‐prone adult and young BB rats. These data show that a defect of the thymic IGF‐2‐mediated tolerogenic function might play an important role in the pathophysiology of autoimmune Type 1 diabetes.
Human T Lymphopoiesis: In Vitro and In Vivo Study Models
Authors: PLUM J. , De SMEDT M. , VERHASSELT B. , KERRE T. , VANHECKE D. , VANDEKERCKHOVE B. , LECLERCQ G.
Published: July 2010

Abstract: Successive Steps In T lymphocyte differentiation and T potential of human stem cells (HSC) can be tested in the following models: (a) the infusion of cells in NOD‐SCID MICE, (b) the injection of cells in renconstituted SCID/hu mice, (c) the differentiation of cells in fetal thymus organ culture (FTOC), and (d) on thymic stromal layers. using mixed human‐murine FTOC, we showed (a) TCRαβ, TCRγδ lymphocytes, NK cells, and dendritic cells complete their differentiation, (b) IL‐7Rα signaling and IL‐7 are essential, (c) a detailed phenotypic and functional analysis of discrete successive steps of positively selected thymocytes, (d) an efficient transduction of genes in HSC with persistent gene expression throughout the T‐lymphocyte differentiation, and (e) adaptation to submerging high oxygen culture increases the test sensitivity to a clonal assay. Other approaches are the in vivo SCID/hu reconstitution model. With this method small fragments of human fetal liver and thymus are implanted under the kidney capsule of an adult SCID mouse with result in an impressive human thymus organ, six months after transplantation. We use this model to study thymus T‐cell developmental kinetics, development of gene‐marked precursor cellsand thymic homing of precursor cells.
Expression of Delta Opioid Receptors and Transcripts by Splenic T Cells
Authors: SHARP BURT M. , LI MING D. , MATTA SHANNON G. , McALLEN KATHY , SHAHABI NAHID A.
Published: July 2010

Abstract:Delta opioid receptors (DORs) and preproenkephalin‐A‐derived opiate peptides are expressed by mononuclear cells in various lymphoid organs. DOR ligands modulate a variety of immune functions, such as T‐cell proliferation, calcium mobilization, and cytokine production. recently, quiescent T‐cells were found to express low levels of DOR transcripts, which increased due to the following: cell culture of unstimulated murine splenocytes (depending on cell density); cross‐linking the T‐cell receptor (TCR) with anti‐CD3‐ε and a singlein vivoexposure to staphylococcal enterotoxin B (SEB). Enhanced expression of DOR mRNA was mediated transcriptionally. Moreover, PMA + ionomycin, which mimic the proliferative signal of anti‐CD3, inhibited the expression of DOR mRNA. Using semiquantitative immunofluorescence to detect DORs, SEB was found to increase the fraction of T cells that expressed DOR and to enhance the relative level of DOR expression per T cell. Previous studies have shown that DOR agonists inhibited the anti‐CD3‐stimulated production of interleukin‐2 and T‐cell proliferation. Therefore, the enhanced expression of DORs by activated T cells may be capable of downregulating the T‐cell activation program.
Susceptibility to Autoimmune Disease and Drug Addiction in Inbred Rats: Are There Mechanistic Factors in Common Related to Abnormalities in Hypothalamic‐Pituitary‐Adrenal Axis and Stress Response Function?
Authors: WILDER RONALD L. , GRIFFITHS MARIE M. , CANNON GRANT W. , CASPI RACHEL , REMMERS ELAINE F.
Published: July 2010

Abstract:DA and LEW inbred rats are extraordinarily susceptible to a wide range of experimental autoimmune diseases. These diseases include rheumatoid arthritis models such as collagen‐induced arthritis (CIA) and adjuvant‐induced arthritis (AIA), ultiple sclerosis models such as myelin‐basic‐protein (mbp)‐induced experimental autoimmune encephalomyelitis (MBP‐EAE), and autoimmune uveitis models such as retinal S antigen (SAG) and interphotoreceptor‐retinoid‐binding‐protein (IRBP) ‐induced experimental autoimmune uveitis (SAG‐EAU and IRBP‐EAU, respectively). DA and LEW rats are also addiction‐prone to various drugs of abuse, such as cocaine. Moreover, they exhibit a variety of behavioral and biochemical characteristics that appear to be related to their susceptibility to addiction. by contrast, F344 and BN rats show quite different phenotypes. they are relatively resistant to CIA, AIA, MBP‐EAE, SAG‐EAU, and IRBP‐EAU, and they are relatively resistant to addiction. Interestingly, both DA and LEW rats, in contrast to F344 and BN rats, have abnormalities in hypothalamic‐pituitary‐adrenal (HPA) axis function. For example, circadian production of corticosteroids is very abnormal in DA and LEW rats; that is, they exhibit minimal circadian variation in corticosterone levels. Since corticosteroids potentially have significant influences on immune function and autoimmune disease susceptibility and may also influence sensitivity to drugs of abuse, we have begun to dissect genetic control of these various phenotypic differences, focusing initially on the regulation of autoimmune disease expression. Using genomewide scanning techniques involving F2 crosses of DA × F344 (CIA and AIA), DA × BN (CIA), and LEW × F344 [IRBP‐EAU and streptococcal‐cell‐wall arthritis (SCWA)], we have identified, to date, 14 genomic regions [quantitative trait loci (QTL)] that regulate disease expression in these crosses. Development and analysis of QTL‐congenic rats involving these loci are in progress and should permit us to address the relationships among autoimmune disease susceptibility, drug addiction, and HPA axis and stress response function. These initial data, however, indicate that the genetic control of the autoimmune disease traits is highly complex.
Acute Stress Enhances While Chronic Stress Suppresses Skin Immunity: The Role of Stress Hormones and Leukocyte Trafficking
Authors: DHABHAR FIRDAUS S.
Published: July 2010

Abstract:Delayed‐type hypersensitivity (DTH) reactions are antigen‐specific, cell‐mediated immune responses that, depending on the antigen, mediate beneficial (resistance to viruses, bacteria, fungi) or harmful (allergic dermatitis, autoimmunity) aspects of immunity. Contrary to the widely held notion that stress is immunosuppressive, we have shown that under certain conditions, stress can enhance immune function. DTH reactions can be studied in rats or mice by challenging the pinnae of previously sensitized animals with antigen. studies have shown that acute stress administered immediately before antigen exposure significantly enhances skin DTH. In contrast, chronic stress significantly suppresses skin DTH. Stress‐induced changes in leukocyte distribution may contribute to these bidirectional effects of stress, since acute stress induces a significant mobilization of leukocytes from the blood to the skin, whereas chronic stress suppresses leukocyte mobilization. In order to identify the hormonal mediators of the observed effects of stress, we first showed that adrenalectomy (ADX) eliminates the stress‐induced enhancement of DTH. Acute administration (to ADX animals) of low doses of corticosterone and/or epinephrine significantly enhances skin DTH. In contrast, acute administration of high doses of corticosterone, low doses of dexamethasone, or chronic administration of moderate doses of corticosterone suppress skin DTH. Thus, the timing and duration of stress may significantly affect the nature (enhancing versus suppressive) of the effects of stress on skin immune function. These results suggest that during acute stress, stress hormones may help enhance immune function by informing the immune system about impending challenges (e.g., wounding or infection) that may be imposed by a stressor (e.g., an aggressor). Thus, during acute stress, the brain may send a warning signal to the immune system, just as it does to other fight/flight systems in the body.
Local Regulation of Glucocorticoid Activity in Sites of Inflammation: Insights from the Study of Tuberculosis
Authors: ROOK G. , BAKER R. , WALKER B. , HONOUR J. , JESSOP D. , HERNANDEZ‐PANDO R. , ARRIAGA K. , SHAW R. , ZUMLA A. , LIGHTMAN S.
Published: July 2010

Abstract:In sites of inflammation there is a change in the equilibrium between the enzymes that inactivate cortisol by conversion to cortisone and those that reactivate cortisone by conversion to cortisol. Current evidence suggests that during an immune response with a Type 1 cytokine profile such as tuberculosis, there is locally enhanced reductase activity with locally increased cortisol concentrations due to recruitment of cortisone. This results in enhanced cortisol mediated feedback on the inflammatory process, and deviation of the response towards Type 2. Preliminary data suggest that eventually, in the presence of Type 2 cytokine polarization, the enzyme equilibrium may reverse again and cortisol is then locally inactivated to cortisone. Together with changes in glucocorticoid receptor expression and function this may result in local cortisol resistance and susceptibility to tissue damage mediated by proinflammatory cytokines. These observations help to explain the sequence of events in several infectious, inflammatory and autoimmune diseases.
Changes in Cortisol/DHEA Ratio in HIV‐Infected Men Are Related to Immunological and Metabolic Perturbations Leading to Malnutrition and Lipodystrophy
Authors: CHRISTEFF NÉVÉNA , NUNEZ EMMANUEL A. , GOUGEON MARIE‐LISE
Published: July 2010

Abstract: HIV‐1 infection is associated with immune deficiency and metabolic perturbations leading to malnutrition and lipodystrophy. Because immune response and metabolic perturbations (protein and lipid metabolism) are partly regulated by glucocorticoids and DHEA, we determined serum cortisol and DHEA concentrations, and the cortisol/DHEA ratio in HIV‐positive men, either untreated or receiving various antiretroviral treatments (ART), including highly active antiretroviral therapy (HAART). Cortisol levels were found increased in all patients, whatever the stage of the disease and independently of the ART treatment. in contrast, serum DHEA was elevated in the asymptomatic stage, and it was below normal values in aids patients, either untreated or mono‐ART‐treated. The DHEA level was low in HAART‐treated patients with lipodystrophy (LD+) and highly increased in HAART‐treated patients without lipodystrophy (LD−). Consequently, the cortisol/DHEA ratio was similar to controls in asymptomatic untreated or mono‐ART‐treated patients, but increased in AIDS patients. Interestingly, this ratio was increased in LD+ HAART‐treated men, but normalized in LD− HAART‐treated patients. Changes in the cortisol/DHEA ratio were negatively correlated with the in vivo CD4 T‐cell counts, with the malnutrition markers, such as body‐cell mass and fat mass, and with the increased circulating lipids (cholesterol, triglycerides, and apolipoprotein B) associated to the lipodystrophy syndrome. Our observations show that the cortisol/DHEA ratio is dramatically altered in HIV‐infected men, particularly during the syndromes of malnutrition and lipodystrophy, and this ratio remains elevated whatever the antiretroviral treatment, including HAART. These findings have practical clinical implications, since manipulation of this ratio could prevent metabolic (protein and lipid) perturbations.
The Role of Antiretrovirals and Drug Resistance in Vertical Transmission of HIV‐1 Infection
Authors: BRENNER BLUMA G. , WAINBERG MARK A.
Published: July 2010

Abstract: Large‐cohort studies in North America, Europe, and Thailand have shown that zidovudine/azidothymidine (AZT) monotherapy, given at the late stages of pregnancy, is of proven benefit in reducing mother‐to‐infant HIV transmission by 51% to 68%. AZT monotherapy will not be of long‐term benefit for mothers because no single drug can counteract viral infection; benefits to babies will be short‐lived if HIV‐1 is acquired through breastfeeding after birth. Unfortunately, ongoing mutation of HIV under conditions of drug pressure allows for the evolution and selection of AZT‐resistant viruses. Emergence of AZT‐resistant variants in pregnant mothers (7‐29%) and their infected offspring (5‐21%) has been described in several studies. Drug resistance arises more frequently in those mothers who received AZT therapy before pregnancy. Recent advances in combination chemotherapy may provide alternative strategies in prevention of vertical transmission and drug resistance. Genotypic screening of the HIV‐1 isolated from pregnant mothers may provide rational modifications in antiretroviral (ARV) strategies to circumvent vertical HIV transmission. This may be of advantage for resource‐rich nations but not for underdeveloped nations with limited access to ARVs. Public health programs are vital to have an impact on the tragic pandemic of pediatric AIDS.
Nutritional Factors and Vertical Transmission of HIV‐1 Epidemiology and Potential Mechanisms
Authors: FAWZI WAFAIE
Published: July 2010

Abstract:Transmission of HIV from mothers to children may occur through the transplacental, intrapartum, or breastfeeding routes. Adequate nutritional status may reduce vertical transmission by affecting several maternal or fetal and child risk factors for transmission including enhancing systemic immune function in the mother or fetus/child; reducing the rate of clinical, immunological, or virological progression in the mother; reducing viral load or the risk of viral shedding in lower genital secretions or breast milk; reducing the risks of low birth weight or prematurity; or by maintaining the integrity of the fetus/child gastrointestinal integrity. In prospective observational studies, low plasma vitamin A levels were associated with higher risks of vertical transmission. However, findings from randomized, controlled trials suggest that supplements of vitamin A or other vitamins are unlikely to have an effect on vertical transmission during pregnancy or the intrapartum period. The effect of other nutrient supplements, such as zinc and selenium, is unknown. Similarly, whether nutrition supplements of mothers during the breastfeeding period has an effect on transmission is unknown. The potential benefits of direct supplementation of children born to HIV‐infected women on transmission of HIV, as well as on the risk and severity of childhood infections and mortality, are also important to examine.
Future Directions
Authors: LHOTSKA LUDMILA , ARMSTRONG HELEN
Published: July 2010

Abstract: Despite progress in promotion and support of breastfeeding over the past decade, the HIV pandemic necessitates new actions based on human rights, such as voluntary and confidential testing and counseling, offering HIV‐positive women objective information on the risks and costs of all infant feeding options, and providing appropriate support for their decisions. Implementation of the Baby‐Friendly Hospital Initiative and the International Code of Marketing are essential components of a rights‐based policy response to HIV and will lessen spillover of replacement feeding among HIV‐negative women. Protective effects of nevirapine and exclusive breastfeeding, as well as the listed additional topics, require further research. We have yet to make exclusive breastfeeding easy and common when mothers choose to breastfeed.
Some Recent Developments in the International Guidelines on the Ethics of Research Involving Human Subjectsa
Authors: LEVINE ROBERT J.
Published: July 2010

Abstract: We are in a period of reconsideration and revision of international ethical guidelines for the conduct of biomedical research involving human subjects. The proximate cause of much of this activity is the recent controversy over the ethics of the use of a placebo control in the clinical trials of the short‐duration regimen of zidovudine for prevention of perinatal transmission of HIV infection, trials that were carried out in several so‐called technologically developing countries. Critics of these trials claimed that they were in violation of Article II.3 of the Declaration of Helsinki, which states: “In any medical study, every patient‐including those of a control group, if any‐should be assured of the best proven diagnostic and therapeutic method. This does not exclude the use of inert placebo in studies where no proven diagnostic or therapeutic method exists.” The critics claimed that since the “best proven … method” is the 076 regimen, this is what must be provided to members of the control groups. Failure to do so, they asserted, was a serious breach of ethics. In response to this allegation, several major international and national agencies convened multidisciplinary groups to consider the ethics of multinational clinical research. The first thing they realized was that Article II.3 was in error in that it did not reflect contemporary ethical thinking. Moreover, it was routinely violated in research conducted in developed as well as in developing countries. What replaces this standard? The 1993 CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects include several criteria for justification of research carried out in developing countries. Most importantly, the research must be responsive to the health needs and priorities of the host country. They also require that any therapeutic products developed in such research must be made “reasonably available” to residents of the host country. A new standard is emerging for selecting therapies to be administered to participants in multinational clinical trials and for use as the control “treatment” in such trials. It is called the “highest attainable and sustainable” therapeutic method. Application of this standard differs from application of the “best proven method” standard in that it permits the evaluation of new therapies that are responsive to the health needs and priorities of resource‐poor countries. It has long been recognized that the Declaration of Helsinki is a flawed document in that it relies on the illogical distinction between therapeutic and nontherapeutic research. This distinction has been removed from the most recent draft revisions of the Helsinki and the CIOMS documents.
Organizational Approaches to the HIV/AIDS Crisis
Authors: ROGERS MARTHA F. , STOCKTON P. LYNNE
Published: July 2010

Abstract: The Centers for Disease Control and Prevention (CDC) has played a major role in controlling the HIV/AIDS epidemic in the United States. After implementation of perinatal zidovudine therapy in 1994, the efforts of the CDC and others produced a dramatic decline in perinatal HIV transmission. However, in recent years, approximately 300 perinatally infected infants have been born annually in the United States. To further reduce this number, the CDC has identified four prevention goals: improve prenatal care, recommend HIV testing, ensure treatment for HIV‐infected pregnant women, and ensure follow‐up care. To address these goals, the CDC launched a prevention plan consisting of surveillance, research, outreach strategies, grant programs, evaluation efforts, and policy development. Globally, the CDC tailors this plan to meet the needs of developing countries. The CDC provides technical assistance to international organizations to help develop, implement, and evaluate global prevention programs. Specific international sites are targeted for new research and programs to reduce perinatal HIV transmission.
Evaluating the Safety of Interventions for Prevention of Perinatal Transmission of HIV
Authors: FLEMING THOMAS R.
Published: July 2010

Abstract: Efficient approaches are needed for obtaining reliable insights into the safety, in developing and developed country settings, of interventions for prevention of mother‐to‐child transmission (MCT) of HIV. A randomized trial designed with an appropriate sample size and adequate duration of follow‐up provides a powerful tool for obtaining causal evidence regarding the safety and efficacy of MTC prevention interventions. Such trials are ideal for detecting adverse effects (AEs) that occur in the short or moderate term and with moderate to high frequency. Passive and active surveillance procedures, where practical, can provide valuable insights regarding long‐term or rare AEs. Ideally, surveillance procedures should be carefully planned sufficiently early to allow prospective definition and uniform collection of important classes of AEs, enhancing the sensitivity and specificity of these surveillance data.
Rapid Characterization of HIV Clade C‐Specific Cytotoxic T Lymphocyte Responses in Infected African Children and Adults
Authors: GOULDER PHILIP J. R.
Published: July 2010

Abstract: Cytotoxic T lymphocytes (CTL) play a central role in successful control of HIV. Induction of effective CTL responses may therefore be an essential requirement of HIV vaccines. Knowledge of CTL epitopes targeted either in natural infection or following vaccination will be critical to understanding the anti‐HIV immune response. Until recently, epitope definition was a slow and laborious process that could only be undertaken in laboratories specialized in this work. Recent incremental advances in the technologies that may be applied to this field have transformed what is possible, so that within 48 hours of receipt of a blood sample, novel epitopes may be optimized and the HLA restriction defined. Moreover, these technologies can now be applied in nonspecialized laboratories, so that new epitopes can be characterized locally in sites where the epidemic is most severe. Sub‐Saharan Africans and C clade infection have been relatively neglected in terms of the HIV‐specific CTL epitopes that have been defined to date. This review summarizes the evidence that cellular immunity is important in successful containment of HIV and describes the novel methods of epitope detection, illustrating their ready application to the study of C‐clade infected persons in sub‐Saharan Africa.
Measles Infection in HIV‐Infected African Infants
Authors: PERRY ROBERT T. , MMIRO FRANCIS , NDUGWA CHRISTOPHER , SEMBA RICHARD D.
Published: July 2010

Abstract: Measles infection remains a serious threat to child survival in the developing world despite vaccination and treatment with vitamin A. This report reviews the epidemiology of measles in HIV‐infected children in Africa. In hospitalized infants, the rate of malnutrition before measles and the rate of death after measles are both higher in HIV‐positive than in HIV‐negative infants. However, the rates of pneumonia and diarrhea in infants hospitalized with measles are the same in HIV‐positive as in HIV‐negative infants. In an autopsy study, measles was associated with death in HIV‐positive children, only for those over 15 months of age. A cohort study found that infants of HIV‐positive women were more likely than infants of HIV‐negative women to have measles before 9 months of age, although the rates of complications did not differ between the two groups. The HIV status of the infants and the measles serology were too incomplete to draw firm conclusions, though only 1 of 54 infants tested was seropositive for measles at 6 months of age. In the context of the HIV epidemic, further work is needed to determine the risk of measles and its complications in HIV‐positive infants and the optimal age of measles immunization.
Discovery and Perspectives from the Blastokinin Era
Authors: DANIEL JOSEPH C.
Published: July 2010

Abstract: The events and rationalizations that led to one discovery of the rabbit uterine protein, then called blastokinin, are narrated in historical perspective and related to the independent discovery of the same protein, named uteroglobin. The period when the name “blastokinin” remained in partial use, roughly from the original publication in 1967 until the early 1980s, is considered here as the blastokinin era. Subsequent perspectives, originating from the era, are presented on the hormonal regulation of blastokinin, as well as its distribution, biological function, and potential relationships with other entities that exist coincidentally.
Clara Cell Proteins
Authors: SINGH GURMUKH , KATYAL SIKANDAR L.
Published: July 2010

Abstract:Clara cells are nonciliated, nonmucous, secretory cells of the pulmonary airways. These cells are known to secrete a variety of proteins, including Clara cell 10‐kDa protein/uteroglobin. This protein consists of a homodimer of 70–77 amino acid polypeptides arranged in antiparallel fashion. In vitro testing suggests that the protein suppresses inflammation. The physiologic role of the protein remains to be determined.
Crystal Structure Analysis of Recombinant Human Uteroglobin and Molecular Modeling of Ligand Binding
Authors: PATTABIRAMAN N. , MATTHEWS JOHN H. , WARD KEITH B. , MANTILE‐SELVAGGI GIUDITTA , MIELE LUCIO , MUKHERJEE ANIL B.
Published: July 2010

Abstract: Uteroglobin, a steroid‐inducible, cytokine‐like, secreted protein with immunomodulatory properties, has been reported to bind progesterone, polychlorinated biphenyls (PCB), and retinol. Structural studies may delineate whether binding of ligands is a likely physiological function of human uteroglobin (hUG). We report a refined crystal structure of uncomplexed recombinant hUG (rhUG) at 2.5‐Å resolution and the results of our molecular modeling studies of ligand binding to the central hydrophobic cavity of rhUG. The crystal structure of rhUG is very similar to that of reported crystal structures of uteroglobins. Using molecular modeling techniques, the three ligands‐PCB, progesterone, and retinol‐were docked into the hydrophobic cavity of the dimer structure of rhUG. We undocked the progesterone ligand by pulling the ligand from the cavity into the solvent. From our modeling and undocking studies of progesterone, it is clear that these types of hydrophobic ligands could slip into the cavity between helix‐3 and helix‐3′ of the dimer instead of between helix‐1 and helix‐4 of the monomer, as proposed earlier. Our results suggest that at least one of the physiological functions of UG is to bind to hydrophobic ligands, such as progesterone and retinol.
Regulation of the Clara Cell Secretory Protein/Uteroglobin Promoter in Lung
Authors: NORD MAGNUS , CASSEL TOBIAS N. , BRAUN HARALD , SUSKE GUNTRAM
Published: July 2010

Abstract:Clara cell secretory protein/uteroglobin (CCSP/UG) is specifically expressed in the conducting airway epithelium of the lung in a differentiation‐dependent manner. The proximal promoter region of the rodent CCSP/UG gene directs Clara cell specificity. Previously, it was shown that the forkhead transcription factors HNF‐3α and β and the homeodomain factor TTF‐1 are important transcription factors acting through this region, suggesting that they contribute to cell specificity of the CCSP/UG gene. Members of the C/EBP family of transcription factors can also interact with elements of the proximal rat and mouse CCSP/UG promoters. The onset of C/EBPα expression in Clara cells correlates with the strong increase of CCSP/UG expression. Thus, C/EBPalpha; may play a crucial role for differentiation‐dependent CCSP/UG expression. Transfection studies demonstrate that C/EBPα and TTF‐1 can synergistically activate the murine CCSP/UG promoter. Altogether, these results suggest that C/EBPalpha;, TTF‐1, and HNF‐3 determine the Clara cell‐specific, differentiation‐dependent expression of the CCSP/UG gene in murine lung. The relative importance of these three transcription factors, however, differs in rabbits and humans.
Insight into the Physiological Function(s) of Uteroglobin by Gene‐Knockout and Antisense‐Transgenic Approaches
Authors: ZHANG ZHONGJIAN , KUNDU GOPAL C. , ZHENG FENG , YUAN C‐J. , LEE ERIC , WESTPHAL HEINER , WARD JERROLD , DEMAYO FRANCESCO , MUKHERJEE ANIL B.
Published: July 2010

Abstract: To determine the physiological function(s) of uteroglobin (UG), a steroid‐inducible, homodimeric, secreted protein, we have generated transgenic mice that either are completely UG‐deficient due to UG gene‐knockout (UG‐KO) or are partially UG‐deficient due to the expression of UG antisense RNA (UG‐AS). Both the UG‐KO and UG‐AS mice develop immunoglobulin A (IgA) nephropathy (IgAN), characterized by microhematuria, albuminuria, and renal glomerular deposition of IgA, fibronectin (Fn), collagen, and C3 complement. This phenotype of both UG‐KO and UG‐AS mice is virtually identical to that of human IgAN, the most common primary glomerulopathy worldwide. The molecular mechanism by which UG prevents this disease in mice appears to center around UG's interaction with Fn. Since Fn, IgA, and UG are present in circulation and high plasma levels of IgA‐Fn complex have been reported in human IgAN, we sought to determine whether UG interacts with Fn and prevents Fn‐Fn and/or IgA‐Fn interactions, essential for abnormal tissue deposition of Fn and IgA. Our coimmunoprecipitation studies uncovered the formation of Fn‐UG heteromers in vitro and these heteromers are detectable in the plasma of normal mice, but not UG‐KO mice. Further, high plasma levels of IgA‐Fn complex, a characteristic of human IgAN patients, were also found in UG‐KO mice. Finally, coadministration of UG + Fn or UG + IgA to UG‐KO mice prevented glomerular deposition of Fn and IgA, respectively. Our results define a possible molecular mechanism of IgAN and provide insight into at least one important physiological function of UG in maintaining normal renal function in mice.
Rationale for the Development of Recombinant Human CC10 as a Therapeutic for Inflammatory and Fibrotic Disease
Authors: PILON APRILE L.
Published: July 2010

Abstract: CC10/uteroglobin is a remarkable protein whose physiological roles have only recently been explored in vivo. Both transgenic mice that have been rendered deficient and humans that have been characterized as deficient in this protein exhibit tendencies toward inflammatory, fibrotic, and oncologic disease, demonstrating the potential of the protein as a therapeutic agent. The protein itself is an excellent candidate for clinical development because of its inherent physical properties. It is relatively small, resistant to proteases, stable to extremes of heat and pH, and can be produced by recombinant methods. The physiological roles of this multifunctional protein continue to be uncovered as research progresses in vitro, in animals, and eventually in humans. The pathways through which CC10 mediates its effects, its receptors, and other family members will be a rich source of exciting research, as well as potential diagnostic and therapeutic agents. This paper is an introductory, noncomprehensive review of some of the scientific and medical rationale in support of CC10‐based therapies in selected clinical applications.
Genetic Factors in the Genesis of Alzheimer's Disease
Authors: ST GEORGE‐HYSLOP P. H.
Published: July 2010

Abstract: At least four different genes have been identified that are associated with inherited susceptibility to Alzheimer's disease. Some of the genes are highly penetrant (PS1, PS2, bAPP); the other, APOE, is a weaker susceptibility factor. Several additional genes are suspected to exist but have not yet been cloned.
Arson: Tracking the Culprit in Alzheimer's Disease
Authors: SMITH MARK A. , JOSEPH JAMES A. , PERRY GEORGE
Published: July 2010

Abstract: By focusing on the lesions in Alzheimer's disease, and regarding them as either critical or irrelevant, researchers may have missed much regarding the origin and pathogenesis of this disease. In this article we consider that the lesions are so obvious not only because they are pathognomonic for Alzheimer's disease, but also because they represent a major departure from normal physiology. We suggest that these myriad pathological changes are homeostatic compensatory mechanisms to aging.
The Role of Synaptic Proteins in Alzheimer's Disease
Authors: MASLIAH ELIEZER
Published: July 2010

Abstract: Synaptic damage is an early event common to neurodegenerative disorders such as Alzheimer's disease (AD) and is the best correlate to the cognitive impairment found in these patients. Recent studies have shown that several of the molecules involved in neurodegenerative disorders are in fact synaptic proteins with amyloidogenic potential (SPWAP). Here we propose a unified theory to explain the neurodegenerative process in AD based on the idea that abnormal folding and/or aggregation of these molecules leads to cell death. The most important predictions of this hypothesis are that: (1) there are other yet unknown SPWAP that might be involved in AD, and their identity can be predicted by defining what makes a protein amyloidogenic; (2) there are endogenous anti‐amyloidogenic molecules that regulate the aggregation state of SPWAP; and (3) there might be forms of the disease associated with decreased production of endogenous anti‐amyloidogenic molecules or with unbalance of pro‐ versus anti‐amyloidogenic factors.
Comprehensive Theory of Alzheimer's Disease: The Effects of Cholesterol on Membrane Receptor Trafficking
Authors: LYNCH CASEY , MOBLEY WILLIAM
Published: July 2010

Abstract: Neurotrophic factors (NTFs), once known for their role in development, have recently been shown to contribute to the maintenance and plasticity of the adult nervous system. This knowledge has provoked hypotheses implicating NTFs in neurodegenerative conditions, particularly Alzheimer's disease (AD). Many of these hypotheses, however, fail to place the possibility of trophic factor dysfunction in the context of recent advances in the molecular pathogenesis of AD. Most notable has been the discovery of several genetic risk factors and three causative Alzheimer's genes. Genetic advances, in turn, have not yet shed much light on an important pathological feature of AD, synaptic loss. We propose here an hypothesis based on recent cell biological research that attempts to integrate findings in these areas. Our hypothesis states that AD pathogenesis results from disruption of cholesterol uptake and metabolism and that this in turn results in abnormal trafficking of membrane proteins critical to normal neuronal function and synaptic plasticity.
The Brain's Microenvironment, Early Functional Loss, and the Conversion to Alzheimer's Disease
Authors: COTMAN CARL W. , ANDERSON AILEEN J.
Published: July 2010

Abstract: We hypothesize that insults in the local microenvironment may cause selective, local neurite degeneration by apoptotic‐like mechanisms, leading to the loss of synaptic connectivity observed in the Alzheimer disease brain. This may be an early mechanism of neurodegeneration, potentially contributing to neuronal vulnerability and disease pathogenesis.
Oxidative Stress Leading to Loss of Critical Proteases in Alzheimer's Disease: An Alternative View of the Etiology of AD
Authors: CARNEY JOHN M.
Published: July 2010

Abstract: An alternative view of the etiology of Alzheimer's disease is suggested which focuses on the relationship between oxidative stress and the decrease in proteases seen in aging. Proteases act to govern the acceleration of the pathology of aging and, as damage from oxidative stress increases, the loss of proteases in at‐risk persons leads to symptoms of AD. Controlling the damage to proteases or controlling the generator(s) of oxidative stress may help to control the onset or progression of Alzheimer's disease.
Oxidative Metabolism
Authors: BEAL M. FLINT
Published: July 2010

Abstract: There is a large body of evidence showing both metabolic defects and oxidative damage in Alzheimer's disease. Studies of cybrid cell lines show reduced cytochrome oxidase. There is also substantial evidence for a defect in a‐ketoglutarate dehydrogenase. It is therefore possible that therapeutic strategies to improve brain metabolism or ameliorate oxidative damage might be useful in treating Alzheimer's disease.
Globalization of Research and International Standards of Ethics in Anthropology
Authors: FLUEHR‐LOBBAN CAROLYN
Published: July 2010

Abstract: Ethics and anthropology have entered the era of globalization, and professional discourse about ethics can no longer be confined to a national or domestic dialogue. Anthropology must vigorously join the international dialogue and debate over globalization and the conduct of research across cultures; indeed it is the discipline most suited to command the high ground in this discourse. American anthropology historically has been more reactive than proactive in ethics, but cannot remain so as the nature and condition of research have fundamentally changed in a postcolonial world. Indigenous peoples, Third World researchers, international development workers in government and non‐government agencies, and other anthropologists outside of the U.S. are raising questions about international research that are generating new standards of conduct. Anthropology as a discipline and a profession must keep apace with these developments or it will lose ground in a crucial arena of global discourse.
Facing Racism and the Moral Responsibility of Human Rights Knowledge
Authors: HARRISON FAYE V.
Published: July 2010

Abstract: Anthropologists working in arenas of human rights advocacy must be prepared to negotiate dilemmas of human responsibility. Those focusing on racial discrimination as a breach of international human rights conventions must contend with trends in social research that feed into politically consequential claims that neither race nor racism exist as significant social facts. An examination of the global sociocultural and geopolitcal landscape, the human rights system, and models of change reveals that contemporary racism in both its marked and unmarked varieties warrants anthropologists' critical scrutiny and, depending on individual epistemological and political inclination, sociopolitical intervention.
If Anthropology Is Global, Then So Are Its Ethical Dilemmas
Authors: YOON SOON‐YOUNG
Published: July 2010

Abstract: This paper reviews three personal situations of the author as a student: an NGO activist in the women's movement and a UN official working on women's health and tobacco. Each situation, the kinds of ethical issue posed and lessons for the future direction of ethics in anthropology are outlined. The paper argues that applied anthropology is embedded in the position of the field of anthropology within the politics of the State and that this defines the parameters of individual choice. Contradictions in ethical situations and decision‐making are posed by changing from the distant observer to active involvement and these may not be resolved by logic alone. Furthermore, governance and defining global ethical standards such as for the behavior of the tobacco multinational corplorations is a fascinating new realm for anthropological ethical resolve.
Negotiating Ethical and Legal Mazes in the Federal Workplace
Authors: CRESPI MURIEL , MATTIX CARLA
Published: July 2010

Abstract: The mandates that control actions in the federal workplace often challenge academic principles of conduct. Particularly vulnerable is the anthropologists' image of themselves as champions of powerless and voiceless groups in an arena perceived as dominated by a hostile government. This is coupled with convictions that socially responsible anthropology respects individual privacy while disseminating data to encourage culturally informed public and federal decisions. Using examples involving federal cultural and natural resources, we show conflicts within this suite of perspectives and with the demands of the federal workplace. The need for legally defensible decisions, responses to publics with diverse agendas, and requirements for confidentiality and public access to government records test our anthropological convictions as well as available legal protections of individual privacy and the public's right to know. Perhaps the anthropological community will strategize about more effective remedies for the problems of meeting the concerns of the individuals and the publics it cares about.