bluuebunny/crossref_metadata_2025 huggingface dataset:
Illness, Cytokines, and Depression
Authors: YIRMIYA R. , POLLAK Y. , MORAG M. , REICHENBERG A. , BARAK O. , AVITSUR R. , SHAVIT Y. , OVADIA H. , WEIDENFELD J. , MORAG A. , NEWMAN M. E. , POLLMÄCHER T.
Published: July 2010

Abstract: Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double‐blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus‐induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS‐induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS‐induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive‐like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS‐induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF‐α mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness‐associated depression.
Experimental Immunomodulation, Sleep, and Sleepiness in Humans
Authors: POLLMÄCHER THOMAS , SCHULD ANDREAS , KRAUS THOMAS , HAACK MONIKA , HINZE‐SELCH DUNJA , MULLINGTON JANET
Published: July 2010

Abstract: Infection, inflammation, and autoimmune processes are accompanied by serious disturbances of well‐being, psychosocial functioning, cognitive performance, and behavior. Here we review those studies that have investigated the effects of experimental immunomodulation on sleep and sleepiness in humans. In most of these studies bacterial endotoxin was injected intravenously to model numerous aspects of infection including the release of inflammatory cytokines. These studies show that human sleep‐wake behavior is very sensitive to host defense activation. Small amounts of endotoxin, which affect neither body temperature nor neuroendocrine systems but slightly stimulate the secretion of inflammatory cytokines, promote non‐rapid‐eye‐movement sleep amount and intensity. Febrile host responses, in contrast, go along with prominent sleep disturbances. According to present knowledge tumor necrosis factor‐α (TNF‐α) is most probably a key mediator of these effects, although it is likely that disturbed sleep during febrile host responses involves endocrine systems as well. There is preliminary evidence from human studies suggesting that inflammatory cytokines such as TNF‐α not only mediate altered sleep‐wake behavior during infections, but in addition are involved in physiological sleep regulation and in hypnotic effects of established sedating drugs.
Variability of Interactions Between Neuroendocrine and Immunological Functions in Physiological Aging and Dementia of the Alzheimer's Type
Authors: FERRARI E. , FIORAVANTI M. , MAGRI F. , SOLERTE S. B.
Published: July 2010

Abstract: A link between neuroendocrine and immunological changes has been suggested in the pathophysiology of dementia of the Alzheimer's type (DAT). Healthy young and old subjects and patients with DAT were recruited to evaluate the chrononeuroendocrine organization of cortisol, GH, and melatonin (MLT) secretions. The study was carried out together with the evaluation of natural killer (NK) cell function: cytotoxic activity (NKCC) and TNF‐α and IFN‐γ release after exposure to IL‐2 (100 U/mL). Moreover, a cerebral morphometric analysis of hippocampus and temporal lobe (MRI) was performed. The activation of hypothalamo‐pituitary‐adrenal (HPA) axis and the decrease of GH, and MLT nocturnal peaks were associated with normal NKCC and TNF‐α/IFN‐γ in healthy elderly subjects, whereas in DAT patients the same neuroendocrine changes occurred together with abnormal NKCC (spontaneous and IL‐2/IFN‐β‐modulated) and with alterations of TNF‐α/INF‐γ generation from NK. Moreover significant correlations among the increase of NKCC and TNF‐α and the decrease of cognitive function were found in the DAT group. These correlations were associated with the impairment of nocturnal GH and MLT levels and with the relatively higher serum cortisol concentrations. Moreover, the impairment of cortisol suppression after dexamethasone (1 mg orally at 23:00) was significantly correlated with the increase of spontaneous release of TNF‐α and with IL‐2‐modulated NKCC. Finally the imunoneuroendocrine alterations found in DAT were associated with the reduction of cerebral volume in hippocampus and temporal lobes. Taken together these data indicate that the immmunoneuroendocrine balance is maintained in physiological aging, whereas NK immune dysregulation in DAT could contribute to altering the neuroendocrine functions and to extend the progression of neurodegeneration and dementia.
In Vivo Immunomodulation by Peripheral Adrenergic and Cholinergic Agonists/Antagonists in Rat and Mouse Models
Authors: SCHAUENSTEIN K. , FELSNER P. , RINNER I. , LIEBMANN P. M. , STEVENSON J. R. , WESTERMANN J. , HAAS H. S. , COHEN R. L. , CHAMBERS D. A.
Published: July 2010

Abstract: Our work is devoted to defining relationships between the immune system and the adrenergic and cholinergic systems in vivo. In the rat model, we have shown that the cells of different immune compartments express the genes of a defined set of adrenergic/cholinergic receptors, and it was shown that lymphocytes are a site of non‐neuronal production of norepinephrine and acetylcholine. Furthermore, using implantable slow‐release tablets containing adrenergic or cholinergic agonists/antagonists, distinct and partly opposite effects were observed on peripheral immune functions. Concerning sympathetic immunoregulation, our data‐in contrast to those of other studies‐suggest that an enhanced adrenergic tonus leads to immunosuppression primarily via α2‐receptor‐mediated mechanisms. Beta‐blockade strongly enhances this effect, most likely by inhibition of pineal melatonin synthesis. In recent experiments on the kinetics it was found that the continuous α‐adrenergic treatment entails a strong suppression of cellular responsiveness during the first few hours, which is increasingly followed by a general loss of lymphocytes in blood and lymphoid organs most likely due to enhanced apoptosis. More recently, we have extended our studies to the mouse model. First data obtained with RNAse protection assays suggest a biphasic effect on the gene expression of several cytokines in spleen cells due to adrenergic in vivo treatment.
Cytokines, Leptin, and the Hypothalamo‐Pituitary‐Adrenal Axis
Authors: GAILLARD R. C. , SPINEDI E. , CHAUTARD T. , PRALONG F. P.
Published: July 2010

Abstract: The endocrine and immune systems are linked via an elaborated communication system constituted by an array of cytokines and neuropeptides which interact to modulate the integrated response of an organism to infection. Weight loss and anorexia, probably secondary to cytokine release, frequently accompany infection, but leptin could also play a role. Like cytokines, leptin serves as a peripheral messenger to convey signals to the brain. Expression of leptin is stimulated by glucocorticoids, endotoxins, and cytokines; on the other hand, leptin seems to inhibit the activation of the hypothalamo‐pituitary‐adrenal (HPA) axis. Indeed leptin exerts a direct, dose‐dependent inhibition of stimulated cortisol secretion by normal human and rat adrenal cells in vitro. These effects are mediated by the long isoform of the leptin receptor, because its transcript is expressed in the adrenal tissue. In addition we investigated the role played by the glucocorticoids in the development of tolerance of the hypothalamo‐corticotropic, immune and adipose system responses to repeated endotoxin administration. Unlike that of the corticotropic axis, tolerance of the immune and adipose systems is at least partially glucocorticoid‐independent. This crosstalk between the endocrine, immune, and adipose systems may be of prime importance to homeostasis in pathophysiological events occurring during infection.
Functional Cross‐talk among Cytokines, T‐Cell Receptor, and Glucocorticoid Receptor Transcriptional Activity and Action
Authors: ARZT E. , KOVALOVSKY D. , IGAZ L. MÜLLER , COSTAS M. , PLAZAS P. , REFOJO D. , PÁEZ‐PEREDA M. , REUL J. M.H.M. , STALLA G. , HOLSBOER F.
Published: July 2010

Abstract: The main communicators between the neuroendocrine and immune systems are cytokines and hormones. We studied the molecular interaction between immune activators (cytokines and T‐cell receptors [TCRs]) and the glucocorticoid receptor (GR) in cells in which glucocorticoids play a key regulatory function: (1) cellular targets of TNF‐induced cytotoxicity; (2) the pituitary gland; and (3) thymic cells. Cytokines (TNF‐alpha and IL‐1) increase glucocorticoid‐induced transcriptional activity of the GR via the DNA‐glucocorticoid response elements (GREs) in cells transfected with a glucocorticoid‐inducible reporter plasmid. As a functional physiological correlate, priming of fibroblastic cells with a low dose of TNF significantly increases the sensitivity to glucocorticoid inhibition of TNF‐induced apoptosis (without involving NF‐κB). Priming of AtT‐20 mouse corticotrophs and Cushing pituitary cells with IL‐1 increases the sensitivity to glucocorticoid inhibition of CRH‐induced ACTH/POMC expression. In thymocytes, activation of the T‐cell receptor counteracts the glucocorticoid‐induced thymic apoptosis by downregulating the glucocorticoid action on GRE‐driven apoptotic genes. Thus, cytokines and immune mediators prevent their own deleterious effects not only by stimulating glucocorticoid production, but also by modifying the sensitivity of the target cells for the glucocorticoid counter‐regulatory action. The functional cross‐talk at the molecular level between immune signals and glucocorticoids is essential to determine the biological response to both mediators and constitutes the ultimate level of interaction between the immune and neuroendocrine mediators.
Role of Glucocorticoids in Early T‐Cell Differentiation
Authors: SACEDÓN ROSA , VICENTE ANGELES , VARAS ALBERTO , JIMÉNEZ EVA , MUÑOZ JUAN JOSÉ , ZAPATA AGUSTIN G.
Published: July 2010

Abstract: The results of the t‐cell differentiation in the progeny of adrenalectomized pregnant rats (adx fetuses), an experimental model that ensures the absence of glucocorticoids (GCs) during the first stages of development, are summarized. in Adx thymuses there is an accelerated maturation of thymocytes that is reversed by in vivo GC replacement. in addition, Adx thymuses show decreased cell content, which correlates with both the increased numbers of apoptotic cells and an early migration of DP (CD4+CD8+) and SP (both CD4+CD8− and CD4−CD8+) thymocytes to the spleen. As shown by in vitro recolonization assays, accelerated T‐cell differentiation is a consequence of changes in the biology of lymphoid precursors occurring in the fetal liver of Adx fetuses. They arrive at the thymic primordium earlier and mature faster than the fetal liver lymphoid progenitors from Sham control fetuses. After the establishment of a fetal hypothalamus‐pituitary‐gland‐adrenal‐gland (HPA) axis, there is a gradual normalization of the T‐cell development Adx fetuses.
Is There a Role for Growth Hormone upon Intrathymic T‐Cell Migration?
Authors: SAVINO WILSON , SMANIOTTO SALETE , De MELLO‐COELHO VALÉRIA , DARDENNE MIREILLE
Published: July 2010

Abstract: Intrathymic T‐cell Differentiation is essentially driven by the thymic microenvironment, a tridimensional network formed by thymic epithelial cells and to a lesser extent, dendritic cells, macrophages, fibroblasts, and extracellular matrix components. thymocyte migration throughout the thymus is partially dependent on extracellular‐matrix (ECM) ‐mediated interactions. Herein we investigated the putative role of growth hormone (GH) upon events related to intrathymic T‐cell migration. we demonstrated that GH upregulates the expression of ECM ligands and receptors in distinct preparations of cultured thymic epithelial cells TECs). We also showed that adhesion of thymocytes to thymic epithelial cells was significantly increased by GH treatment, an effect that could be consistently abrogated when TECs were treated to antifibronectin, anti‐VLA5, antilaminin, or anti‐VLA6 antibodies before addition of thymocytes to the cultures. We also studied thymic nurse cells (TNCs), lymphoepithelial complexes that can be isolated ex vivo from the thymus. In this system, we had previously demonstrated that ECM ligands and receptors control both inward and outward thymocyte traffic. We then showed that GH enhances thymocyte release from TNCs, as well as the reconstitution of these lymphoepithelial complexes. Lastly, we evaluated the in vivo influence of GH on thymocyte exit. This was done by means of intrathymic injection of GH plus fluorescein isothiocyanate (FITC), and further analysis of recent thymic emigrants (FITC+ cells) in peripheral lymphoid organs, as defined by CD4/CD8‐based cytofluorometric phenotyping. The proportions of FITC+ T cells appeared augmented in lymph nodes in GH‐treated mice, as compared to controls. Taken together, these data indicate that GH stimulates intrathymic T‐cell traffic, an effect that is at least partially mediated by extracellular matrix‐mediated interactions.
Gonadotropin‐Releasing Hormone and G Proteins: Potential Roles in Autoimmunity
Authors: JACOBSON J. D.
Published: July 2010

Abstract: The hypothalamic homone gonadotropin‐releasing hormone (GnRH) displays gender‐specific actions. Pituitary responsiveness to GnRH is generally increased by estrogens and decreased by androgens. GnRH is now known to be produced by the immune system and to exert potent immunologic actions. Our central hypothesis is that gender differences in responsiveness to GnRH in the immune system play a pivotal role in the gender differences in immunity and autoimmunity. Studies in lupus‐prone mice demonstrate that gnrh exacerbates murine lupus in a gender‐specific fashion. Subsequent studies from our laboratory suggest that the gender differences in immunologic responsiveness to GnRH may relate to differences in the expression of the signal transducers through which GnH acts namely, the G proteins, GS, and GQ/11. We have further demonstrated gender differences in second messengers for GnRH, IP3, and camf in immune cells. we have also demonstrated that GnRH agonist increases the quantities and/or activity of G proteins in immune cells in a gender‐specific fashion. we speculate that gender differences in GnRH production and action, and in g protein expression play a role in a variety of autoimmune diseases that affect females predominantly.
Neuroendocrine and Other Factors in the Regulation of Inflammation: Animal Models
Authors: JAFARIAN‐TEHRANI MEHRNAZ , STERNBERG ESTHER M.
Published: July 2010

Abstract:A variety of animal models have been used to study the role of neuroendocrine responses in various aspects of autoimmune/inflammatory disease. Complex models of autoimmune disease, such as inflammatory arthritis in rats and thyroiditis in chickens, indicate a role for blunted HPA axis and dysregulated sympathoneuronal responses in susceptibility to autoimmune disease. A variety of approaches including pharmacological, surgical (ablation, transplantation), genetic linkage and segregation studies have been used to identify factors contributing to the phenotypes of susceptibility or resistance to inflammatory/autoimmune disease. Innate inflammation, or the earliest nonspecific form of the inflammatory response, which is characterized by fluid exudation and migration of immune cells to inflammatory sites, is a subtrait of these forms of inflammatory disease. Genetic linkage and segregation studies in inflammatory susceptible and resistant rat strains indicate that this subtrait is multigenic and polygenic; that is, that multiple loci on multiple chromosomes, each with a weak effect, control this trait, and that there is a large environmental component to the variability of this trait. Such information derived from animal studies can be used to target candidate genes for further study and to inform the design of human studies.
Environmental Factors Favoring the Allergen‐specific Th2 Response in Allergic Subjects
Authors: PICCINNI MARIE‐PIERRE , MAGGI ENRICO , ROMAGNANI SERGIO
Published: July 2010

Abstract: Allergen‐reactive type 2 helper T cells (Th2) play a triggering role in the activation and/or recruitment of IgE antibody‐producing B cells, mast cells, and eosinophils, i.e., the cellular triad involved in the allergic inflammation. Interleukin (IL)‐4 production at the time of antigen presentation to the Th cell is critical for the development of Th2 cells. Other cytokines, such as IL‐1 and IL‐10, and hormones, such as calcitriol and progesterone, also play a positive role. In contrast, cytokines such as interferon (IFN)‐α, IFN‐γ, IL‐12, and transforming growth factor (TGF)‐β, and relaxin play a negative regulatory role on the development of Th2 cells. However, the mechanisms underlying the preferential activation by environmental allergens of Th2 cells in atopic individuals still remain obscure. Some gene products selectively expressed in Th2 cells or selectively controlling the expression of IL‐4 have recently been described. Moreover, cytokines and other gene products that dampen the production of IL‐4, as well as the development and/or the function of Th2 cells, have been identified. These findings allow us to suggest that the upregulation of genes controlling IL‐4 expression and/or abnormalities of regulatory mechanisms of Th2 development and/or function may be responsible for Th2 responses against common environmental allergens in atopic subjects.
Conditioning Rhinitis in Allergic Humans
Authors: BARRETT JUDITH E. , KING MAURICE G. , PANG GERALD
Published: July 2010

Abstract: A classical pavlovian paradigm pairing an olfactory cue with allergen challenge for a single training trial was used to produce conditioned histamine release and conditioned nasal airflow decrease in seasonal allergic rhinitis sufferers. There was no conditioned increase in subjective symptoms. histamine release and airflow decrease showed evidence of extinction by a second test trial. A second study comparing the effects of the number of training trials showed that three training trials produced greater histamine release and airflow decrease than a single training trial, suggesting stronger effects with additional training.
Altered Glucocorticoid Regulation of the Immune Response in the Chronic Fatigue Syndrome
Authors: VISSER JEROEN T.J. , De KLOET E. RONALD , NAGELKERKEN LEX
Published: July 2010

Abstract: It is increasingly recognized that glucocortiocoids (GCS) can have subtle modulatory effects in immunoregulation rather than having generalized immunosuppressive effects. GCs suppress Th1 cells and cellular immunity, but may favor Th2 responses and humoral immunity. The chronic fatigue syndrome (CFS) appears to be associated with a disturbed HPA‐axis. Moreover, CFS patients show several immunological changes suggestive of decreased cellular immunity. It is postulated herein that in CFS patients a decreased Th1/Th2 balance may be the result of selective effects of GC on the IL‐10/IL‐12 regulatory circuit.
Chemical Sympathectomy Alters Cytotoxic T Lymphocyte Responses to Herpes Simplex Virus Infection
Authors: LEO NICOLE A. , BONNEAU ROBERT H.
Published: July 2010

Abstract:Numerous studies have sought to delineate the impact of neuroendocrine function on overall immune responsiveness. using various murine models, we and others have previously shown that both adrenal‐dependent and adrenal‐independent mechanisms regulate components of the primary and memory cellular immune responses to herpes simplex virus type 1 (HSV‐1) infection. we have extended these studies by determining the impact of 6‐hydroxydopamine (6‐OHDA)‐induced peripheral sympathetic denervation on these responses. C57BL/6 mice treated with 6‐OHDA (200 mg/kg) were inhibited in their ability to generate primary, HSV‐specific cytotoxic T lymphocytes (CTL) in response to HSV infection. sympathectomy also suppressed the activation and function of HSV‐specific memory CTL (CTLm). in addition, administration of 6‐OHDA resulted in a transient but substantial increase in levels of circulating corticosterone and hypothalamic fos expression. together, these findings suggest that peripheral sympathetic denervation may modulate immune function via activation of the hypothalamic‐pituitary‐adrenal (HPA) axis.
Steroid Hormone Regulation of Antiviral Immunity
Authors: PADGETT D. A. , LORIA R. M. , SHERIDAN J. F.
Published: July 2010

Abstract: Recent observations in both humans and animals have demonstrated that stress is immunomodulatory and can alter the pathogenesis of microbial infections to the extent that it may be adverse to health. Stress disrupts homeostasis, and the body responds through endocrine and nervous system interactions in an effort to re‐establish the health of the host. However, the resulting physiologic changes associated with stress, such as the rise in serum glucocorticoids (GCs), are implicated in suppression of antiviral immunity. Therefore, it would be of significance to counterregulate stress‐mediated immunosuppression during viral infection to improve immune responses and limit virus‐mediated damage. The data in this study focus upon the antiglucocorticoid influence of a native steroid hormone that has been shown to augment immune function and protect animals against lethal viral infections. Androstenediol (5‐androstene‐3β,17β‐diol, AED), a metabolite of dehydroepiandrosterone (DHEA), confers protection against lethal infection with influenza A virus. The protective activity appears to counterbalance the function of the regulatory GCs because AED prevents GC‐mediated suppression of IL‐1, TNF‐α and IL‐2 secretion. Furthermore, AED inhibits GC‐induced transcription of a GC‐sensitive reporter gene.
Prevention of Perinatal HIV Infection: What Do We Know? Where Should Future Research Go?
Authors: FOWLER MARY GLENN
Published: July 2010

Abstract: Major progress has been made in reduction of perinatal HIV transmission in the United States and Europe following the PACTG 076 results using zidovudine (ZDV) for prevention of mother‐to‐infant HIV transmission. Internationally in the past two years, short‐course antiretroviral trials have shown efficacy for both antenatal or intrapartum and postnatal interventions. Trials in Bankok, Thailand, and Cote d'Ivoire demonstrated that antenatal ZDV started at 36 weeks could reduce transmission by 50% among non‐breastfeeding women and about 37% among breastfeeding women. Uganda trial results with one dose of nevirapine given to the mother at the onset of labor and to the newborn resulted in a 47% reduction in transmission when compared to a regimen of ZDV given intrapartum and for 1 week to the newborn. These recent international research findings provide evidence that both short‐course antenatal/intrapartum and intrapartum/neonatal prophylaxis can effectively reduce perinatal HIV transmission in resource‐poor settings. In order to avert the 1600 new infant HIV infections occurring daily, the world community must act to rapidly implement these international perinatal trial results.
Rapid Voluntary Testing and Counseling for HIV: Acceptability and Feasibility in Zambian Antenatal Care Clinics
Authors: BAKARI J. P. , McKENNA S. , MYRICK A. , MWINGA K. , BHAT G. J. , ALLEN S.
Published: July 2010

Abstract: Voluntary testing and counseling (VTC) for HIV/AIDS is now widely accepted as an effective HIV prevention and control strategy among heterosexual couples in sub‐Saharan Africa. The most appropriate format and venue for VTC remains a topic of debate among clinicians and public health professionals. Our research done in Lusaka, Zambia, took a tripartite approach to exploring the most acceptable format and venue for VTC: a community survey of attitudes towards VTC, a pre‐ and postcounseling knowledge survey, and a pilot study of same‐day VTC in urban antenatal care clinics. A community survey of 181 individuals was conducted in July‐August 1996 based on a structured questionnaire. A pre‐ and post‐VTC intervention knowledge survey was conducted during the same period among 82 couples attending the Zambia‐UAB HIV Research Project (ZUHRP) HIV VTC center in Lusaka. Finally, same‐day HIV VTC was pilot tested in six antenatal clinic locations during February‐May 1997 and June‐August 1998. The community survey revealed that 98% of participants support promotion of HIV VTC in the community and 83.8% prefer the same‐day testing format. The knowledge survey revealed misconceptions about discordance within a couple and perinatal transmission of HIV. Pilot testing in antenatal clinics was well received, with 84% of pregnant women requesting testing and 25% having positive HIV serologies. Women with primary school or less education, those seeking antenatal care in local clinics, and those seen before the third trimester of pregnancy were more likely to request HIV testing. Testing and counseling for HIV were shown to be feasible and effective in the antenatal clinic setting. Implementation of sameday HIV VTC in antenatal clinics is an effective strategy to prevent vertical transmission and should be expanded to include couples to leverage a decrease in heterosexual transmission as well.
Achievable Standard of Care in Low‐Resource Settings
Authors: LOU C.
Published: July 2010

Abstract:The gap between rich and resource‐poor countries has continued to grow as reproductive care providers integrate interventions to limit mother‐to‐child transmission (MTCT) of HIV in a manner consistent with existing information. There are two major reasons for this difference: access to prophylactic antiretroviral therapy (ARV) for HIV‐infected pregnant mothers and availability of alternative feeding for babies. In resource‐poor settings, these options are beyond reach for the majority of the women. Infant and under‐five mortality rates from other infections are high in these settings and breastfeeding remains the norm. Answering the question, What is an achievable standard of care in resource‐poor settings? still remains a major challenge today. Dialogue has begun in most resource‐poor settings to address the key elements in the package of interventions to reduce MTCT of HIV. These elements include the following: (1) overall prevention of HIV in mothers and fathers; (2) provision of good‐quality voluntary testing and counseling (VCT) in antenatal clinics; (3) a comprehensive package of interventions during pregnancy, during labor, and after delivery, including screening for sexually transmitted diseases (STDs), family planning, and‐where possible‐ARVs; (4) provision of infant and maternal nutrition within the socioeconomic realities; (5) advocacy and program communication; and (6) other supportive measures, including community mobilization to address issues such as stigmatization of and violence against HIV‐infected women. This paper discusses the challenges faced by most resource‐poor settings in integrating some of these activities into reproductive care services.
Future Directions for NIH‐Supported Pediatric AIDS Research
Authors: NATHANSON NEAL , EISINGER ROBERT W.
Published: July 2010

Abstract: The Office of AIDS REsearch (OAR) at the National Institutes of Health (NIH) is responsible for the coordination of AIDS research. In June 1999, the OAR, in conjunction with the NIH Institutes and Centers, initiated a review of NIH‐sponsored pediatric AIDS research. This article discusses a number of important priorities for future clinical research in NIH‐sponsored pediatric AIDS, both in developed and developing countries. These have the potential to significantly prevent perinatal transmission, reduce adolescent in‐fections, and impact treatment of pediatric infections.
Lack of Definitive Severe Mitochondrial Signs and Symptoms among Deceased HIV‐Uninfected and HIV‐Indeterminate Children ≤ 5 Years of Age, Pediatric Spectrum of HIV Disease Project (PSD), USA
Authors: DOMINGUEZ K. , BERTOLLI J. , FOWLER M. , PETERS V. , ORTIZ I. , MELVILLE S. , RAKUSAN T. , FREDERICK T. , HSU H. , D'ALMADA P. , MALDONADO Y. , WILFERT C. ,   THE PSD CONSORTIUM, AND THE PERINATAL SAFETY REVIEW WORKING GROUP
Published: July 2010

Abstract: Background: In response to recent reports of mitochondrial dysfunction in HIV‐uninfected infants exposed to antiretroviral (ARV) prophylaxis, the Perinatal Safety Review Working Group reviewed deaths in five large HIV‐exposed perinatal cohorts in the United States to determine if similar cases of severe mitochondrial toxicity could be detected. We describe the results of this review for the PSD cohort.

Methods: Hospitalization, clinic and death records for deceased HIV‐uninfected and HIV‐indeterminate children who were less than 5 years of age were reviewed. Standard definitions were used to classify HIV infection status and the likelihood that signs and symptoms were related to mitochondrial dysfunction. Children were classified as having signs and symptoms that were considered (1) unrelated, (2) unlikely, (3) consistent with, or (4) likely related to mitochondrial disease. SIDS deaths were put into a separate category.

Results: 8,465 of 13,125 HIV‐exposed children were either HIV‐uninfected or HIV‐indeterminate. Among the 84 deaths in the subgroup of 8,465 children, 9 were considered in Class 2 (unlikely), 4 were considered in Class 3 (consistent with), and none were considered in Class 4 (likely). 97% of those children who received ARV prophylaxis received zidovudine alone. None of the HIV‐uninfected deaths were classified in 2, 3, or 4; and only one of these was exposed to ARV prophylaxis. Among the 3 HIV‐indeterminate children who were classified in 3 (consistent with), 2 had no or unknown ARV exposure before 1994 when use of ZDV prophylaxis became the standard of care. Both HIV‐uninfected and HIV‐indeterminate children with ARV exposure or unknown exposure had lower mortality rates than children without ARV exposure.

Conclusion: Monoprophylaxis with ZDV was not associated with higher death rates in the cohort of 8,465 children or with any findings likely consistent with mitochondrial dysfunction among the 85 deaths. Ongoing monitoring of drug safety in large multi‐site prospective cohort studies of HIV‐exposed children is essential in the era of highly active antiretroviral therapy.
Antiretroviral Pharmacology in Pregnant Women and Their Newborns
Authors: MIROCHNICK MARK
Published: July 2010

Abstract:The physiologic changes of pregnancy have an impact on antiretroviral pharmacokinetic parameters, but the effect is generally not of sufficient magnitude to warrant alterations in dosing. Although administration of oral zidovudine during labor may not provide equivalent serum drug exposure as with continuous intravenous infusion, the clinical relevance of the difference is unknown. Nevirapine is well absorbed during labor, and sufficient drug for prophylaxis against perinatal transmission crosses the placenta if an oral dose is administered to the mother at least 1 hour before delivery. Placental transfer of reverse transcriptase inhibitors is good, whereas preliminary data suggest that protease inhibitors do not cross the placenta well. The use of antiretrovirals during pregnancy is becoming increasingly common, although their safety, toxicity, and teratogencity in pregnancy have not been well described. Normal growth and development have a profound impact on the pharmacokinetics of antiretrovirals in newborns and infants. Washout elimination of transplacentally acquired drug is slow. The pattern of increase in drug clearance over time will depend on the specific elimination pathway for the agent. Dosing regimens must take into account developmental changes in clearance and appropriate scaling for size. Adherence to antiretroviral regimens is a critical factor in determining the success of prophylactic and therapeutic regimens and is made difficult by the inability of infants to swallow pills and capsules.
Antiflammins: Bioactive Peptides Derived from Uteroglobin
Authors: MIELE LUCIO
Published: July 2010

Abstract:Uteroglobin/Clara cell 10‐kDa protein (UG/CC10) is a hormonally regulated small secretory protein that has a variety ofin vitroandin vivopharmacological effects. These include a potent anti‐inflammatory activity and inhibitory effects on neutrophil migration, thrombin‐induced platelet aggregation,in vitrochemoinvasion, as well as “tumor suppressor”‐like effects and other properties. Several mechanisms of action have been proposed for these effects. Pharmacological properties suggest that UG itself or substances derived from it may be used as experimental drugs for several indications. The group of oligopeptides collectively known as “antiflammins” (AFs) were originally described in 1988. Their design was derived from the region of highest sequence similarity between UG and another group of proteins with anti‐ inflammatory properties, the lipocortins or annexins. Nanomolar concentrations of these peptides can reproduce several of the pharmacological activities of UG, including itsin vivoanti‐inflammatory effects and inhibition of platelet aggregation. The AFs have been safely and effectively used to suppress inflammation and fibrosis in several animal models. Progress in clarifying the mechanism of action of the AFs may facilitate the structure‐based design of a novel class of potent anti‐inflammatory, antichemotactic drugs.
Uteroglobin Gene Transcription: What's the RUSH?
Authors: CHILTON BEVERLY S. , HEWETSON AVELINE , DEVINE JERRY , HENDRIX ERICKA , MANSHARAMANI MALINI
Published: July 2010

Abstract: Prolactin enhances progesterone‐dependent transcription of the rabbit uteroglobin gene. RUSH transcription factors are implicated in the signal transduction pathway. The RUSH acronym identifies key features of these nuclear phosphoproteins, that is, RING‐finger motif, binds the uteroglobin promoter, structurally related to the SWI/SNF family of transcription factors, and helicase‐like. Cloned by recognition site screening, RUSH proteins bind to an 85‐bp region (−170/−85) of the uteroglobin promoter that was subsequently identified as a novel prolactin‐responsive region by promoter deletion analysis. Gel shift and linker‐scanning assays further reduced the RUSH target site to −160/−110. A hexameric core of MCWTDK was identified as the RUSH‐specific DNA‐binding site (−126/−121) by CASTing. This site overlaps authentic HNF3b and OCT‐1 binding sites. A unique Type IV P‐type ATPase that is embedded in the inner nuclear membrane binds the RING domain of RUSH. The conformationally flexible loop portion of this RING‐finger binding protein (RFBP) extends into the nucleoplasm to contact euchromatin. The physical association of RFBP with transcriptionally active chromatin supports the speculation that RFBP targets RUSH transcription factors to the active uteroglobin promoter.
Uteroglobin Binding Proteins: Regulation of Cellular Motility and Invasion in Normal and Cancer Cells
Authors: KUNDU GOPAL C. , ZHANG ZHONGJIAN , MANTILE‐SELVAGGI GIUDITTA , MANDAL ASIM , YUAN CHIUN‐JYE , MUKHERJEE ANIL B.
Published: July 2010

Abstract: Uteroglobin (UG) is a multifunctional, secreted protein with anti‐inflammatory and antichemotactic properties. While its anti‐inflammatory effects, in part, stem from the inhibition of soluble phospholipase A2 (sPLA2) activity, the mechanism(s) of its antichemotactic effects is not clearly understood. Although specific binding of UG on microsomal and plasma membranes has been reported recently, how this binding affects cellular function is not clear. Here, we report that recombinant human UG (hUG) binds to both normal and cancer cells with high affinity (20–35 nM, respectively) and specificity. Affinity cross‐linking studies revealed that 125I‐hUG binds to the NIH 3T3 cell surface with two proteins of apparent molecular masses of 190 and 49 kDa, respectively. UG affinity chromatography yielded similar results. While both the 190‐ and 49‐kDa proteins were expressed in the heart, liver, and spleen, the lung and trachea expressed only the 190‐kDa protein. Some cancer cells (e.g., mastocytoma, sarcoma, and lymphoma) expressed both the 190‐ and 49‐kDa proteins. Further, using functional assays, we found that UG dramatically suppressed the motility and extracellular matrix invasion of both NIH 3T3 and some cancer cells. In order to further characterize the anti‐ECM‐invasive properties of UG, we induced expression of hUG into cancer cell lines derived from organs that, under physiological circumstances, secrete UG at a high level. Interestingly, it has been reported that a high percentage of the adenocarcinomas arising from the same organs fail to express UG. Our results on induced hUG expression in these cells show that inhibition of motility and ECM invasion requires the expression of both UG and its binding proteins. Taken together, our data define receptor‐mediated functions of UG in which this protein regulates vital cellular functions by both autocrine and paracrine pathways.
Development of an Enzyme‐Linked Immunosorbent Assay for Clara Cell 10‐kDa Protein: In Pursuit of Clinical Significance of Sera in Patients with Asthma and Sarcoidosis
Authors: SHIJUBO NORIHARU , ITOH YOSHIHISA , YAMAGUCHI TETSUJI , ABE SHOSAKU
Published: July 2010

Abstract: We have produced nine monoclonal antibodies to human CC10/protein‐1 and analyzed their characterization. TY‐5, TY‐7, and TY‐8 recognized restricted possible hydrophobic epitopes and their binding to CC10 prevented the other clones from CC10 binding, suggesting that these antibodies induce strong conformational change. TY‐1, TY‐2, TY‐3, TY‐6, and 6D4 recognize amino acid residues 61–68 and the presence of disulfide bonds might be essential for epitope expression of these five clones. The best combination was TY‐1 and TY‐2 in developing an enzyme‐linked immunosorbent assay (ELISA), whereas TY‐5 was most suitable for immunohistochemistry and immunoblotting. We found significantly lower serum CC10 levels in asthmatic subjects and higher serum CC10 levels in sarcoidosis subjects than in controls. Data of CC10 levels in BAL fluids of sarcoidosis subjects were similar to those in the circulation. CC10‐positive epithelial cells were significantly lower in small airways of asthmatic subjects than in controls, and CC10‐positive epithelial cells were inversely correlated with T cell and mast cell accumulation in the airways of asthmatic subjects. CC10 may be a downregulator in both Th1‐ and Th2‐mediated chronic inflammatory diseases. The use of these MoAbs and recombinant CC10 is a powerful tool to investigate the clinical roles of CC10/P1 and the structure and function of CC10/P1.
Toward a Comprehensive Theory for Alzheimer's Disease. Hypothesis: Alzheimer's Disease Is Caused by the Cerebral Accumulation and Cytotoxicity of Amyloid β‐Protein
Authors: SELKOE DENNIS J.
Published: July 2010

Abstract: A central challenge of research on Alzheimer's disease (AD) is to assemble the enormous body of scientific observations about the disorder, some of them seemingly in conflict with others, into a coherent and credible mechanism of pathogenesis. In this article, I attempt to synthesize the disparate findings on AD into a unified sequence that essentially begins with alterations in the production or clearance of the amyloid β‐protein (Aβ). Mounting evidence from many laboratories supports an Aβ accumulation in limbic and association cortices as the fundamental initiator of the disease, with attendant therapeutic implications.
The Pathogenesis of Alzheimer's Disease: Is Amyloid β‐Protein the Beginning or the End?
Authors: YANKNER BRUCE A.
Published: July 2010

Abstract: A central issue in Alzheimer's disease research is whether amyloid β‐protein (Aβ) is a cause or effect of the pathogenic process. Several independent lines of evidence argue for causality, although human clinical trials may be required to finally settle the issue.
Pathways to Primary Neurodegenerative Disease
Authors: HARDY JOHN
Published: July 2010

Abstract: Genetic analysis has revealed the pathogenic lesions that cause autosomal dominant Alzheimer's disease, prion disease, and some forms of Parkinson's disease. Molecular biological experiments based on these genetic findings allow a hypothesis to be configured linking these and the other diseases in which tangles or Lewy bodies are a pathological feature. In this article, this hypothesis is presented in the context of deriving curative treatments for these disorders.
Estrogens and Estrogen‐Like Non‐Feminizing Compounds: Their Role in the Prevention and Treatment of Alzheimer's Disease
Authors: GREEN PATTIE S. , SIMPKINS JAMES W.
Published: July 2010

Abstract: The present position paper is intended to provide evidence that estrogen deprivation contributes to the occurrence and course of Alzheimer's disease (AD) and that currently available estrogen preparations may be useful in the prevention and treatment of AD in women. Additionally, there is now substantial preclinical evidence to support the development of novel non‐feminizing estrogens for use in male and female subjects for the protection of neurons from damage and death that underlies the neuropathology of AD. Estrogens and non‐feminizing estrogen‐like compounds may exert their beneficial effects in AD through a variety of mechanisms, directly through their neuroprotective actions and indirectly through their neurotrophic effects. Inasmuch as estrogens are comparatively free of both acute and chronic toxicities, and non‐feminizing estrogens are expected to be even safer, their use for years to decades for the prevention or treatment of AD is possible.
A “Protease Activation Cascade” in the Pathogenesis of Alzheimer's Disease
Authors: NIXON RALPH A.
Published: July 2010

Abstract: A pathway to Alzheimer's disease (AD) relevant to sporadic AD pathogenesis is described that involves the early and progressive activation of proteolytic systems including, but not limited to, the calpain‐calpastatin and endosomal‐lysosomal systems. Activation of these proteolytic systems is initiated by normal brain aging and is propelled by the genetic and environmental factors known to increase AD risk. Recent studies show how cathepsins and calpains, acting directly or indirectly through other proteolytic pathways and cellular signaling cascades, may promote β‐amyloidogenesis, neurofibrillary pathology, as well as mediate neurodegeneration in AD.
Impaired Cerebromicrovascular Perfusion: Summary of Evidence in Support of Its Causality in Alzheimer's Disease
Authors: DE LA TORRE J. C.
Published: July 2010

Abstract:After nearly a century of inquiry, the cause of Alzheimer's disease (AD) remains to be found. In this review, basic and clinical evidence is presented that assembles and hypothetically explains most of the key pathologic events associated with the development of AD. These pathologic events are triggered in AD by impaired cerebral perfusion originating in the microvasculature that affects the optimal delivery of glucose and oxygen and results in an energy metabolic breakdown of brain cell biosynthetic and synaptic pathways. We propose that two factors must be present before cognitive dysfunction and neurodegeneration is expressed in the AD brain: (1) advanced aging, (2) presence of a condition that lowers cerebral perfusion, such as a vascular risk factor. The first factor introduces a normal but potentially menacing process that lowers cerebral blood flow in proportion to increased aging, while the second factor adds a crucial burden that further lowers brain perfusion and places vulnerable neurons in a state of metabolic compromise leading to a death pathway. These two factors will lead to acritically attained threshold of cerebral hypoperfusion(CATCH). CATCH is a self‐sustaining and progressive circulatory insufficiency that will destabilize neurons, synapses, neurotransmission, and cognitive function, creating in its wake a neurodegenerative process characterized by the formation of senile plaques, neurofibrillary tangles, amyloid angiopathy, and, in some cases, Lewy bodies. Since any of a considerable number of vessel‐related conditions must be present in the aging individual for cognition to be affected, CATCH supports the heterogeneic disease profile assumed to be characteristic of the AD syndrome. A brief discussion of target therapy based on the proposed pathogenesis of AD is also reviewed.
Existing Data Suggest That Alzheimer's Disease Is Preventable
Authors: MATTSON MARK P.
Published: July 2010

Abstract: The ultimate goal of Alzheimer's disease (AD) research is to prevent the onset of the neurodegenerative process and thereby allow successful aging without cognitive decline. Herein I argue that a simple and effective preventative approach for AD may be in hand. AD is a disorder associated with the aging process and is, accordingly, characterized by cellular and molecular changes that occur in age‐related diseases in other organ systems. Such changes include increased levels of oxidative stress, perturbed energy metabolism, and accumulation of insoluble (oxidatively modified) proteins (prominent among which are amyloid β‐peptide and tau). The risk of several other prominent age‐related disorders, including cardiovascular disease, cancer, and diabetes, is known to be influenced by the level of food intake‐high food intake increases risk, and low food intake reduces risk. An overwhelming body of data from studies of rodents and monkeys has documented the profound beneficial effects of dietary restriction (DR) in extending life span and reducing the incidence of age‐related diseases. Reduced levels of cellular oxidative stress and enhancement of energy homeostasis contribute to the beneficial effects of DR. Recent findings suggest that DR may enhance resistance of neurons in the brain to metabolic, excitotoxic, and oxidative insults relevant to the pathogenesis of AD and other neurodegenerative disorders. While further studies will be required to establish the extent to which DR will reduce the incidence of AD, it would seem prudent (based on existing data) to recommend DR as widely applicable preventative approach for age‐related disorders including neurodegenerative disorders.
The Mitochondrial Spiral: An Adequate Cause of Dementia in the Alzheimer's Syndrome
Authors: BLASS JOHN P.
Published: July 2010

Abstract: A variety of chronic, relatively low‐grade injuries to the brain occur in Alzheimer's disease (AD). The extent to which each of these contributes to the clinical syndrome is unclear. Several of the abnormalities that occur in AD brain can cause dementia by themselves, even in people who do not have the neuropathological hallmarks of AD. Prominent among these abnormalities is a deleterious “mitochondrial spiral,” which consists of reduced brain metabolism, oxidative stress, and calcium dysregulation. The hypothesis presented in this paper is that the mitochondrial spiral contributes to dementia in AD and presents a reasonable target for the development of new approaches to the treatment of this syndrome.