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Developmental Origins of Chronic Renal Disease: An Integrative Hypothesis  [PDF]
F. Boubred,M. Saint-Faust,C. Buffat,I. Ligi,I. Grandvuillemin,U. Simeoni
International Journal of Nephrology , 2013, DOI: 10.1155/2013/346067
Abstract: Cardiovascular diseases are one of the leading causes of mortality. Hypertension (HT) is one of the principal risk factors associated with death. Chronic kidney disease (CKD), which is probably underestimated, increases the risk and the severity of adverse cardiovascular events. It is now recognized that low birth weight is a risk factor for these diseases, and this relationship is amplified by a rapid catch-up growth or overfeeding during infancy or childhood. The pathophysiological and molecular mechanisms involved in the “early programming” of CKD are multiple and partially understood. It has been proposed that the developmental programming of arterial hypertension and chronic kidney disease is related to a reduced nephron endowment. However, this mechanism is still discussed. This review discusses the complex relationship between birth weight and nephron endowment and how early growth and nutrition influence long term HT and CKD. We hypothesize that fetal environment reduces moderately the nephron number which appears insufficient by itself to induce long term diseases. Reduced nephron number constitutes a “factor of vulnerability” when additional factors, in particular a rapid postnatal growth or overfeeding, promote the early onset of diseases through a complex combination of various pathophysiological pathways. 1. Introduction Cardiovascular diseases ((CVD) hypertension, coronary disease and stroke, and heart failure) are one of the leading causes of mortality in industrialized countries, and the prevalence is increasing in emerging societies. All cardiovascular diseases account for 4.3 million deaths per year in the European Union, and the prevalence of chronic heart failure in the United States of America is approximately 6 million [1, 2]. In industrialized countries, hypertension (HT) affects 25% to 35% of the global population and reaches 60% to 70% of the population aged 60 or more. Hypertension is the principal risk factor of death worldwide [3]. It increases the severity of ischemic vascular diseases and, with obesity and type 2 diabetes, is one of the important risk factors for chronic kidney disease (CKD). Chronic kidney disease is defined as reduced glomerular filtration rate (GFR) up to end-stage renal disease (ESRD), proteinuria, or both. Prevalence of ESRD, estimated to be 0.5–2.5‰ worldwide, is increasing in several countries [4]. In turn, impaired renal factor favors the development of and amplifies the severity of CVD [5–7]. During the last two decades, it has been raised the concept of developmental programming of adult chronic
HIV, malaria and beyond: reducing the disease burden of female adolescents
Loretta Brabin, Bernard Brabin
Malaria Journal , 2005, DOI: 10.1186/1475-2875-4-2
Abstract: The current generation of adolescents – over one billion – is the largest in history [1] and, far from representing a picture of health [2], many will suffer untimely disease and death. HIV and malaria are responsible for much of the disease burden affecting female adolescents, who suffer disproportionately from these combined infections relative to other age groups. This is due to a high HIV incidence during the period when many adolescents become pregnant for the first time – an event which greatly increases their susceptibility to Plasmodium falciparum malaria [3]. Biological interactions between malaria and HIV in pregnancy complicate therapy, which can also be compromised by inappropriate adolescent health-seeking behaviour. The public health importance of HIV and malaria synergism is only now emerging. It has led to a recommendation by the World Health Organization (WHO) that the two disease programs should collaborate to ensure integrated service delivery, especially within the framework of reproductive health services [4]. A case has also been made for linking disease control programs as a more efficient and effective way for lowering the malaria and HIV disease burden [5]. Nevertheless, it is difficult to seen how these goals will be attained unless adolescents are accorded a much higher priority by disease control programs. In this paper we consider the justification, as well as the challenges, of using common approaches to improve delivery of HIV and malaria interventions to female adolescents.Prevalence estimates for HIV infection [1] for 35 sub-Saharan African countries, for young males and females (15–24 years), are shown in Figure 1. Estimations are often derived from sentinel surveillance of women attending antenatal care (ANC) and tend to overestimate prevalence in adolescents due to the selection of sexually active [6] and less-educated groups [7]. Accepting this bias, in every country, listed HIV prevalence is two to three times higher among femal
Developmental origins of non-communicable disease: Implications for research and public health
Robert Barouki, Peter D Gluckman, Philippe Grandjean, Mark Hanson, Jerrold J Heindel
Environmental Health , 2012, DOI: 10.1186/1476-069x-11-42
Abstract: For many years biologists considered the developmental period to be controlled by a strict, hard-wired genetic program, and thus it was uncertain how it could be influenced by the environment. It is now clear that development is plastic, and that it allows the organism to respond to the surrounding environment, especially during early development when cells are differentiating and tissues are developing. This capacity is based on molecular pathways that lead to control of gene expression and induction of specific phenotypes in the absence of DNA sequence modification [1]. These pathways, as currently understood, include DNA methylation, histone covalent modification, and noncoding RNA expression. Such epigenetic modifications can be passed from one cell generation to the next and, in some cases, when germ cells are targeted, can be transgenerationally transmitted [2]. Furthermore, these changes can be cell, tissue, and sex specific, and time dependent. In many cases they may not be apparent during a latent period which may last from months to years or decades. Thus, each individual has one genome, but will hold multiple epigenomes.The ability to respond to environmental conditions can be evolutionarily advantageous by allowing fine-tuning of gene expression, likely through epigenetic mechanisms [3]. Thus, developmentally plastic processes allow the organism to adapt to changing environments in order to maintain or improve reproductive capability in part by sustaining health through the reproductive period. However, interference with these developmentally-adaptive processes may also have adverse consequences on some functions and disease risks later in life. Furthermore, these mechanisms are also sensitive to environmental stimuli other than the nutrients and physiological factors that are normative, in evolutionary terms, to the human environment. Indeed, drugs, industrial chemicals, tobacco smoke, and other environmental exposures can affect these same mechanisms l
Progress and Impact of 13 Years of the Global Programme to Eliminate Lymphatic Filariasis on Reducing the Burden of Filarial Disease  [PDF]
K. D. Ramaiah,Eric A. Ottesen
PLOS Neglected Tropical Diseases , 2014, DOI: 10.1371/journal.pntd.0003319
Abstract: Background A Global Programme to Eliminate Lymphatic Filariasis was launched in 2000, with mass drug administration (MDA) as the core strategy of the programme. After completing 13 years of operations through 2012 and with MDA in place in 55 of 73 endemic countries, the impact of the MDA programme on microfilaraemia, hydrocele and lymphedema is in need of being assessed. Methodology/Principal findings During 2000–2012, the MDA programme made remarkable achievements – a total of 6.37 billion treatments were offered and an estimated 4.45 billion treatments were consumed by the population living in endemic areas. Using a model based on empirical observations of the effects of treatment on clinical manifestations, it is estimated that 96.71 million LF cases, including 79.20 million microfilaria carriers, 18.73 million hydrocele cases and a minimum of 5.49 million lymphedema cases have been prevented or cured during this period. Consequently, the global prevalence of LF is calculated to have fallen by 59%, from 3.55% to 1.47%. The fall was highest for microfilaraemia prevalence (68%), followed by 49% in hydrocele prevalence and 25% in lymphedema prevalence. It is estimated that, currently, i.e. after 13 years of the MDA programme, there are still an estimated 67.88 million LF cases that include 36.45 million microfilaria carriers, 19.43 million hydrocele cases and 16.68 million lymphedema cases. Conclusions/Significance The MDA programme has resulted in significant reduction of the LF burden. Extension of MDA to all at-risk countries and to all regions within those countries where MDA has not yet reached 100% geographic coverage is imperative to further reduce the number of microfilaraemia and chronic disease cases and to reach the global target of interrupting transmission of LF by 2020.
Developmental Origins of Health and Disease  [PDF]
Simon C. Langley-Evans,Barbara Alexander,Harry J. McArdle,Deborah M. Sloboda
Journal of Nutrition and Metabolism , 2012, DOI: 10.1155/2012/838640
Developmental Origins of Health and Disease  [PDF]
Simon C. Langley-Evans,Barbara Alexander,Harry J. McArdle,Deborah M. Sloboda
Journal of Nutrition and Metabolism , 2012, DOI: 10.1155/2012/838640
Reducing Amyloid Plaque Burden via Ex Vivo Gene Delivery of an Aβ-Degrading Protease: A Novel Therapeutic Approach to Alzheimer Disease  [PDF]
Matthew L Hemming,Michaela Patterson,Casper Reske-Nielsen,Ling Lin,Ole Isacson,Dennis J Selkoe
PLOS Medicine , 2007, DOI: 10.1371/journal.pmed.0040262
Abstract: Background Understanding the mechanisms of amyloid-β protein (Aβ) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain Aβ levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain Aβ in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce Aβ levels in AD. The objective of this study was to determine if enhancing the clearance of Aβ in the brain by ex vivo gene delivery of an Aβ-degrading protease can reduce amyloid plaque burden. Methods and Findings We generated a secreted form of the Aβ-degrading protease neprilysin, which significantly lowers the levels of naturally secreted Aβ in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of β-amyloid precursor protein (APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment (72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site (34% reduction, p = 0.0020; and 55% reduction, p = 0.0081, respectively). Conclusions Ex vivo gene delivery of an Aβ-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of Aβ-degrading proteases as a means to therapeutically lower Aβ levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease.
Maternal origins of developmental reproducibility  [PDF]
Mariela D. Petkova,Feng Liu,Thomas Gregor
Quantitative Biology , 2013,
Abstract: Cell fate decisions in multicellular organisms are precisely coordinated, leading to highly reproducible macroscopic outcomes of developmental processes. The origins of this reproducibility can be found at the molecular level during the earliest stages of development when spatial patterns of morphogen (form-generating) molecules emerge reproducibly. However, the initial conditions for these early stages are determined by the female during oogenesis, and it is unknown whether reproducibility is passed on to the zygote or whether it is reacquired by the zygote. Here we examine the earliest reproducible pattern in the Drosophila embryo, the Bicoid protein gradient. Using a unique combination of absolute molecule counting techniques, we show that it is generated from a highly controlled source of mRNA molecules that is reproducible from embryo to embryo to within ~8%. This occurs in a perfectly linear feed-forward process: changes in the female's gene dosage lead to proportional changes in the mRNA and protein counts in the embryo. In this setup, noise is kept low in the transition from one molecular species to another, allowing the female to precisely deposit the same absolute number of mRNA molecules in each embryo and therefore confer reproducibility to the Bicoid pattern. Our results indicate that the reproducibility of the morphological structures that emerge in the embryo originates during oogenesis when all initial patterning signals are controlled with precision similar to what we observe for the Bicoid pattern.
DNA methylation differences at growth related genes correlate with birth weight: a molecular signature linked to developmental origins of adult disease?
Nahid Turan, Mohamed F Ghalwash, Sunita Katari, Christos Coutifaris, Zoran Obradovic, Carmen Sapienza
BMC Medical Genomics , 2012, DOI: 10.1186/1755-8794-5-10
Abstract: We performed DNA methylation and transcript profiling on cord blood and placenta from newborns. We then used novel computational approaches to identify genes correlated with birth weight.We identified 23 genes whose methylation levels explain 70-87% of the variance in birth weight. Six of these (ANGPT4, APOE, CDK2, GRB10, OSBPL5 and REG1B) are associated with growth phenotypes in human or mouse models. Gene expression profiling explained a much smaller fraction of variance in birth weight than did DNA methylation. We further show that two genes, the transcriptional repressor MSX1 and the growth factor receptor adaptor protein GRB10, are correlated with transcriptional control of at least seven genes reported to be involved in fetal or placental growth, suggesting that we have identified important networks in growth control. GRB10 methylation is also correlated with genes involved in reactive oxygen species signaling, stress signaling and oxygen sensing and more recent data implicate GRB10 in insulin signaling.Single time point measurements of gene expression may reflect many factors unrelated to birth weight, while inter-individual differences in DNA methylation may represent a "molecular fossil record" of differences in birth weight-related gene expression. Finding these "unexpected" pathways may tell us something about the long-term association between low birth weight and adult disease, as well as which genes may be susceptible to environmental effects. These findings increase our understanding of the molecular mechanisms involved in human development and disease progression.One common non-disease phenotype that puts children at increased risk for multiple adverse outcomes is "low birth weight". Low birth weight is simply the transformation of the quantitative phenotype of birth weight into a discrete trait by truncation at the lowest decile of infant birth weights; i.e., a birth weight of less than 2,500 g. Low birth weight increases the risk of neonatal death b
Reducing the Health Burden of HPV Infection Through Vaccination  [PDF]
David Soper
Infectious Diseases in Obstetrics and Gynecology , 2006, DOI: 10.1155/idog/2006/83084
Abstract: Human papillomavirus (HPV), a sexually transmitted infection and the etiologic cause of genital warts and cervical cancer, is highly prevalent in sexually active men and women. Although cervical screening procedures have significantly reduced the disease burden associated with HPV infection, they are expensive and abnormal results cause significant emotional distress. Therefore, prevention may be an effective strategy for reducing the economic, psychosocial, and disease burden of HPV infection. Multivalent vaccines are now in clinical development. A bivalent vaccine that protects against HPV 16 and 18, and a quadrivalent vaccine which protects against HPV types 6, 11, 16, and 18, have been shown to significantly reduce the occurrence of incident and persistent HPV infections in phase 2 clinical trials; phase 3 trials are currently underway. HPV vaccines will be most effective when administered prior to initiation of sexual activity, and vaccination campaigns should aggressively target preadolescent and adolescent populations.
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